U.S. patent application number 13/065638 was filed with the patent office on 2011-08-25 for use of d4 and 5-ht2a antagonists, inverse agonists or partial agonists.
Invention is credited to Erik Buntinx.
Application Number | 20110207776 13/065638 |
Document ID | / |
Family ID | 34658360 |
Filed Date | 2011-08-25 |
United States Patent
Application |
20110207776 |
Kind Code |
A1 |
Buntinx; Erik |
August 25, 2011 |
Use of D4 and 5-HT2A antagonists, inverse agonists or partial
agonists
Abstract
The present invention relates to the use of compounds and
compositions of compounds having D4 and 5-HT2A antagonistic,
partial agonistic or inverse agonistic activity for the treatment
of the underlying dysregulation of the emotional functionality of
mental disorders (i.e. affect
instability--hypersensitivity--hyperaesthesia--dissociative
phenomena--etc). The invention also relates to methods comprising
administering to a patient diagnosed as having a neuropsychiatric
disorder a pharmaceutical composition containing (i) compounds
having D4 antagonistic, partial agonistic or inverse agonistic
activity and (ii) compounds having 5-HT2A antagonistic, partial
agonistic or inverse agonistic, and (iii) any known medicinal
compound and compositions of said compounds. The combined D4 and
5-HT2A antagonistic, partial agonistic or inverse agonistic effects
may reside within the same chemical or biological compound or in
two different chemical and/or biological compounds.
Inventors: |
Buntinx; Erik; (Alken,
BE) |
Family ID: |
34658360 |
Appl. No.: |
13/065638 |
Filed: |
March 25, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10580962 |
May 31, 2006 |
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PCT/BE2004/000172 |
Dec 2, 2004 |
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13065638 |
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Current U.S.
Class: |
514/316 |
Current CPC
Class: |
A61P 25/22 20180101;
A61K 31/4545 20130101; A61P 25/24 20180101; A61P 25/18 20180101;
A61P 25/16 20180101; A61P 25/28 20180101; A61K 31/343 20130101;
A61P 25/00 20180101; A61K 31/343 20130101; A61K 2300/00 20130101;
A61K 31/4545 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/316 |
International
Class: |
A61K 31/4545 20060101
A61K031/4545; A61P 25/18 20060101 A61P025/18 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 2, 2003 |
CA |
2,451,798 |
Dec 2, 2003 |
EP |
03447279.5 |
Jan 5, 2004 |
EP |
04447001.1 |
Mar 18, 2004 |
CA |
2,461,248 |
Mar 18, 2004 |
EP |
04447066.4 |
Oct 21, 2004 |
EP |
04025035.9 |
Nov 4, 2004 |
JP |
2004/349085 |
Nov 15, 2004 |
CA |
2,487,529 |
Claims
1-81. (canceled)
82. A pharmaceutical composition for treating a psychotic disorder
comprising: (a) pipamperone, (b) a D2 receptor antagonist, and a
pharmaceutically acceptable carrier, wherein the composition
provides a daily dose of 5-15 mg pipamperone.
83. The pharmaceutical composition of claim 82 for treating
schizophrenia.
84. The pharmaceutical composition of claim 82, wherein the
composition provides a daily dose of 5 mg pipamperone.
85. The pharmaceutical composition of claim 83, wherein the
composition provides a daily dose of 5 mg pipamperone.
86. The pharmaceutical composition of claim 82, wherein the
composition provides a daily dose of 10 mg pipamperone.
87. The pharmaceutical composition of claim 83, wherein the
composition provides a daily dose of 10 mg pipamperone.
88. The pharmaceutical composition of claim 82, wherein the
composition provides a daily dose of 15 mg pipamperone.
89. The pharmaceutical composition of claim 83, wherein the
composition provides a daily dose of 15 mg pipamperone.
90. The pharmaceutical composition of claim 82, wherein pipamperone
is in the form of a pharmaceutically acceptable salt.
91. The pharmaceutical composition of claim 83, wherein pipamperone
is in the form of a pharmaceutically acceptable salt.
92. The pharmaceutical composition of claim 82, wherein said D2
receptor antagonist is in the form of a pharmaceutically acceptable
salt.
93. The pharmaceutical composition of claim 83, wherein said D2
receptor antagonist is in the form of a pharmaceutically acceptable
salt.
94. A pharmaceutical composition comprising: (a) 5-15 mg
pipamperone, (b) a D2 receptor antagonist, and a pharmaceutically
acceptable carrier.
95. The pharmaceutical composition of claim 94, wherein pipamperone
and said D2 receptor antagonist are present in an amount effective
to treat a psychotic disorder.
96. The pharmaceutical composition of claim 94, wherein pipamperone
and said D2 receptor antagonist are present in an amount effective
to treat schizophrenia.
97. The pharmaceutical composition of claim 94, wherein pipamperone
is present in a dose of 5 mg.
98. The pharmaceutical composition of claim 94, wherein pipamperone
is present in a dose of 10 mg.
99. The pharmaceutical composition of claim 94, wherein pipamperone
is present in a dose of 15 mg.
100. The pharmaceutical composition of claim 94, wherein
pipamperone is in the form of a pharmaceutically acceptable
salt.
101. The pharmaceutical composition of claim 94, wherein said D2
receptor antagonist is in the form of a pharmaceutically acceptable
salt.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/580,962, filed on May 31, 2006, which is a
national stage entry under 35 U.S.C. .sctn.371 of PCT International
Application No. PCT/BE2004/000172, filed Dec. 2, 2004, and claims
priority of U.S. patent application Ser. No. 10/725,965, filed Dec.
2, 2003, now U.S. Pat. No. 7,884,096, Canadian Patent Application
No. 2,451,798, filed Dec. 2, 2003, European Patent Application No.
03447279.5, filed Dec. 2, 2003, European Patent Application No.
04447001.1, filed Jan. 5, 2004, U.S. patent application Ser. No.
10/752,423, filed Jan. 6, 2004, now U.S. Pat. No. 7,855,195,
European Patent Application No. 04447066.4, filed Mar. 18, 2004,
U.S. patent application Ser. No. 10/803,793, filed Mar. 18, 2004,
Canadian Patent Application No. 2,461,248, filed Mar. 18, 2004,
European Patent Application No. 04025035.9, filed Oct. 21, 2004,
Japanese Patent Application No. 2004-349085, filed Nov. 4, 2004,
U.S. patent application Ser. No. 10/984,683, filed Nov. 9, 2004,
and Canadian Patent Application No. 2,487,529, filed Nov. 15,
2004.
FIELD OF THE INVENTION
[0002] The invention relates to the field of neuropsychiatry. More
specifically, the invention relates to the use of compounds, which
have D4 and 5-HT2A antagonist, inverse agonist or partial agonist
activity, for the preparation of medicaments.
BACKGROUND OF THE INVENTION
[0003] Conventionally, mental disorders are divided into types
based on criteria sets with defining features. DSM-IV (American
Psychiatric Association, (1993--ISBN 0-89042-061-0)) is the in the
art well-known golden standard of such a categorical
classification. In DSM-IV, there is no assumption that each
category of mental disorder is a completely discrete entity with
absolute boundaries dividing it from other mental disorders or from
no mental disorder. There is also no assumption that all
individuals described as having the same mental disorder are alike
in all important ways. Individuals sharing a diagnosis are likely
to be heterogeneous even in regard to the defining features of the
diagnosis. Thus, the categorical defined mental disorders as mood
and anxiety disorders are having an external and even internal
variable co-incidence of symptoms concerning e.g. mood, anxiety,
perception, feeding, somatic sensations, sexual functions, sleep,
cognitive functioning, impulse control, attention, substance use,
personality, bereavement, identity, phase of life, abuse or neglect
and other aspects of behavior.
[0004] In a dimensional system, clinical presentations are
classified based on quantification of attributes i.e. dysfunctions
rather than the assignment to categories and works best in
describing phenomena that are distributed continuously and that do
not have clear boundaries.
[0005] Emotion dysregulation is known as such an attribution or
dysfunction that plays an important role in the development and
course of mental disorders (Gross, J. J. & Munoz, R. F., 1995,
Emotion regulation and mental health, Clinical Psychology: Science
and Practice, 2, 151-164; Mennin, D. S., Heimberg, R. G., Turk, C.
L. & Fresco, D. M., 2002, Applying an emotion regulation
framework to integrative approaches to generalized anxiety
disorder, Clinical Psychology: Science and Practice, 9, 85-90;
Linehan, M. M., 1993, Cognitive-behavioral treatment of borderline
personality disorder, New York, The Guilford Press; Gratz, K. L.,
Roemer, L., 2001 & 2004, Multidimensional assessment of emotion
regulation and dysregulation: development, factor structure, and
initial validation of the Difficulties in Emotion Regulation Scale,
Annual meeting of the Association for Advancement of Behavior
Therapy, November 2001 & Journal of Psychopathology and
Behavioral Assessment, Vol. 26, No. 1, March 2004) besides
behavioural and cognitive dysfunctions. D4 dopamine receptors
(D4DR), almost exclusively present in the mesocortical and
mesolimbic systems (O'Malley, K. L., Harmon, S., Tang, L., Todd, R.
D., The rat dopamine D4 receptor: sequence, gene structure, and
demonstration of expression in the cardiovascular system, New
Biol., 4, 137-46, 1992), are in the art known as modulators of
emotion and cognition. D4DR agonistic activity gives a behavioural
sensitisation; D4DR antagonistic activity leads to an emotion
modulation (Svensson, T. H., Mathe, A. A., Monoaminergic
Transmitter Systems, Biological Psychiatry (eds. D'Haenen, H., et
al.), 45-66, 2002, John Wiley & Sons, Ltd). Data demonstrate
that agonism of the dopamine D4 receptors play an important role in
the induction of behavioral sensitization to amphetamine and
accompanying adaptations in pre- and postsynaptic neural systems
associated with the mesolimbocortical dopamine projections (D. L.
Feldpausch et al.; The Journal of Pharmacology and Experimental
Therapeutics Vol. 286, Issue 1, 497-508, July 1998).
[0006] Results suggest that the antagonisms of cortical D2 dopamine
receptors are a common target of traditional and atypical
antipsychotics for therapeutic action. Higher in vivo binding to
the D2 receptors in the cortex than in the basal ganglia is
suggested as an indicator of favorable profile for a putative
antipsychotic compound (X. Xiberas and J. L. Martinot; The British
Journal of Psychiatry (2001) 179: 503-508). Results show that
dopamine D4 receptor antagonism in the brain does not result in the
same neurochemical consequences (increased dopamine metabolism or
hyperprolactinemia) observed with typical neuroleptics (Smita Patel
et al., The Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 2, 636-647, 1997). The selective D4 dopamine
receptor antagonist L-745,870 was ineffective as an antipsychotic
for the treatment of neuroleptic responsive patients with acute
schizophrenia (Kramer, M. S. et al., Arch. Gen. Psychiatry 1997
December; 54(12):1080).
[0007] Finally, in the biological system, mental disorders are
defined on other levels of abstraction than in the categorical and
dimensional system. Structural pathology (e.g. amyloid plaques in
Alzheimer Disease), etiology (e.g. HIV Dementia) and deviance from
a physiological norm (e.g. reduced cerebral blood flow) are often
used as indicative biological markers for a mental disorder. The
underlying dysregulation of various neurotransmitter systems
(glutaminergic, GABAergic, cholinergic, monoaminergic
(nor-adrenergic, dopaminergic, serotonergic), etc.) is the in the
art used model for the explanation of the biological determinants
of the clinical presentation of mental disturbances. It is known
that the Serotonin 2A Receptor (5-HT2A receptor)--which is
widespread in the Central Nervous System (CNS)--has a regulating
role on the dysregulation of various neuro-transmitter systems.
5-HT2A agonism gives several behavioural disturbances; 5-HT2A
antagonism leads to a governance of mood, social behaviour,
anxiety, cognitive function, stress, sleep functions, nociception,
sexual functions, feeding and other aspects of behaviour (J. E.
Leysen (2004) 5-HT2 Receptors; Current Drug Targets--CNS &
Neurological Disorders, 2004, 3, 11-26).
[0008] Dysregulation of the HPA axis
(hypothalamic-pituitary-adrenal axis) has frequently been reported
in patients with psychiatric disorders, and is among the most
robustly demonstrated neurobiological changes among psychiatric
patients (D. A. Gutman and C. B. Nemeroff, Neuroendocrinology,
Biological Psychiatry (eds. D'Haenen, H., et al), 99, 2002, John
Wiley & Sons, Ltd). The resulting elevated plasma cortisol
concentrations leads to an enhanced binding of serotonin for the
5-HT2A receptor (E. A. Young, Mineralocorticoid Receptor Function
in Major Depression, Arch. Gen. Psychiatry, January 2003; 60:
24-28) and thus agonism.
[0009] Additionally 5-HT2A antagonism gives a des-inhibiting of the
inhibitory effect of the 5-HT2A receptor on (i) the 5-HT1A receptor
stimulation by serotonin (S. M. Stahl, Newer Antidepressants and
Mood Stabilizers, Essential Psychopharmacology, 265, University
Press; 2 edition (Jun. 15, 2000); ISBN: 0521646154) and on (ii) the
dopamine release in the mesocortical systems (S. M. Stahl,
Classical Antidepressants, Serotonin Selective and Noradrenargic
Reuptake Inhibitors, Essential Psychopharmacology, 233, University
Press; 2 edition (Jun. 15, 2000); ISBN: 0521646154).
[0010] Clinical or real effectiveness of psychopharma is very rare
via common pooping-out; many treatment-refractory patients and up
to half of patients fail to attain remission (S. M. Stahl,
Essential Psychopharmacology, Depression and Bipolar Disorders,
151, University Press; 2 edition (Jun. 15, 2000); ISBN:
0521646154). Implications of not attaining remission for Mental
Disorders are increased relapse rates, continuing functional
impairment and increased suicide rate (S. M. Stahl, Essential
Psychopharmacology, Depression and Bipolar Disorders, 152,
University Press; 2 edition (Jun. 15, 2000); ISBN: 0521646154).
Clinical causes of not attaining remission by the Current
Psychopharmacological Compounds are inadequate early treatment,
underlying emotion dysregulation (affecting
instability-hypersensitivity-hyperaesthesia-dissociative phenomena,
etc.) and competitive antagonism. There is thus a growing need for
a more efficient therapy and more efficient, selective and
efficacious medicaments for treating mental disorders.
SUMMARY OF THE INVENTION
[0011] The present invention relates to the use of compounds and
pharmaceutical compositions having D4 and 5-HT2A antagonistic,
partial agonistic or inverse agonistic activity for the treatment
of the underlying emotion dysregulation of mental disorders (e.g.
affecting instability-hypersensitivity-hyperaesthesia-dissociative
phenomena-etc.) and to methods entailing administering to a patient
diagnosed as having a mental disorder a pharmaceutical composition
containing (i) compounds having specific high selective D4 and
5-HT2A antagonistic, partial agonistic or inverse agonistic
activity and (ii) a known medicinal compound and/or compositions of
compounds. The combined D4 and 5-HT2A antagonistic, partial
agonistic or inverse agonistic effects may reside within the same
chemical or biological compound.
[0012] Taken into account the above mentioned (i) rare clinical or
real effectiveness of psycho tropics, (ii) the governance of the
features and dysfunctions responsible--in a variable
co-incidentally--for the clinical state of the mental disorders by
D4 dopamine receptor (D4DR) and 2A serotonin receptor (5-HT2A)
antagonism and (iii) the fact that 5-HT2A antagonism gives a
des-inhibiting of the inhibitory effect of the 5-HT2A receptor on
(a) the 5-HT1A receptor stimulation by serotonin and on (b) the
dopamine release in the mesocortical systems, the present invention
relates to the use of a compound for the preparation of a
medicament for treating a disease or disorder with an underlying
emotion dysregulation, characterised in that said compound has (i)
a selective affinity for the Dopamine-4 (D4) receptor with a pKi
value equal to or higher than 8 towards the D4 receptor and less
than 8 towards other Dopamine receptors, and (ii) a selective
affinity for the 5-HT2A receptor with a pKi value equal to or
higher than 8 towards the 5-HT2A receptor and less than 8 towards
other 5-HT receptors and wherein said compound is administered to a
patient in a dose ranging between 5 and 15 mg of the active
ingredient. Preferably, said compound is pipamperon.
[0013] In a preferred embodiment, in a mono therapeutic context,
the invention relates to the use of a compound as defined above,
preferably pipamperon, for preparing a medicament for treating a
disease or disorder selected from the group comprising anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders, factitious disorders, dissociative disorders, sexual and
gender identity disorders, sleep disorders, adjustment disorders,
cognitive disorders, impulse control disorders, pervasive
development, attention-deficit and disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational, identity, phase of life;
academic problem, problems related to abuse or neglect.
[0014] According to a further embodiment the invention relates to
the use of a first compound as defined above for the preparation of
a medicament for treating a mental disease or disorder with an
underlying emotion dysregulation whereby a second compound is
administered simultaneously with, separate from or sequential to
said first compound to augment the therapeutic effect of said
second compound on said disease, or to provide a faster onset of
the therapeutic effect of said second compound on said disease.
[0015] The mental diseases or disorders characterized by an
underlying emotion dysregulation can be grouped into subclasses as
follows: (i) non-cognitive mental disorders comprising mood
disorders, anxiety disorders, psychotic disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, attention-deficit disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
psychological factors affecting medical conditions, malingering,
antisocial behaviour, bereavement, occupational problems, identity
problem, phase of life problem, academic problem and problems
related to abuse or neglect; (ii) cognitive diseases comprising
delirium, Alzheimer Disease, substance-related persisting dementia,
vascular dementia, dementia due to HIV disease, dementia due to
head trauma, dementia due to Parkinson Disease, dementia due to
Huntington Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder, other cognitive disorders;
(iii) pain disorders; and (iv) Parkinson Disease.
[0016] In a preferred embodiment, the first compound is
administered daily at least one day before administering said
second compound.
[0017] Preferably, said second compound is characterized by the
physiological property of influencing positively the activity of
the Central Nervous System.
[0018] The invention also relates to a method for preparing a
compound having a selective D4 and 5-HT2A antagonist, reverse
agonist or partial agonist activity comprising the following steps:
(a) measuring the selective affinity of a test compound to the D4
receptor and selecting a compound that has a pKi value equal to or
greater than 8 towards the D4 receptor in respect to all the other
D receptors, and measuring the selective efficacy of the selected
compound to the D4 receptor and selecting a compound which is a
selective antagonist, inverse agonist or partial agonist of the D4
receptor; (b) measuring the selective affinity of a test compound
to the 5-HT2A receptor and selecting a compound that has a pKi
value equal to or greater than 8 towards the 5-HT2A receptor in
respect to all the other 5HT receptors, and measuring the selective
efficacy of the selected compound to the 5-HT2A receptor and
selecting a compound which is a selective antagonist, inverse
agonist or partial agonist of the 5-HT2A receptor; (c) identifying
a compound which is selected in (a) and (b), (d) preparing the
compound identified in (c).
[0019] The invention further also relates to a compound prepared by
the described method.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The present inventors surprisingly found that compounds
which have a high selective affinity towards the 5-HT2A receptor
and which, at the same time have a high selective affinity towards
the dopamine-4 (D4) receptor show an improved effect in treating
underlying emotion dysregulation of mental disorders.
[0021] The compounds according to the invention may be chemical or
biological in nature, or may be chemically synthesised. Preferably,
the compounds of the invention are provided as a pharmaceutically
acceptable salt.
[0022] One example of such a compound which has both a selective
affinity for the 5-HT2A receptor with a pKi value equal to or
higher than 8 towards the 5-HT2A receptor and less than 8 towards
other 5HT receptors, and a selective affinity for the D4 receptor
with a pKi value equal to or higher than 8 towards the D4 receptor
and less than 8 towards other dopamine receptors is pipamperon.
Pipamperon is the conventional name given for the compound of the
formula
1'-[3-(p-Fluorobenzoyl)propyl]-[1,4'-bipiperidine]-4'-carboxamide.
Pipamperon is also the active ingredient of for instance the
commercially available Dipiperon (Janssen, Cilag B.V).
[0023] Further, the present inventors surprisingly found that the
dosage of active ingredient for pipamperon in treatment (in
monotherapy as well as in combination therapy as described in more
detail further) could be very low compared to conventionally used
dosages. Preferred dosages which, according to the invention, have
been shown to be effective for treating these mental disorders,
range between 5 and 15 mg per day or between 5 and 10 mg per day.
More preferably, dosages of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15
mg per day are used in treatment of the diseases of the invention.
In conventional pipamperon treatment, the active ingredient is
available in tablets of 40 mg per tablet or in solutions of 2 mg
per drop. Conventional usage of high doses ranging from 40 to 360
mg is prescribed. For instance, for children up to the age of 14,
doses corresponding with 2 to 6 mg per kg body weight are
conventionally prescribed. The high selective affinity of
pipamperon towards the 5-HT2A receptor and the D4 receptor is
reflected in the low dosage which is needed for the treatment of
the mental diseases listed below and also contributes to the
efficacy of the treatment.
[0024] The mental disorders which can be treated using pipamperon
in a mono therapy at such low doses are for instance anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders, factitious disorders, dissociative disorders, sexual and
gender identity disorders, sleep disorders, adjustment disorders,
cognitive disorders, impulse control disorders, pervasive
development, attention-deficit and disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational, identity, phase of life,
academic problem, problems related to abuse or neglect.
[0025] Mental disorders such as depression are commonly treated
with serotonin re-uptake inhibitors. Unfortunately, however, these
compounds can give rise to side effects in use. Moreover, a
substantial problem in most treatment of mental disorders is the
non-response to selective serotonin re-uptake inhibitors (SSRIs).
Also the onset of the therapeutic effect can be delayed
undesirable.
[0026] A problem to be solved by the present invention is thus the
provision of a more efficient therapy and efficient, highly
selective and efficacious medicaments for treating mental
disorders.
[0027] The inventors found that, for instance, the non-response to
selective serotonin re-uptake inhibitors (SSRIs) in depression may
be declared by (partial) inhibition of the 5-HT1A stimulation via
5-HT2A stimulation. Des-inhibition thereof via 5-HT2A antagonism
seems to be an answer to this problem.
[0028] The present inventors found that a simultaneous or foregoing
treatment with a compound having a high selective 5-HT2A
antagonist, inverse agonist or partial agonist activity, could lead
to a greater response towards, for instance, SSRIs. However, not
all compounds exhibiting 5-HT2A antagonism are useful: competition
between 5-HT2A stimulation via serotonin and 5-HT2A antagonism via
the compound could be responsible for the lack of more efficacy of
compounds which have both a selective serotonin re-uptake
inhibitory and 5-HT2A antagonist profile, such as trazodone and
nefazodone.
[0029] The present inventors further surprisingly found that a
simultaneous or foregoing treatment with a compound having a high
selective D4 antagonist, inverse agonist or partial agonist
activity in combination with a compound having a high selective
5-HT2A antagonist, inverse agonist or partial agonist activity
could lead to a greater response towards, for instance, SSRIs, or
any of the compounds listed in Table 6 or below. In addition, the
inventors found that a combination treatment provides less residual
symptoms and more remission relative to a mono therapy with these
compounds.
[0030] As such, in a combination treatment, the doses of the
compounds listed in Table 6 for treating patients with mental
disorders may be decreased to about 10-90% of the conventional
dose, preferably to about 20-80%, or 30-70%, or 40-60% or to about
50% of the conventional dose. Even if the administered dose of the
compound is decreased in the combination therapy, the therapeutical
effect may be sustained or ameliorated relative to the conventional
dose. The danger of side effects of a treatment with such compounds
can be decreased or minimized in the combination therapy of the
invention. In this regard, the term conventional dose refers to the
dose used heretofor for a particular compound in treating patients
with a mental disorder, for instance, according to the supplier's
or physician's description or as listed in Table 6.
[0031] In this invention, the term "antagonist" refers to an
interaction between chemicals in which one partially or completely
inhibits the effect of the other, in particular agents having high
affinity for a given receptor, but which do not activate this
receptor.
[0032] In this invention, the term "inverse agonist" refers to a
ligand which produces an effect opposite to that of the agonist by
occupying the same receptor.
[0033] In this invention, the term "agonist" relates to an agent
which both binds to a receptor and has an intrinsic effect.
[0034] In this invention, the term "partial agonist" relates to an
agent with lower intrinsic activity than a full agonist, and which
produces a lower maximum effect.
[0035] The present inventors found that a compound which binds to
the 5-HT2A receptor with a pKi of at least 8 but for which the
binding affinity, i.e. pKi, towards other 5HT receptors is less
than 8 in combination with a high selective affinity for the D4
receptor, i.e. which bind to the D4 receptor with a pKi of at least
8 but for which the binding affinity, i.e. pKi, towards other
dopamine receptors is less than 8 also show such an improved effect
in treatment. These effects, i.e. D4 antagonism, inverse agonism or
partial agonism and 5-HT2A antagonism, inverse agonism or partial
agonism, may reside in the same compound.
[0036] The term "other 5HT receptors" as used herein relate to for
instance 5-HT1 receptors (e.g. 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E,
5-HT1F), 5-HT2B, 5-HT2C, 5-HT6 (rat) and 5-HT7 (rat).
[0037] By the expression "selective affinity for the 5-HT2A
receptor" is meant that the receptor has a higher affinity for the
5-HT2A receptor than for other 5-HT receptors.
[0038] The expression "selective affinity for the D4 receptor"
means that the receptor has a higher affinity for the dopamine D4
receptor than for other dopamine receptors.
[0039] The term "other dopamine receptors" are, for instance, D1,
D2 and D3 dopamine receptors.
[0040] pKi values of test compounds for dopamine receptors as well
as 5-HT2A receptors can be measured using commonly known
assays.
[0041] Compounds which have a selective affinity for the D4
receptor preferably have a pKi value equal to or higher than 8
towards the D4 receptor and less than 8 towards other dopamine
receptors.
[0042] Preferably, the compounds of the invention which have a
selective affinity for the 5-HT2A receptor (or the D4 receptor),
are compounds which have a pKi value equal to or higher than 8
towards the 5-HT2A receptor and the D4 receptor, and less than 8
towards other 5-HT receptors or dopamine receptors, respectively,
as can be measured, for instance by methods known in the art. For
instance, the "NIMH Psychoactive Drug Screening Program (PDSP)"
K.sub.i database (http://kidb.cwru.edu/nimh/5htp.php), is a unique
resource in the public domain which provides information on the
abilities of drugs to interact with an expanding number of
molecular targets. The PDSP K.sub.i database serves as a data
warehouse for published and internally-derived pKi, or affinity,
values for a large number of drugs and drug candidates at an
expanding number of G-protein coupled receptors, ion channels,
transporters and enzymes. The PDSP internet site also provides for
commonly used protocols and assays for measuring pKi values of 5-HT
and dopamine receptors.
[0043] A preferred example of a compound which has both a selective
affinity for the 5-HT2A receptor with a pKi value equal to or
higher than 8 towards the 5-HT2A receptor and less than 8 towards
other 5-HT receptors, and a selective affinity for the D4 receptor
with a pKi value equal to or higher than 8 towards the D4 receptor
and less than 8 towards other Dopamine receptors and which is
therefore useful in a combination therapy is pipamperon.
[0044] Table 1 illustrates the selective affinity of for instance
pipamperon for the 5-HT2A and for the D4 receptor. In addition,
Table 1 also illustrates the low or absence of affinity of
pipamperon for other receptors such as the adrenergic receptors
Alpha 1A, Alpha 2A, Alpha 2B, Alpha 2C, Beta 1, Beta 2, and the
histamine receptor H1. As such, treating patients with pipamperon
will provide for less side effects which otherwise result from
simultaneous stimulation of other receptors. Therefore, and
according to preferred embodiments, useful compounds according to
the invention not only have a selective 5-HT2A and/or D4 affinity
but also a low affinity for other receptors such as the adrenergic
and histamine receptors.
[0045] The low dosage which can be used in pipamperon treatment, as
already described earlier, contributes to the high selective
affinity of the compound towards the 5-HT2A receptor and the D4
receptor and therefore also to the efficacy of the treatment.
[0046] The mental diseases or disorders characterized by an
underlying emotion dysregulation can be grouped into subclasses as
follows: (i) the non-cognitive mental disorders comprising mood
disorders, anxiety disorders, psychotic disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, attention-deficit disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
psychological factors affecting medical conditions, malingering,
antisocial behaviour, bereavement, occupational problems, identity
problem, phase of life problem, academic problem and problems
related to abuse or neglect; (ii) cognitive diseases comprising
delirium, Alzheimer Disease, substance-related persisting dementia,
vascular dementia, dementia due to HIV disease, dementia due to
head trauma, dementia due to Parkinson Disease, dementia due to
Huntington Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder, other cognitive disorders;
(iii) the pain disorders; and (iv) Parkinson Disease. In Table 5,
this classification has been used for summarizing the diseases and
disorders relative to known psychotropics. In Table 6, an overview
of pharmacological grouping is provided, indicating the
pharmalogical profile numbering, the pharmalogical profile, the
main disease or disorder indication(s), the name of the compound,
the dose range, and the company producing or selling said
compound.
[0047] These diseases and their diagnosis are very clearly defined
in the "Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV)" published by the American Psychiatric Association. This
manual sets forth diagnostic criteria, descriptions and other
information to guide the classification and diagnosis of mental
disorders and is commonly used in the field of neuropsychiatry. It
is for instance available on the internet under:
http://www.behavenet.com/capsules/disorders/dsm4tr.htm.
[0048] The expression "non-cognitive diseases or disorders" used in
some of the embodiments of the invention comprises the following
group of diseases or disorders: mood disorders, anxiety disorders,
psychotic disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, pervasive development disorders, attention-deficit
disorders, disruptive behaviour disorders, substance-related
disorders, personality disorders, psychological factors affecting
medical conditions, malingering, antisocial behaviour, bereavement,
occupational problems, identity problem, phase of life problem,
academic problem and problems related to abuse or neglect.
[0049] In other embodiments of the invention, the mental diseases
or disorders that are characterized by an underlying emotion
dysregulation belong to the group of pain disorders. For instance,
the combination therapy with pipamperon is especially advantageous
for management of acute pain in diseases such as, but not limited
to, musculoskeletal diseases, rheumatoid arthritis, osteoarthritis
and ankylosing spondylitis. For the classification of pain
disorders, reference is also made to the DSM-IV where these
disorders are clearly described in the section of somatoform
disorders by way of internationally accepted diagnostic
criteria.
[0050] In other embodiments of the invention, the 5-HT2A receptor
and/or Dopamine-4 receptor antagonist, inverse agonist or partial
agonist (e.g. pipamperon) is used in treatment of patients having
neuro-degenerative diseases or disorders, or related cognitive
diseases or disorders. The diseases or disorders of the present
invention are characterized by an underlying degeneration of the
Central Nervous System (CNS), preferably selected from the group
consisting of, but not limited to, neurodegenerative diseases such
as Parkinson Disease, and in other embodiments of the invention,
selected from the group of (related) cognitive diseases or
disorders such as Alzheimer Disease.
[0051] For instance, Parkinson Disease, which is a chronic
progressive nervous disease chiefly of later life, is linked to
decreased dopamine production in the substantia nigra and is marked
by tremor and weakness of resting muscles and by a shuffling gait.
Dopamine agonists and even levodopa, widely used in Parkinson
Disease, gives via a dopamine D4 receptor stimulation psychiatric
manifestations. The induced release of serotonin acts via 5-HT2A
stimulation as a "brake" on dopamine release (Young B. K.,
Camicioli R., Ganzini L., Neuropsychiatric adverse effects of
antiparkinsonian drugs. Characteristics, evaluation and treatment.
Drugs Aging. 1997 May; 10(5): 367-83). Because of the need of
specific D4 and 5-HT2A antagonism in the treatment of Parkinson
Disease with dopamine agonists and even levodopa, it seems
reasonable to combine with a compound with a high selective D4 and
5-HT2A antagonism i.e. having merely no activity towards the other
receptors especially the D2 receptor because of the primary need of
the relieve of the excessive burden of remaining dopaminergic
neurons. Therefore, the use of the so-called atypical
anti-psychotics or serotonin-dopamine antagonists (SDAs) is
absolutely contra-indicated since their high affinity for the D2
receptor. Even the use of serotonin releasing compounds such as
SSRIs in the absence of an effective 5-HT2A antagonism are
contra-productive towards the Parkinson Disease symptoms although
many Parkinson patients are in need for an antidepressant since
major depression is a very common and disabling condition in this
kind of patients.
[0052] The expression "(related) cognitive diseases or disorders"
according to the invention comprises, the following group of
diseases or disorders: delirium (F05), dementia (such as Alzheimer
Disease (F00), vascular dementia (F01), dementia due to other
general medical conditions (HIV disease (F02.4), head trauma
(F06.8), Parkinson Disease (F02.3), Huntington Disease (F02.2),
Pick Disease (F02.0), Creutzfeldt-Jacob Disease (F02.1) and other
(F02.8)), substance-induced persisting dementia (F1x.6)), amnestic
disorders due to a general medical condition (F06.8) or a
substance-induced persisting amnestic disorder (F1x.6), mild
cognitive impairment disorder (F06.7) and other cognitive disorders
(F04). The above list of diseases is provided by way of example and
is not intended to limit the invention.
[0053] For instance, Alzheimer Disease is a degenerative brain
disease of unknown cause that is the most common form of dementia.
Alzheimer Disease usually starts in late middle age or in old age
as a memory loss for recent events spreading to memories for more
distant events and progresses over the course of five to ten years
to a profound intellectual decline characterized by dementia and
personal helplessness. The disease is marked histologically by the
degeneration of brain neurons especially in the cerebral cortex and
by the presence of neurofibrillary tangles and plaques containing
beta-amyloid. Because dopamine receptor D4 (DRD4) antagonism can
inhibit the behavioral disturbances--merely aggression and
confusion--caused by the degeneration of dopamine D2 receptors
(Esiri, M. M., The basis for behavioural disturbances in dementia,
J. Neurol. Neurosurg. Psychiatry, 1996; 61(2):127-130.2)
accompanied with Alzheimer disease and 5-HT2A antagonism has an
important boosting effect towards the effect of cholinesterase
inhibitors such as used in the treatment by facilitating the
affected dopamine release in the mesocortical dopamine pathways, a
high selective D4/5-HT2A-antagonist would be a more preferable
compound to combine with a cholinesterase inhibitor since this
avoids the counteracting effect of the in the art used SDAs on the
cognitive functioning by its dopamine receptor D2-antagonism.
[0054] These diseases and their diagnoses are very clearly defined
in the "International Statistical Classification of Diseases and
Related Health Problems, 1989 Revision, Geneva, World Health
Organization, 1992 (ICD-10). This manual sets forth diagnostic
criteria, descriptions and other information to guide the
classification and diagnosis of neurodegenerative disorders and is
commonly used in the field of neurology. According to the ICD-10
classification, the cognitive disorders are classified under
several classes of disorders, i.e. dispersed under categories F00
to F19 (see above: respective classification between parentheses).
Following the DSM classification, however, they are grouped in one
class of diseases or disorders.
[0055] The terms "treatment", "treating", and the like, as used
herein include amelioration or elimination of a developed mental
disease or condition once it has been established or alleviation of
the characteristic symptoms of such disease or condition. As used
herein these terms also encompass, depending on the condition of
the patient, preventing the onset of a disease or condition or of
symptoms associated with a disease or condition, including reducing
the severity of a disease or condition or symptoms associated
therewith prior to affliction with said disease or condition. Such
prevention or reduction prior to affliction refers to
administration of the compound or composition of the invention to a
patient that is not at the time of administration afflicted with
the disease or condition. "Preventing" also encompasses preventing
the recurrence or relapse-prevention of a disease or condition or
of symptoms associated therewith, for instance after a period of
improvement. It should be clear that mental conditions may be
responsible for physical complaints. In this respect, the term
"treating" also includes prevention of a physical disease or
condition or amelioration or elimination of the developed physical
disease or condition once it has been established or alleviation of
the characteristic symptoms of such conditions.
[0056] As used herein, the term "medicament" also encompasses the
terms "drug", "therapeutic", "potion" or other terms which are used
in the field of medicine to indicate a preparation with therapeutic
or prophylactic effect.
[0057] The present inventors not only found that the selective
5-HT2A and D4 antagonists, inverse agonists or partial agonists
have an effect in augmenting the therapeutic effect or in providing
a faster onset of the therapeutic effect of a diversity of other
pharmaceutical compounds, i.e. also named "second compounds" in the
present invention, in the treatment of specific diseases or
disorders. A few examples of other pharmaceutical compounds whose
effects are augmented or where the onset of the effect is fastened
upon simultaneous or fore-going treatment with a selective 5-HT2A
and D4 antagonist, preferably pipamperon in a low dose, are
nor-epinephrine re-uptake inhibitors, neuroleptic agents, dopamine
antagonists, or compounds used for treating or alleviating
musculoskeletal diseases or disorders. A further list of other
pharmaceutical compounds or second compounds useful according to
the invention is provided in Table 5. It should be clear, given the
general applicable character of the invention, that this list of
other pharmaceutical compounds is very brief and that the invention
should not be restricted to the ones exemplified herein. It should
be clear that in the present invention, pipamperon is never to be
seen as a "second compound".
[0058] According to the invention, it thus has been found that the
compounds having a selective 5-HT2A and D4 antagonist, inverse
agonist or partial agonist activity as described above are useful
for augmenting the therapeutic effect of a second compound on a
disease.
[0059] According to another embodiment of the invention, it has
also been found that the compounds having a selective 5-HT2A and D4
antagonist, inverse agonist or partial agonist activity as
described above are useful for providing a faster onset of the
therapeutic effect of a second compound on a disease.
[0060] From the above it should be clear that the selective 5-HT2A
and D4 antagonist, inverse agonist or partial agonist is also named
`the first compound` in the embodiments of the invention.
[0061] According to the invention, when the 5-HT2A and D4
antagonist, inverse agonist or partial agonist activity reside in
separate compounds, the term "composition" may be used.
Compositions of the invention comprise a first element having (i) a
selective affinity for the D4 receptor with a pKi value equal to or
higher than 8 towards the D4 receptor and less than 8 towards other
dopamine receptors, and a second element having (ii) a selective
affinity for the 5-HT2A receptor with a pKi value equal to or
higher than 8 towards the 5-HT2A receptor and less than 8 towards
other 5-HT receptors.
[0062] The expression "the 5-HT2A and D4 antagonist, inverse
agonist or partial agonist" is used herein to indicate a single
compound having both activities or to indicate the composition
comprising the activities in separate elements.
[0063] It should be clear that when, in the present invention, a
composition of separate elements is used instead of a single
compound, this composition of separate elements may be used in
combination with another, i.e. a second, compound to augment the
therapeutic effect of the other, i.e. the second, compound on the
same or another disease.
[0064] When the 5-HT2A and D4 antagonist, inverse agonist or
partial agonist or the composition comprising both elements and the
second compound are administered simultaneously, the compounds or
active ingredients may be present in a single pharmaceutical
composition or formulation. Alternatively the compounds or active
ingredients are administered in separate pharmaceutical
compositions or formulations for simultaneous or separate use. The
invention thus also relates to pharmaceutical compositions
comprising pipamperon and a second compound of the invention and to
the uses of these pharmaceutical compositions.
[0065] When the 5-HT2A and D4 antagonist, inverse agonist or
partial agonist or the composition comprising both elements of the
invention are administered prior to the second compound as defined,
the 5-HT2A and D4 antagonist, inverse agonist or partial agonist or
the composition comprising both elements is administered at least
during 1 day prior to said second compound. Preferably, the 5-HT2A
and D4 antagonist, inverse agonist or partial agonist (e.g.
pipamperon) or the composition comprising both elements is
administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days
prior to the administration of the second compound. Preferably, the
5-HT2A and D4 antagonist, inverse agonist or partial agonist (e.g.
pipamperon) or the composition comprising both elements is
administered for at least 2, 3, 4 or 5 weeks prior to the
administration of the second compound, or even for at least 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months prior to the
administration of the second compound.
[0066] According to a preferred embodiment of the invention, the
above described compounds or the composition comprising both
elements having a 5-HT2A and D4 antagonist, inverse agonist or
partial agonist activity are useful for augmenting the therapeutic
effect of citalopram or for providing a faster onset of the
therapeutic effect of citalopram.
[0067] Citalopram or citalopram hydrobromide is a selective
serotonin (5-hydroxytryptamine/5-HT) re-uptake inhibitor (SSRI) and
is the conventional name given for the compound of the formula
(RS)-1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitril-
e hydro-bromide.
[0068] According to an embodiment, a daily dose of active
ingredient of SSRI, preferably citalopram, ranges between 10 and 40
mg per day. Preferably, daily doses of active ingredient ranging
between 20 and 30 mg per day are administered. More preferably, a
daily dose of 10, 15, 20, 25, 30, 35 or 40 mg per day is
administered.
[0069] According to another preferred embodiment of the invention,
the above described compounds or the composition comprising both
elements having a 5-HT2A and D4 antagonist, inverse agonist or
partial agonist activity are useful for augmenting the therapeutic
effect of fluvoxamine or for providing a faster onset of the
therapeutic effect of fluvoxamine.
[0070] Fluvoxamine or fluvoxamine maleate (luvox, fevarin) is a
selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to a
new chemical series, the 2-aminoethyl oxime ethers of
aralkylketones. It is chemically unrelated to other SSRIs and
clomipramine. It is chemically designated as
5-methoxy-4'-(trifluoromethyl)valerophenone
(E)-O-(2-aminoethyl)oxime maleate (1:1).
[0071] According to an embodiment, a daily dose of active
ingredient of fluvoxamine maleate ranges between 100 and 300 mg per
day. Preferably, daily doses of active ingredient ranging between
150 and 200 mg per day are administered. More preferably, a daily
dose of 100, 150, 200, 250 or 300 mg per day is administered.
[0072] According to a preferred embodiment of the invention, the
above described compounds or the composition comprising both
elements having a 5-HT2A and D4 antagonist, inverse agonist or
partial agonist activity are useful for augmenting the therapeutic
effect of selegiline or for providing a faster onset of the
therapeutic effect of selegiline.
[0073] Selegiline or L-deprenyl or phenylisopropyl methyl propynyl
amine is a monoamine oxidase B inhibitor (MAO-B inhibitor) and is
the conventional name given for the compound of the formula
(R)-(-)-N,.alpha.-dimethyl-N-(2-propynyl)phenethylamine--HCl.
[0074] According to an embodiment, a daily dose of active
ingredient of MAO-B inhibitor, preferably selegiline, ranges
between 5 and 60 mg per day. Preferably, daily doses of active
ingredient ranging between 20 and 40 mg per day are administered.
More preferably, a daily dose of 10, 15, 20, 25, 30, 35 or 40 mg
per day is administered.
[0075] Most of the second compounds herein described are known in
the art and may be used in doses according to the supplier's or
physician's prescription, or may be used according to specific
embodiments described herein.
[0076] Also encompassed by the invention are pro-drugs to these
second compounds or active metabolites of these compounds. For
instance, for risperidone it is known that, among other products,
bio transformation in the liver produces 9-hydroxyrisperidone,
which is of the same pharmacological activity and intensity as
parent risperidone. Therefore, also 9-hydroxyrisperidone, naturally
produced or chemically synthesized may be used in the methods and
uses according to the invention.
[0077] The term "active metabolite" as used herein relates to a
therapeutically active compound produced by the metabolism of a
parent drug. Drugs administered to treat diseases are usually
transformed (metabolized) within the body into a variety of related
chemical forms (metabolites), some of which may have therapeutic
activity (an active metabolite).
[0078] The present invention also encompasses the use of these
second compounds, administered in the form of a pharmaceutically
acceptable salt in admixture with a suitable pharmaceutically
acceptable excipient.
[0079] To prepare the pharmaceutical compositions, comprising the
compounds or the combination of the first and second compound
described herein, an effective amount of the active ingredients, in
acid or base addition salt form or base form, is combined in
admixture with a pharmaceutically acceptable carrier, which can
take a wide variety of forms depending on the form of preparation
desired for administration. These pharmaceutical compositions are
desirably in unitary dosage form suitable, for administration
orally, nasal, rectally, percutaneously, transdermally, by
parenteral, intramuscular, intravascular injection or intrathecal
administration. For example, in preparing the compositions in oral
dosage form, any of the usual pharmaceutical media may be employed,
such as, for example, water, glycols, oils, alcohols and the like
in the case of oral liquid preparations such as suspensions,
syrups, elixirs and solutions; or solid carriers such as starches,
sugars, kaolin, lubricants, binders, disintegrating agents and the
like in the case of powders, pills, capsules and tablets. Because
of their ease in administration, tablets and capsules represent the
most advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are obviously employed. For parenteral
compositions, the carrier will usually comprise sterile water, at
least in large part, though other ingredients, for example, to aid
solubility, may be included.
[0080] The pharmaceutical compounds for treatment are intended for
parenteral, topical, oral or local administration and generally
comprise a pharmaceutically acceptable carrier and an amount of the
active ingredient sufficient to reverse or prevent the bad effects
of mental disorders. The carrier may be any of those conventionally
used and is limited only by chemico-physical considerations, such
as solubility and lack of reactivity with the compound, and by the
route of administration.
[0081] Examples of pharmaceutically acceptable acid addition salts
for use in the present inventive pharmaceutical composition include
those derived from mineral acids, such as hydrochloric,
hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids,
and organic acids, such as tartaric, acetic, citric, malic, lactic,
fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic
acids, and arylsulphonic, for example.
[0082] The pharmaceutically acceptable excipients described herein,
for example, vehicles, adjuvants, carriers or diluents, are
well-known to those who are skilled in the art and are readily
available to the public. It is preferred that the pharmaceutically
acceptable carrier be one that is chemically inert to the active
compounds and one that has no detrimental side effects or toxicity
under the conditions of use.
[0083] The following formulations for oral, aerosol, parenteral,
subcutaneous, intravenous, intramuscular, interperitoneal, rectal,
and vaginal administration are merely exemplary and are in no way
limiting. Overall, the requirements for effective pharmaceutical
carriers for parenteral compositions are well known to those of
ordinary skill in the art. See Pharmaceutics and Pharmacy Practice,
J.B. Lippincott Company, Philadelphia, Pa., Banker and Chalmers,
eds., pages 238-250, (1982), and ASHP Handbook on Injectable Drugs,
Toissel, 4th ed., pages 622-630 (1986). Topical formulations,
including those that are useful for transdermal drug release, are
well-known to those of skill in the art and are suitable in the
context of the present invention for application to skin.
[0084] Formulations suitable for oral administration require extra
considerations considering the nature of the compounds and the
possible breakdown thereof if such compounds are administered
orally without protecting them from the digestive secretions of the
gastrointestinal tract. Such a formulation can consist of (a)
liquid solutions, such as an effective amount of the compound
dissolved in diluents, such as water, saline, or orange juice; (b)
capsules, sachets, tablets, lozenges, and troches, each containing
a predetermined amount of the active ingredient, as solids or
granules; (c) powders; (d) suspensions in an appropriate liquid;
and (e) suitable emulsions. Liquid formulations may include
diluents, such as water and alcohols, for example, ethanol, benzyl
alcohol, and the polyethylene alcohols, either with or without the
addition of a pharmaceutically acceptable surfactant, suspending
agent, or emulsifying agent. Capsule forms can be of the ordinary
hard- or soft-shelled gelatin type containing, for example,
surfactants, lubricants, and inert fillers, such as lactose,
sucrose, calcium phosphate, and corn starch. Tablet forms can
include one or more of lactose, sucrose, mannitol, corn starch,
potato starch, alginic acid, microcrystalline cellulose, acacia,
gelatin, guar gum, colloidal silicon dioxide, croscarmellose
sodium, talc, magnesium stearate, calcium stearate, zinc stearate,
stearic acid, and other excipients, colorants, diluents, buffering
agents, disintegrating agents, moistening agents, preservatives,
flavoring agents, and pharmacologically compatible excipients.
Lozenge forms can comprise the active ingredient in a flavor,
usually sucrose and acacia or tragacanth, as well as pastilles
comprising the active ingredient in an inert base, such as gelatin
and glycerin, or sucrose and acacia, emulsions, gels, and the like
containing, in addition to the active ingredient, such excipients
as are known in the art.
[0085] The compounds of the present invention, alone or in
combination with other suitable components, can be made into
aerosol formulations to be administered via inhalation. For aerosol
administration, the compounds are preferably supplied in finely
divided form along with a surfactant and propellant. Typical
percentages of compounds are 0.01%-20% by weight, preferably
1%-10%. The surfactant must, of course, be nontoxic, and preferably
soluble in the propellant. Representative of such agents are the
esters or partial esters of fatty acids containing from 6 to 22
carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic,
linoleic, linolenic, olesteric and oleic acids with an aliphatic
polyhydric alcohol or its cyclic anhydride. Mixed esters, such as
mixed or natural glycerides may be employed. The surfactant may
constitute 0.1%-20% by weight of the compounds, preferably 0.25-5%.
The balance of the compounds is ordinarily propellant. A carrier
can also be included as desired, e.g., lecithin for intranasal
delivery. These aerosol formulations can be placed into acceptable
pressurized propellants, such as dichlorodifluoromethane, propane,
nitrogen, and the like. They also may be formulated as
pharmaceuticals for non-pressured preparations, such as in a
nebulizer or an atomizer. Such spray formulations may be used to
spray mucosa.
[0086] It will be understood that, apart from daily doses, the
compounds can be administered by other schedules. For instance, the
present invention also contemplates depot injection, in which a
long acting form of the active compound is injected into the body,
such as the muscles. From there the active compound slowly enters
the rest of the body, so one injection can last from 1 to 4 weeks
or even multiple months. Other form of dosage administrations
relate to "once-a-week" pills, in which the ingredient is slowly
released over a period of a week, and slow-release patches, e.g. a
CDS (Continuous Delivery System), or Once-a-Day Transdermal
Patches.
[0087] According to a further embodiment, the invention also
relates to a method for preparing a compound or composition having
a selective D4 and 5-HT2A antagonist, reverse agonist or partial
agonist. The invention also relates to the compounds prepared by
the claimed method, with the proviso that said compound is not an
already known compound, such as pipamperon.
[0088] It should be clear that the compounds and compositions
described herein are useful for treating any patient in need
thereof. As used herein the term "patient" is not restricted to
humans but also to other mammals, for instance, domestic animals
which may also suffer from any form of a mental disease or disorder
described herein.
[0089] The second compounds of the invention can be further grouped
according to their pharmacological profile, which is summarized in
Table 6.
[0090] The present invention is now described in more detail by the
following embodiments. The compounds belonging to different
pharmacological profiles can be further grouped according to their
action on the same pathway or system as follows.
1: Combination Therapy with a 5-HT (Serotonin) Reuptake
Enhancer
[0091] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a 5-HT
(serotonin) reuptake enhancer, are chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
substance related disorder, personality disorders, antisocial
behaviour, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0092] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance related disorder, personality disorders,
antisocial behaviour, bereavement, occupational problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a 5-HT (serotonin) reuptake enhancer compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said 5-HT (serotonin) reuptake enhancer
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0093] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a 5-HT (serotonin) reuptake enhancer compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said 5-HT (serotonin) reuptake enhancer compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0094] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said 5-HT (serotonin)
reuptake enhancer compound is tianeptine or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Preferably, tianeptine is to be administered in a daily dose
ranging between 25 and 50 mg of the active ingredient.
[0095] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a 5-HT (serotonin) reuptake
enhancer, preferably tianeptine or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance related disorder,
personality disorder, antisocial behaviour, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0096] A pharmaceutical composition as described above wherein
pipamperon is provided in a unitary dose of between 5 and 15 mg of
the active ingredient and wherein said 5-HT (serotonin) reuptake
enhancer is tianeptine, preferably provided in a unitary dose of
between 25 and 50 mg of the active ingredient.
2: Combination Therapy with a 5-HT1 Autoreceptor Agonist
[0097] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a 5-HT1
autoreceptor agonist, are chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance related disorder,
personality disorders, antisocial behaviour, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0098] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance related disorder, personality disorders,
antisocial behaviour, bereavement, occupational problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a 5-HT1 autoreceptor agonist compound to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said 5-HT1 autoreceptor agonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0099] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a 5-HT1 autoreceptor agonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said 5-HT1 autoreceptor agonist compound, further characterized in
that pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0100] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said 5-HT1 autoreceptor
agonist compound is sunepitron or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0101] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a 5-HT1 autoreceptor agonist,
preferably sunepitron or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance related disorder,
personality disorder, antisocial behaviour, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
3: Combination Therapy with a 5-HT1A (Serotonin 1A Receptor)
Agonist Compound
[0102] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a 5-HT1A
(serotonin 1A receptor) agonist compound, are chosen from the group
of diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender disorders, sleep
disorders, adjustment disorders, impulse control disorders,
attention-deficit disorders, substance-related disorder,
personality disorders, antisocial behaviour, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0103] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender disorders,
sleep disorders, adjustment disorders, impulse control disorders,
attention-deficit disorders, substance-related disorder,
personality disorders, antisocial behaviour, bereavement,
occupational problem and problems related to abuse or neglect,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a 5-HT1A (serotonin
1A receptor) agonist compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said 5-HT1A
(serotonin 1A receptor) agonist compound, further characterized in
that pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0104] The present invention further also relates to the use of
pipamperon or a pharmaceutically acceptable salt thereof for the
preparation of a medicament for treating the underlying emotion
dysregulation of pain disorders, characterized in that pipamperon
or said pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a 5-HT1A (serotonin 1A receptor) agonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said 5-HT1A (serotonin 1A receptor) agonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0105] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said 5-HT1A (serotonin 1A
receptor) agonist compound is chosen from the group consisting of
MN-305, zalospirone, xaliproden, VPI-013 (also known as OPC-14523),
tandospirone, sarizotan, PRX-00023, metanospirone, lesopitron,
gepirone, flesinoxan, EMD 68843, buspirone, bupropion (preferably
controlled release formulation) and alnespirone, preferably
xaliproden, sarizotan, gepirone, flesinoxan and bupropion
(preferably controlled release formulation) or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof. More preferably, said 5-HT1A (serotonin 1A receptor)
agonist is xaliproden and is to be administered in a daily dose
ranging between 1 and 2 mg of the active ingredient. Even more
preferably, said 5-HT1A (serotonin 1A receptor) agonist is
bupropion (controlled release formulation) and is to be
administered in a daily dose ranging between 150 and 450 mg of the
active ingredient. Even more preferably, said 5-HT1A (serotonin 1A
receptor) agonist is gepirone and is to be administered in a daily
dose, ranging between 20 and 80 mg of the active ingredient per
day.
[0106] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a 5-HT1A (serotonin 1A receptor)
agonist, preferably chosen from the group consisting of MN-305,
zalospirone, xaliproden, VPI-013 (also known as OPC-14523),
tandospirone, sarizotan, PRX-00023, metanospirone, lesopitron,
gepirone, flesinoxan, EMD 68843, buspirone, bupropion (preferably
controlled release formulation) and alnespirone, more preferably
xaliproden, sarizotan, gepirone, flesinoxan and bupropion
(preferably controlled release formulation), or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
a mental disease or disorder which is chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender disorders, sleep
disorders, adjustment disorders, impulse control disorders,
attention-deficit disorders, substance-related disorder,
personality disorders, antisocial behaviour, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0107] The present invention also relates to a pharmaceutical
composition as described above wherein pipamperon is provided in a
unitary dose of between 5 and 15 mg of the active ingredient and
wherein said 5-HT1A (serotonin 1A receptor) agonist is xaliproden,
preferably provided in a unitary dose of between 1 and 2 mg of the
active ingredient.
[0108] The present invention also relates to a pharmaceutical
composition as described above wherein pipamperon is provided in a
unitary dose of between 5 and 15 mg of the active ingredient and
wherein said 5-HT1A (serotonin 1A receptor) agonist is bupropion
(controlled release formulation), preferably provided in a unitary
dose of between 150 and 450 mg of the active ingredient.
[0109] The present invention also relates to a pharmaceutical
composition as described above wherein pipamperon is provided in a
unitary dose of between 5 and 15 mg of the active ingredient and
wherein said 5-HT1A (serotonin 1A receptor) agonist is gepirone,
preferably provided in a unitary dose of between 20 and 80 mg of
the active ingredient.
4: Combination Therapy with a 5-HT1A (Serotonin 1A Receptor)
Antagonist Compound
[0110] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a 5-HT1A
(serotonin 1A receptor) antagonist compound, are chosen from the
group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender disorders,
adjustment disorders, impulse control disorders, substance-related
disorder, personality disorders, antisocial behaviour, bereavement,
occupational problem and problems related to abuse or neglect.
[0111] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender disorders,
adjustment disorders, impulse control disorders, substance-related
disorder, personality disorders, antisocial behaviour, bereavement,
occupational problem and problems related to abuse or neglect,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a 5-HT1A antagonist
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said 5-HT1A antagonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0112] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said 5-HT1A antagonist
compound is chosen from the group consisting of robalzotan tartrate
hydrate and NAD299 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof.
[0113] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a 5-HT1A antagonist, preferably
chosen from the group consisting of robalzotan tartrate hydrate and
NAD299, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a non-cognitive mental disease
or disorder which is chosen from the group of diseases or disorders
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender disorders, adjustment disorders, impulse control
disorders, substance-related disorder, personality disorders,
antisocial behaviour, bereavement, occupational problem and
problems related to abuse or neglect.
5: Combination Therapy with a 5-HT1B (Serotonin 1B Receptor)
Antagonist Compound
[0114] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a 5-HT1B
(serotonin 1B receptor) antagonist compound, are chosen from the
group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender disorders,
sleep disorders, adjustment disorders, impulse control disorders,
substance-related disorder, personality disorders, antisocial
behaviour, bereavement, occupational problem and problems related
to abuse or neglect.
[0115] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender disorders,
sleep disorders, adjustment disorders, impulse control disorders,
substance-related disorder, personality disorders, antisocial
behaviour, bereavement, occupational problem and problems related
to abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a 5-HT1B antagonist compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said
5-HT1B antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0116] According to a preferred embodiment, the invention relates
to the use as described above, wherein said 5-HT1B antagonist
compound is chosen from the group consisting of elzasonan, AZD1134
and AR-A2, preferably elzasonan, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0117] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a 5-HT1B antagonist, preferably
chosen from the group consisting of elzasonan, AZD1134 and AR-A2,
preferably elzasonan, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a
non-cognitive mental disease or disorder which is chosen from the
group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender disorders,
sleep disorders, adjustment disorders, impulse control disorders,
substance-related disorder, personality disorders, antisocial
behaviour, bereavement, occupational problem and problems related
to abuse or neglect.
6: Combination Therapy with a 5-HT2B (Serotonin 2B Receptor)
Antagonist Compound
[0118] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a 5-HT2B
(serotonin 2B receptor) antagonist compound, are chosen from the
group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender disorders,
sleep disorders, adjustment disorders, impulse control disorders,
substance-related disorder, personality disorders, antisocial
behaviour, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0119] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender disorders,
sleep disorders, adjustment disorders, impulse control disorders,
substance-related disorder, personality disorders, antisocial
behaviour, bereavement, occupational problem, problems related to
abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a 5-HT2B antagonist compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said
5-HT2B antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0120] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a 5-HT2B antagonist compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said
5-HT2B antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0121] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said 5-HT2B antagonist
compound is aglomelatine or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. Preferably,
aglomelatine is to be administered in a daily dose ranging between
25 and 50 mg of the active ingredient.
[0122] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a 5-HT2B antagonist, preferably
aglomelatine or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender disorders, sleep disorders, adjustment disorders,
impulse control disorders, substance-related disorder, personality
disorders, antisocial behaviour, bereavement, occupational problem,
problems related to abuse or neglect and pain disorders.
[0123] A pharmaceutical composition as described above wherein
pipamperon is provided in a unitary dose of between 5 and 15 mg of
the active ingredient and wherein said 5-HT2B antagonist is
aglomelatine, preferably provided in a unitary dose of between 25
and 50 mg of the active ingredient.
7: Combination Therapy with a 5-HT2C (Serotonin 2C Receptor)
Antagonist Compound
[0124] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a 5-HT2C
(serotonin 2C receptor) antagonist compound, are chosen from the
group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender disorders,
sleep disorders, adjustment disorders, impulse control disorders,
substance-related disorder, personality disorders, antisocial
behaviour, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0125] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender disorders,
sleep disorders, adjustment disorders, impulse control disorders,
substance-related disorder, personality disorders, antisocial
behaviour, bereavement, occupational problem, problems related to
abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a 5-HT2C antagonist compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said
5-HT2C antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0126] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a 5-HT2C antagonist compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said
5-HT2C antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0127] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said 5-HT2C antagonist
compound is chosen from the group consisting of SB 243213 and
aglomelatine or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. Preferably, aglomelatine
is to be administered in a daily dose ranging between 25 and 50 mg
of the active ingredient.
[0128] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a 5-HT2C antagonist, preferably
chosen from the group consisting of SB 243213 and aglomelatine or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender disorders, sleep disorders, adjustment disorders,
impulse control disorders, substance-related disorder, personality
disorders, antisocial behaviour, bereavement, occupational problem,
problems related to abuse or neglect and pain disorders.
[0129] The present invention also relates to a pharmaceutical
composition as described above wherein pipamperon is provided in a
unitary dose of between 5 and 15 mg of the active ingredient and
wherein said 5-HT2C antagonist is aglomelatine, preferably provided
in a unitary dose of between 25 and 50 mg of the active
ingredient.
8: Combination Therapy with a 5-HT3 (Serotonin 3 Receptor)
Antagonist Compound
[0130] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a 5-HT3
(serotonin 3 receptor) antagonist compound, are substance-related
disorders.
[0131] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of substance-related disorders, characterized in that pipamperon or
said pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a 5-HT3 antagonist compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said 5-HT3
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0132] According to a preferred embodiment, the invention relates
to the use as described above, wherein said 5-HT3 antagonist
compound is ondansetron or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. Preferably,
ondansetron is to be administered in a daily dose ranging between 8
and 32 mg of the active ingredient.
[0133] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a 5-HT3 antagonist, preferably
ondansetron or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of substance-related
disorders.
[0134] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
5-HT3 antagonist is ondansetron, preferably provided in a unitary
dose of between 8 and 32 mg of the active ingredient.
9: Combination Therapy with a 5-HT6 (Serotonin 6 Receptor)
Antagonist Compound
[0135] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a 5-HT6
(serotonin 6 receptor) antagonist compound, are chosen from the
group of diseases or disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0136] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive disorder selected from the group of diseases and
disorders consisting of Alzheimer Disease, substance-induced
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder
and other cognitive disorders, characterized in that pipamperon or
said pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a 5-HT6 antagonist compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said 5-HT6
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0137] According to a preferred embodiment, the invention relates
to the use as described above, wherein said 5-HT6 antagonist
compound is chosen from the group consisting of SB-271046, 742457
and 271046 or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof.
[0138] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a 5-HT6 antagonist, preferably
chosen from the group consisting of SB-271046, 742457 and 271046 or
a pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of Alzheimer Disease, substance-induced persisting dementia,
vascular dementia, dementia due to HIV disease, dementia due to
head trauma, dementia due to Parkinson Disease, dementia due to
Huntington Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
10: Combination Therapy with an Acetylcholinesterase Inhibitor
Compound
[0139] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an
acetylcholinesterase inhibitor compound, are chosen from the group
of diseases or disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0140] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive disorder selected from the group of diseases and
disorders consisting of Alzheimer Disease, substance-induced
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder,
other cognitive disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an acetylcholinesterase inhibitor compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said acetylcholinesterase inhibitor compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0141] According to a preferred embodiment, the invention relates
to the use as described above, wherein said acetylcholinesterase
inhibitor compound is chosen from the group consisting of tacrine,
rivastigmine tartrate, rivastigmine, physostigmine, phenserine
tartrate, metrifonate, huperzine A, galantamine (preferably
extended release formulation), donezepil, dichlorvos and anseculin
hydrochloride, preferably tartrate, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Preferably, rivastigmine tartrate is to be administered in a daily
dose ranging between 3 and 12 mg of the active ingredient.
Preferably, phenserine tartrate is to be administered in a daily
dose ranging between 20 and 30 mg of the active ingredient.
Preferably, galantamine (extended release formulation) is to be
administered in a daily dose ranging between 8 and 24 mg of the
active ingredient.
[0142] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an acetylcholinesterase
inhibitor, preferably chosen from the group consisting of tacrine,
rivastigmine tartrate, rivastigmine, physostigmine, phenserine
tartrate, metrifonate, huperzine A, galantamine (preferably
extended release formulation), donezepil, dichlorvos and anseculin
hydrochloride, preferably tartrate, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of Alzheimer Disease, substance-related
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder
and other cognitive disorders.
[0143] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
acetylcholinesterase inhibitor is rivastigmine tartrate, preferably
provided in a unitary dose of between 3 and 12 mg of the active
ingredient.
[0144] The invention further relates to a pharmaceutical
composition as described above wherein pipamperon is provided in a
unitary dose of between 5 and 15 mg of the active ingredient and
wherein said acetylcholinesterase inhibitor is phenserine tartrate,
preferably provided in a unitary dose of between 20 and 30 mg of
the active ingredient.
[0145] In addition, the invention relates to a pharmaceutical
composition as described above wherein pipamperon is provided in a
unitary dose of between 5 and 15 mg of the active ingredient and
wherein said acetylcholinesterase inhibitor is galantamine
(preferably extended release formulation), preferably provided in a
unitary dose of between 8 and 24 mg of the active ingredient.
11: Combination Therapy with an Adenosine A2a Receptor Antagonist
Compound
[0146] The mental disorder which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an adenosine
A2a receptor antagonist compound, is Parkinson disease.
[0147] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an adenosine A2a receptor antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said adenosine A2a receptor antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0148] According to a preferred embodiment, the invention relates
to the use as described above, wherein said adenosine A2a receptor
antagonist compound is KW-6002 or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Preferably, KW-6002 is to be administered in a daily dose ranging
between 40 and 80 mg of the active ingredient.
[0149] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an adenosine A2a receptor
antagonist, preferably KW-6002 or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of Parkinson
disease.
[0150] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
acetylcholinesterase inhibitor is KW-6002, preferably provided in a
unitary dose of between 40 and 80 mg of the active ingredient.
12: Combination Therapy with an Adrenergic Transmitter Releaser
[0151] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an
adrenergic transmitter releaser, are chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders,
adjustment disorders, impulse control disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0152] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, adjustment disorders, impulse control disorders,
personality disorders, bereavement, occupational problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of an adrenergic transmitter releaser compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said adrenergic transmitter releaser
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0153] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an adrenergic transmitter releaser compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said adrenergic transmitter releaser compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0154] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said adrenergic transmitter
releaser compound is pipoxazole or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Preferably, pipoxazole is to be administered in a daily dose
ranging between 30 and 60 mg of the active ingredient.
[0155] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an adrenergic transmitter
releaser, preferably pipoxazole, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, adjustment disorders, impulse
control disorders, personality disorders, bereavement, occupational
problem, problems related to abuse or neglect and pain
disorders.
[0156] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
adrenergic transmitter releaser is pipoxazole, preferably provided
in a unitary dose of between 30 and 60 mg of the active
ingredient.
13: Combination Therapy with an Alpha 1 Adrenoreceptor
Antagonist
[0157] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an alpha 1
adrenoreceptor antagonist, are chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect, pain disorders and Parkinson disease.
[0158] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, personality disorders, bereavement, occupational problem
and problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a alpha 1 adrenoreceptor antagonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said alpha 1 adrenoreceptor antagonist
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0159] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an alpha 1 adrenoreceptor antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said alpha 1 adrenoreceptor antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0160] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an alpha 1 adrenoreceptor antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said alpha 1 adrenoreceptor antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0161] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said alpha 1 adrenoreceptor
antagonist compound is chosen from the group consisting of SDZ NVI
085 and flesinoxan or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof.
[0162] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an alpha 1 adrenoreceptor
antagonist, preferably chosen from the group consisting of SDZ NVI
085 and flesinoxan or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of a mental disease
or disorder which is chosen from the group of diseases or disorders
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect, pain disorders and Parkinson disease.
14: Combination Therapy with an Alpha 2 Adrenoreceptor
Antagonist
[0163] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an alpha 2
adrenoreceptor antagonist, are chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders,
psychotic disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance related disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
[0164] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, psychotic disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance related disorders,
personality disorders, bereavement, occupational problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a alpha 2 adrenoreceptor antagonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said alpha 2 adrenoreceptor antagonist
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0165] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an alpha 2 adrenoreceptor antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said alpha 2 adrenoreceptor antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0166] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said alpha 2 adrenoreceptor
antagonist compound is chosen from the group consisting of
UK-14304, sunepitron, mirtazapine, idazoxan, fluparoxan, A75200 and
(R)-A 75200, preferably sunepitron or idazoxan, or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof. Preferably, idazoxan is to be administered in a daily dose
ranging between 5 and 40 mg of the active ingredient.
[0167] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an alpha 2 adrenoreceptor
antagonist, preferably chosen from the group consisting of
UK-14304, sunepitron, mirtazapine, idazoxan, fluparoxan, A75200 and
(R)-A 75200, preferably sunepitron or idazoxan, or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
a mental disease or disorder which is chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, psychotic disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, substance related disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0168] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
alpha 2 adrenoreceptor antagonist is idazoxan, preferably provided
in a unitary dose of between 5 and 40 mg of the active
ingredient.
15: Combination Therapy with an AMPA Receptor Mediator Compound
[0169] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an AMPA
(alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor
mediator compound, are chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders,
psychotic disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, disruptive behaviour disorders, substance-included
disorders, personality disorders, psychological factors affecting
medical conditions, malingering, antisocial behaviour, bereavement,
occupational problem, identity problem, problems related to abuse
or neglect, pain disorders, delirium, Alzheimer Disease,
substance-related persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0170] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, psychotic disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sleep
disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of an AMPA receptor mediator compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said AMPA receptor mediator compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0171] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an AMPA receptor mediator compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said AMPA receptor mediator compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0172] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of delirium, Alzheimer
Disease, substance-induced persisting dementia, vascular dementia,
dementia due to HIV disease, dementia due to head trauma, dementia
due to Parkinson Disease, dementia due to Huntington Disease,
dementia due to Pick Disease, dementia due to Creutzfeldt-Jacob
Disease, amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of an AMPA receptor mediator compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said AMPA receptor mediator compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0173] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said AMPA receptor mediator
compound is chosen from the group consisting of ampakine ORG
24448/CX-619, ampakine CX-717, ampakine CX-691 and ampakine CX-516,
preferably ampakine ORG 24448/CX-619, ampakine CX-717 or ampakine
CX-691, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof.
[0174] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an AMPA receptor mediator,
preferably chosen from the group consisting of ampakine ORG
24448/CX-619, ampakine CX-717, ampakine CX-691 and ampakine CX-516,
preferably ampakine ORG 24448/CX-619, ampakine CX-717 or ampakine
CX-691, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of mood disorders, anxiety disorders, psychotic disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sleep disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem,
problems related to abuse or neglect, pain disorders, delirium,
Alzheimer Disease, substance-induced persisting dementia, vascular
dementia, dementia due to HIV disease, dementia due to head trauma,
dementia due to Parkinson Disease, dementia due to Huntington
Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
16: Combination Therapy with an Amphetamine Compound
[0175] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an
amphetamine compound, are attention-deficit disorders.
[0176] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of attention deficit disorders, characterized in that pipamperon or
said pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an amphetamine compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said
amphetamine compound, further characterized in that pipamperon is
to be administered to a patient in a daily dose ranging between 5
and 15 mg of the active ingredient.
[0177] According to a preferred embodiment, the invention relates
to the use as described above, wherein said amphetamine compound is
methylphenidate (preferably administered by a transdermal system)
or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof.
[0178] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an amphetamine, preferably
methylphenidate (preferably administered by a transdermal system)
or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of attention deficit
disorders.
17: Combination Therapy with an Amyloid Aggregation-Inhibitor
Compound
[0179] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an amyloid
aggregation-inhibitor compound, are chosen from the group of
diseases or disorders consisting of Alzheimer Disease,
substance-related persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0180] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-related persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of an amyloid aggregation-inhibitor compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said amyloid aggregation-inhibitor compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0181] According to a preferred embodiment, the invention relates
to the use as described above, wherein said amyloid
aggregation-inhibitor compound is chosen from the group consisting
of APAN and Alzhemed, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. Preferably,
Alzhemed is to be administered in a daily dose of between 200 and
300 mg of the active ingredient.
[0182] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an amyloid
aggregation-inhibitor, preferably chosen from the group consisting
of APAN and Alzhemed, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of Alzheimer Disease, substance-related
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder
and other cognitive disorders.
[0183] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
amyloid aggregation-inhibitor is Alzhemed, preferably provided in a
unitary dose of between 200 and 300 mg of the active
ingredient.
18: Combination Therapy with an Androgen Receptor Modulator
Compound
[0184] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an androgen
receptor modulator compound, are sexual and gender identity
disorders.
[0185] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of sexual and gender identity disorders, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of an androgen receptor modulator compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said androgen receptor modulator compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0186] According to a preferred embodiment, the invention relates
to the use as described above, wherein said androgen receptor
modulator compound is LGD2226 or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof.
[0187] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an androgen receptor modulator,
preferably LGD2226 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of sexual and gender
identity disorders.
19: Combination Therapy with an Beta 3 Adrenoreceptor Agonist
[0188] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an beta 3
adrenoreceptor agonist, are chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance related disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0189] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a beta 3
adrenoreceptor agonist compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said beta
3 adrenoreceptor agonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0190] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an beta 3 adrenoreceptor agonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said beta 3 adrenoreceptor agonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0191] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said beta 3 adrenoreceptor
agonist compound is SR 58611 or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof.
[0192] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a beta 3 adrenoreceptor agonist,
preferably SR 58611 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of a mental disease
or disorder which is chosen from the group of diseases or disorders
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance related disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
20: Combination Therapy with a Calcium Channel Modulator
Compound
[0193] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a calcium
channel modulator compound, are chosen from the group of diseases
or disorders consisting of Alzheimer Disease, substance-related
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder,
other cognitive disorders and Parkinson disease.
[0194] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-related persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a calcium channel modulator compound to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said calcium channel modulator compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0195] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a calcium channel modulator compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said calcium channel modulator compound, further characterized in
that pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0196] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said calcium channel
modulator compound is chosen from the group consisting of
safinamide and MEM 1003, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof.
[0197] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a calcium channel modulator,
preferably chosen from the group consisting of safinamide and MEM
1003, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of Alzheimer Disease, substance-related persisting dementia,
vascular dementia, dementia due to HIV disease, dementia due to
head trauma, dementia due to Parkinson Disease, dementia due to
Huntington Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder, other cognitive disorders and
Parkinson disease.
21: Combination Therapy with a Cannabioid Receptor 1 (CBI)
Antagonist
[0198] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a cannabioid
receptor 1 (CBI) antagonist, are chosen from the group of diseases
or disorders consisting of mood disorders, anxiety disorders,
psychotic disorders, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sleep
disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem,
problems related to abuse or neglect, pain disorders and
delirium.
[0199] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting mood disorders, anxiety
disorders, psychotic disorders, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sleep disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a cannabioid receptor 1 antagonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said cannabioid receptor antagonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0200] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a cannabioid receptor 1 antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said cannabioid receptor 1 antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0201] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of delirium, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a cannabioid receptor 1 antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said cannabioid receptor 1 antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0202] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said cannabioid receptor
antagonist compound is SR 141716 or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0203] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a cannabioid receptor
antagonist, preferably SR 141716 or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders,
psychotic disorders, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sleep
disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem,
problems related to abuse or neglect, pain disorders and
delirium.
22: Combination Therapy with a Cathepsin K Inhibitor Compound
[0204] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a cathepsin
K inhibitor compound, are pain disorders.
[0205] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a cathepsin K inhibitor compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said cathepsin K inhibitor compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0206] According to a preferred embodiment, the invention relates
to the use as described above, wherein said cathepsin K inhibitor
compound is 462795 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof.
[0207] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a cathepsin K inhibitor,
preferably 462795 or a pro-drug or an active metabolite thereof, or
a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of pain
disorders.
23: Combination Therapy with a Choline Uptake Enhancer Compound
[0208] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a choline
uptake enhancer compound, are chosen from the group of diseases or
disorders consisting of Alzheimer Disease, substance-induced
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder
and other cognitive disorders.
[0209] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a choline uptake enhancer compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said choline uptake enhancer compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0210] According to a preferred embodiment, the invention relates
to the use as described above, wherein said choline uptake enhancer
compound is MKC-231 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof. Preferably, MKC-231
is to be administered in a daily dose of between 20 and 160 mg of
the active ingredient.
[0211] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a choline uptake enhancer,
preferably MKC-231 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of a mental disease
or disorder which is chosen from the group of diseases or disorders
consisting of Alzheimer Disease, substance-induced persisting
dementia, vascular dementia, dementia due to HIV disease, dementia
due to head trauma, dementia due to Parkinson Disease, dementia due
to Huntington Disease, dementia due to Pick Disease, dementia due
to Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
[0212] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
choline uptake enhancer is MKC-231, preferably provided in a
unitary dose of between 20 and 160 mg of the active ingredient.
24: Combination Therapy with a COX-2 Inhibitor Compound
[0213] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a COX-2
inhibitor compound, are pain disorders.
[0214] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a COX-2 inhibitor compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said COX-2
inhibitor compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0215] According to a preferred embodiment, the invention relates
to the use as described above, wherein said COX-2 inhibitor
compound is chosen from the group consisting of valdecoxib,
rofecoxib, parecoxib, etoricoxib, COX 189, celecoxib and ABT-963,
preferably parecoxib, etoricoxib or COX 189, or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof. Preferably, parecoxib is to be administered in a daily
dose of between 20 and 80 mg of the active ingredient. Preferably,
etoricoxib is to be administered in a daily dose of between 20 and
120 mg of the active ingredient. Preferably, COX 189 is to be
administered in a daily dose of between 100 and 800 mg of the
active ingredient.
[0216] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a COX-2 inhibitor, preferably
chosen from the group consisting of valdecoxib, rofecoxib,
parecoxib, etoricoxib, COX 189, celecoxib and ABT-963, preferably
parecoxib, etoricoxib or COX 189, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of pain
disorders.
[0217] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
COX-2 inhibitor is parecoxib, preferably provided in a unitary dose
of between 20 and 80 mg of the active ingredient.
[0218] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
COX-2 inhibitor is etoricoxib, preferably provided in a unitary
dose of between 20 and 120 mg of the active ingredient.
[0219] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
COX-2 inhibitor is COX 189, preferably provided in a unitary dose
of between 100 and 800 mg of the active ingredient.
25: Combination Therapy with a COX-Inhibiting Nitric Oxide Donator
(CINOD) Compound
[0220] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
COX-inhibiting nitric oxide donator (CINOD) compound, are pain
disorders.
[0221] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a COX-inhibiting nitric oxide donator (CINOD) compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said COX-inhibiting nitric oxide donator
(CINOD) compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0222] According to a preferred embodiment, the invention relates
to the use as described above, wherein said COX-inhibiting nitric
oxide donator (CINOD) compound is chosen from the group consisting
of AZD4717 and AZD3582 or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. Preferably,
AZD3582 is to be administered in a daily dose ranging between 93.75
and 750 mg of the active ingredient.
[0223] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a COX-inhibiting nitric oxide
donator (CINOD), preferably chosen from the group consisting of
AZD4717 and AZD3582 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of pain
disorders.
[0224] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
COX-inhibiting nitric oxide donator (CINOD) is AZD3582, preferably
provided in a unitary dose of between 93.75 and 750 mg of the
active ingredient.
26: Combination Therapy with a CRF1 (Corticoid-Releasing Factor
Receptor 1) Antagonist
[0225] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a CRF1
(Corticotropin-Releasing Factor receptor 1) antagonist, are chosen
from the group of diseases or disorders consisting of mood
disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, substance related disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0226] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a CRF1 antagonist
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said CRF1 antagonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0227] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a CRF1 antagonist compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said CRF1
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0228] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said CRF1 antagonist
compound is chosen from the group consisting of R121919, NBI-34041,
elzasonan, CP-448,187, CP-154-526, AAG 561 and 723620, preferably
R121919, elzasonan or AAG 561, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Preferably, R121919 is to be administered in a daily dose of
between 5 and 80 mg of the active ingredient.
[0229] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a CRF1 antagonist, preferably
chosen from the group consisting of R121919, NBI-34041, elzasonan,
CP-448,187, CP-154-526, AAG 561 and 723620, preferably R121919,
elzasonan or AAG 561, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance related disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0230] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
CRF1 antagonist is R121919, preferably provided in a unitary dose
of between 5 and 80 mg of the active ingredient.
27: Combination Therapy with a D1 (Dopamine 1) Receptor Agonist
[0231] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a D1
(dopamine 1) receptor agonist, are chosen from the group of
diseases or disorders consisting of substance related disorders and
Parkinson disease.
[0232] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of substance related disorders, characterized in that pipamperon or
said pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a D1 receptor agonist compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said D1
receptor agonist compound, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0233] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a D1 receptor agonist compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said D1
receptor agonist compound, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0234] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said D1 receptor agonist
compound is DAS-431 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof.
[0235] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a D1 receptor agonist,
preferably DAS-431 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of a mental disease
or disorder which is chosen from the group of diseases or disorders
consisting of substance related disorders and Parkinson
disease.
28: Combination Therapy with D2 (Dopamine 2) Receptor
Antagonist
[0236] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with D2 (dopamine
2) receptor antagonist, are chosen from the group of diseases or
disorders consisting of mood disorders, psychotic disorders,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, disruptive behaviour disorders, substance-related
disorders, personality disorders, psychological factors affecting
medical conditions, malingering, antisocial behaviour, bereavement,
occupational problem, identity problem, problems related to abuse
or neglect, pain disorders and delirium.
[0237] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting mood disorders,
psychotic disorders, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sleep
disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a D2 receptor antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said D2 receptor antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0238] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a D2 receptor antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said D2 receptor antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0239] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of delirium, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a D2 receptor antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said D2 receptor antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0240] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said D2 receptor antagonist
compound is chosen from the group consisting of bifeprunox and
amisulpride, preferably bifeprunox, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0241] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a D2 receptor antagonist,
preferably chosen from the group consisting of bifeprunox and
amisulpride, preferably bifeprunox, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of mood disorders, psychotic disorders,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, disruptive behaviour disorders, substance-related
disorders, personality disorders, psychological factors affecting
medical conditions, malingering, antisocial behaviour, bereavement,
occupational problem, identity problem, problems related to abuse
or neglect, pain disorders and delirium.
29: Combination Therapy with D3 (Dopamine 3) Receptor
Antagonist
[0242] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with D3 (dopamine
3) receptor antagonist, are chosen from the group of diseases or
disorders consisting of psychotic disorders, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, sleep disorders, adjustment disorders, impulse control
disorders, pervasive development disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
psychological factors affecting medical conditions, malingering,
antisocial behaviour, bereavement, occupational problem, identity
problem, problems related to abuse or neglect, pain disorders,
delirium and Parkinson disease.
[0243] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of psychotic disorders,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, disruptive behaviour disorders, substance-related
disorders, personality disorders, psychological factors affecting
medical conditions, malingering, antisocial behaviour, bereavement,
occupational problem, identity problem, problems related to abuse
or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a D3 receptor antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said D3 receptor antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0244] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a D3 receptor antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said D3 receptor antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0245] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of delirium, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a D3 receptor antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said D3 receptor antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0246] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a D3 receptor agonist compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said D3
receptor agonist compound, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0247] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said D3 receptor antagonist
compound is chosen from the group consisting of BSF-201640 and PD
58491, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof.
[0248] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a D3 receptor antagonist,
preferably chosen from the group consisting of BSF-201640 and PD
58491, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of psychotic disorders, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sleep
disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem,
problems related to abuse or neglect, pain disorders, delirium and
Parkinson disease.
30: Combination Therapy with a DA (Dopamine) Uptake Inhibitor
[0249] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a DA
(dopamine) uptake inhibitor, are chosen from the group of diseases
or disorders consisting of substance related disorders and
Parkinson disease.
[0250] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of substance related disorders, characterized in that pipamperon or
said pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a DA uptake inhibitor compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said DA
uptake inhibitor compound, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0251] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a DA uptake inhibitor compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said DA
uptake inhibitor compound, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0252] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said DA uptake inhibitor
compound is chosen from the group consisting of safinamide and GBR
12909, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof.
[0253] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a D2 receptor antagonist,
preferably chosen from the group consisting of safinamide and GBR
12909, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of substance related disorders and Parkinson disease.
31: Combination Therapy with an Dopamine (Receptor) Agonist
[0254] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an dopamine
(receptor) agonist, are chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
adjustment disorders, impulse control disorders, attention-deficit
disorders, substance-related disorders, personality disorders,
problems related to abuse or neglect, pain disorders and Parkinson
disease.
[0255] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, adjustment disorders, impulse control
disorders, attention-deficit disorders, substance-related
disorders, personality disorders and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a dopamine
(receptor) agonist compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said dopamine
(receptor) agonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0256] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a dopamine (receptor) agonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said dopamine (receptor) agonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0257] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a dopamine (receptor) agonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said dopamine (receptor) agonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0258] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said dopamine (receptor)
agonist compound is chosen from the group consisting of sumanirole,
SLV 308, sarizotan, S32504, rotigotine (preferably a Once-a-Day
Transdermal Patch), ropinirole HCL (preferably controlled-release
formulation), pramipexole, DAB452, cabergoline, bromocriptine,
alaptide, cabergoline, lisuride, preferably sumanirole, rotigotine
(preferably a Once-a-Day Transdermal Patch), pergolide or
ropinirole HCL (preferably controlled-release formulation), or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof. Preferably, sumanirole is to be
administered in a daily dose of between 4 and 16 mg of the active
ingredient. Preferably, rotigotine (Once-a-Day Transdermal Patch)
is to be administered in a daily dose of between 4.5 and 13.5 mg of
the active ingredient. Preferably, ropinirole HCL
(controlled-release formulation) is to be administered in a daily
dose of between 0.75 and 24 mg of the active ingredient.
Preferably, pergolide is to be administered in a daily dose of
between 0.5 and 10 mg of the active ingredient.
[0259] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a dopamine (receptor) agonist,
preferably chosen from the group consisting of sumanirole, SLV 308,
sarizotan, S32504, rotigotine (preferably a Once-a-Day Transdermal
Patch), ropinirole HCL (preferably controlled-release formulation),
pramipexole, DAB452, cabergoline, bromocriptine, alaptide,
cabergoline, lisuride and pergolide, more preferably sumanirole,
rotigotine (preferably a Once-a-Day Transdermal Patch), ropinirole
HCL (preferably controlled-release formulation) or pergolide, or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders,
adjustment disorders, impulse control disorders, attention-deficit
disorders, substance-related disorders, personality disorders,
problems related to abuse or neglect, pain disorders and Parkinson
disease.
[0260] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
dopamine (receptor) agonist is sumanirole, preferably provided in a
unitary dose of between 4 and 16 mg of the active ingredient.
[0261] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
dopamine (receptor) agonist is rotigotine (Once-a-Day Transdermal
Patch), preferably provided in a unitary dose of between 4.5 and
13.5 mg of the active ingredient.
[0262] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
dopamine (receptor) agonist is ropinirole HCL (controlled-release
formulation), preferably provided in a unitary dose of between 0.75
and 24 mg of the active ingredient.
[0263] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
dopamine (receptor) agonist is pergolide, preferably provided in a
unitary dose of between 0.5 and 10 mg of the active ingredient.
32: Combination Therapy with a Compound Activating ERK
(Extracellular Signal-Related Kinase)
[0264] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
that activates ERK (extracellular signal-related kinase), are
chosen from the group of diseases or disorders consisting of
Alzheimer Disease, substance-induced persisting dementia, vascular
dementia, dementia due to HIV disease, dementia due to head trauma,
dementia due to Parkinson Disease, dementia due to Huntington
Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
[0265] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a compound that activates ERK (extracellular
signal-related kinase) to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said compound
that activates ERK (extracellular signal-related kinase), further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0266] According to a preferred embodiment, the invention relates
to the use as described above, wherein said compound that activates
ERK (extracellular signal-related kinase) is CPI-1189 or a pro-drug
or an active metabolite thereof, or a pharmaceutically acceptable
salt thereof. Preferably, CPI-1189 is to be administered in a daily
dose of between 50 and 100 mg of the active ingredient.
[0267] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound that activates ERK
(extracellular signal-related kinase), preferably CPI-1189 or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of Alzheimer Disease, substance-induced persisting dementia,
vascular dementia, dementia due to HIV disease, dementia due to
head trauma, dementia due to Parkinson Disease, dementia due to
Huntington Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
[0268] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
compound that activates ERK (extracellular signal-related kinase)
is CPI-1189, preferably provided in a unitary dose of between 50
and 100 mg of the active ingredient.
33: Combination Therapy with a GABA (Gamma-Aminobutyric Acid)
Agonist Compound
[0269] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a GABA
(gamma-aminobutyric acid) agonist compound, are chosen from the
group of diseases or disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0270] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a GABA agonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said GABA agonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0271] According to a preferred embodiment, the invention relates
to the use as described above, wherein said GABA agonist compound
is nefiracetam or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof.
[0272] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a GABA agonist, preferably
nefiracetam or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of Alzheimer Disease, substance-induced persisting dementia,
vascular dementia, dementia due to HIV disease, dementia due to
head trauma, dementia due to Parkinson Disease, dementia due to
Huntington Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
34: Combination Therapy with a GABA-A Agonist Compound
[0273] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a GABA-A
(gamma-aminobutyric acid receptor A) agonist compound, are sleep
disorders.
[0274] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of sleep disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a GABA-A agonist compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said GABA-A
agonist compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0275] According to a preferred embodiment, the invention relates
to the use as described above, wherein said GABA-A agonist compound
is gaboxadol or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. Preferably, gaboxadol is
to be administered in a daily dose of between 5 and 20 mg of the
active ingredient.
[0276] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an GABA-A agonist, preferably
gaboxadol or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of sleep disorders.
[0277] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
GABA-A agonist is Gaboxadol, preferably provided in a unitary dose
of between 5 and 20 mg of the active ingredient.
35: Combination Therapy with a GABA-A Modulator Compound
[0278] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a GABA-A
(gamma-aminobutyric acid receptor A) modulator compound, are chosen
from the group of diseases or disorders consisting of anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
personality disorders, bereavement, occupational problem and
problems related to abuse or neglect.
[0279] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of anxiety disorders,
eating disorders, premenstrual syndrome, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, sexual and gender identity disorders, sleep disorders,
adjustment disorders, impulse control disorders, personality
disorders, bereavement, occupational problem and problems related
to abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a GABA-A modulator compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said GABA-A
modulator compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0280] According to a preferred embodiment, the invention relates
to the use as described above, wherein said GABA-A modulator
compound is chosen from the group consisting of zolpidem
(preferably MR sustained-release version), zaleplon (preferably
extended-release formulation), SL 65.1498, SEP174559, pagoclone,
NGD 96-3, indiplon, eszopiclone, CP-730,330 (NGD 96-3) and
ocinaplon, preferably zolpidem (preferably MR sustained-release
version), zaleplon (preferably extended-release formulation),
pagoclone, indiplon or eszopiclone, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Preferably, zolpidem MR sustained-release version is to be
administered in a daily dose of between 10 and 20 mg of the active
ingredient. Preferably, zaleplon extended-release is to be
administered in a daily dose ranging between 2.5 and 20 mg of the
active ingredient. Preferably, pagoclone is to be administered in a
daily dose ranging between 7.5 and 60 mg of the active ingredient.
Preferably, indiplon is to be administered in a daily dose of
between 10 and 20 mg of the active ingredient. Preferably,
eszopiclone is to be administered in a daily dose of between 2 and
3 mg of the active ingredient. Preferably, ocinaplon is to be
administered in a daily dose of between 10 and 60 mg of the active
ingredient.
[0281] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a GABA-A modulator, preferably
chosen from the group consisting of zolpidem (preferably MR
sustained-release version), zaleplon (preferably extended-release
formulation), SL 65.1498, SEP174559, pagoclone, indiplon,
eszopiclone, CP-730,330 (NGD 96-3) and ocinaplon, preferably
zolpidem (preferably MR sustained-release version), zaleplon
(preferably extended-release formulation), pagoclone, NGD 96-3,
indiplon or eszopiclone, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect.
[0282] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
GABA-A modulator is zolpidem MR sustained-release version,
preferably provided in a unitary dose of between 10 and 20 mg of
the active ingredient.
[0283] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
GABA-A modulator is zaleplon extended-release, preferably provided
in a unitary dose of between 2.5 and 20 mg of the active
ingredient.
[0284] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
GABA-A modulator is Pagoclone, preferably provided in a unitary
dose of between 7.5 and 60 mg of the active ingredient.
[0285] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
GABA-A modulator is indiplon, preferably provided in a unitary dose
of between 10 and 20 mg of the active ingredient.
[0286] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
GABA-A modulator is eszopiclone, preferably provided in a unitary
dose of between 2 and 3 mg of the active ingredient.
[0287] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
GABA-A modulator is ocinaplon, preferably provided in a unitary
dose of between 10 and 60 mg of the active ingredient.
36: Combination Therapy with a GABA-B Antagonist Compound
[0288] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a GABA-B
(gamma-aminobutyric acid receptor B) antagonist compound, are
chosen from the group of diseases or disorders consisting of
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, personality disorders, bereavement, occupational problem
and problems related to abuse or neglect.
[0289] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of anxiety disorders,
eating disorders, premenstrual syndrome, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, sexual and gender identity disorders, sleep disorders,
adjustment disorders, impulse control disorders, personality
disorders, bereavement, occupational problem and problems related
to abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a GABA-B antagonist compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said
GABA-B antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0290] According to a preferred embodiment, the invention relates
to the use as described above, wherein said GABA-B antagonist
compound is AVE 7398 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof.
[0291] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a GABA-B antagonist, preferably
AVE 7398 or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, personality disorders, bereavement, occupational problem
and problems related to abuse or neglect.
37: Combination Therapy with a Glial-Cell Line Derived Neurotrophic
Factor Compound
[0292] The mental disorder which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a Glial-cell
Line Derived Neurotrophic Factor compound, is Parkinson
disease.
[0293] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a Glial-cell Line Derived Neurotrophic Factor compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said Glial-cell Line, Derived Neurotrophic
Factor compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0294] According to a preferred embodiment, the invention relates
to the use as described above, wherein said Glial-cell Line Derived
Neurotrophic Factor compound is GDNF or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Preferably, GDNF is to be administered in a daily dose ranging
between 3.75 and 30 mg of the active ingredient.
[0295] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a Glial-cell Line Derived
Neurotrophic Factor, preferably GDNF or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of Parkinson
disease.
[0296] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
Glial-cell Line Derived Neurotrophic Factor is GDNF, preferably
provided in a unitary dose of between 3.75 and 30 mg of the active
ingredient.
38: Combination Therapy with a Glucocorticoid Synthesis Inhibitor
Compound
[0297] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
glucocorticoid synthesis inhibitor compound, are chosen from the
group of diseases or disorders consisting of substance related
disorders and Parkinson disease.
[0298] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of substance related disorders, characterized in that pipamperon or
said pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a glucocorticoid synthesis inhibitor compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said glucocorticoid synthesis inhibitor compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0299] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a glucocorticoid synthesis inhibitor compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said glucocorticoid synthesis inhibitor compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0300] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said glucocorticoid
synthesis inhibitor compound is metyrapone or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0301] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a glucocorticoid synthesis
inhibitor, preferably metyrapone or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of substance related disorders and Parkinson
disease.
39: Combination Therapy with a Glutamate Receptor Antagonist
Compound
[0302] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a glutamate
receptor antagonist compound, are chosen from the group of diseases
or disorders consisting of anxiety disorders, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, adjustment disorders, impulse control disorders,
substance-related disorders, personality disorders, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0303] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of anxiety disorders,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, adjustment disorders, impulse
control disorders, substance-related disorders, personality
disorders, bereavement, occupational problem, and problems related
to abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a glutamate receptor antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said glutamate receptor antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0304] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a glutamate receptor antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said glutamate receptor antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0305] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said glutamate receptor
antagonist compound is LY354740 or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0306] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a glutamate receptor antagonist,
preferably LY354740 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of a mental disease
or disorder which is chosen from the group of diseases or disorders
consisting of anxiety disorders, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
adjustment disorders, impulse control disorders, substance-related
disorders, personality disorders, bereavement, occupational
problem, problems related to abuse or neglect and pain
disorders.
40: Combination Therapy with an GPCR (G-Protein-Coupled Receptor)
Modulator
[0307] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an GPCR
(G-protein-coupled receptor) modulator, are chosen from the group
of diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
substance-related disorders, personality disorders, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0308] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a GPCR modulator
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said GPCR modulator compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0309] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a GPCR modulator compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said GPCR
modulator compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0310] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said GPCR modulator
compound is R1204 or a pro-drug or an active metabolite thereof, or
a pharmaceutically acceptable salt thereof.
[0311] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a GPCR modulator, preferably
R1204 or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases or disorders consisting
of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
41: Combination Therapy with an GR (Glucocorticoid Receptor)
Antagonist
[0312] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an GR
(glucocorticoid receptor) antagonist, are chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
substance-related disorders, personality disorders, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0313] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a GR antagonist
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said GR antagonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0314] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a GR antagonist compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said GR
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0315] According to a preferred embodiment, the invention relates
to the use as described above, wherein said GR antagonist compound
is chosen from the group consisting of ORG 34517/34850 and
mifepristone, preferably mifepristone, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Preferably, mifepristone is to be administered in a daily dose of
between 600 and 1200 mg of the active ingredient.
[0316] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a GR antagonist, preferably
chosen from the group consisting of ORG 34517/34850 and
mifepristone, preferably mifepristone, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders; substance-related disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0317] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said GR
antagonist is Mifepristone, preferably provided in a unitary dose
of between 600 and 1200 mg of the active ingredient.
42: Combination Therapy with a Histamine H3-Receptor Antagonist
[0318] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a histamine
H3-receptor antagonist, are chosen from the group of diseases or
disorders consisting of Alzheimer Disease, substance-induced
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder
and other cognitive disorders.
[0319] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a histamine H3-receptor antagonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said histamine H3-receptor antagonist
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0320] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said histamine H3-receptor
antagonist compound is chosen from the group of compounds
consisting of ABT-834 and ABT-239, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0321] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a histamine H3-receptor
antagonist, preferably chosen from the group consisting of ABT-834
and ABT-239 or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a cognitive mental disease or
disorder which is chosen from the group consisting of Alzheimer
Disease, substance-related persisting dementia, vascular dementia,
dementia due to HIV disease, dementia due to head trauma, dementia
due to Parkinson Disease, dementia due to Huntington Disease,
dementia due to Pick Disease, dementia due to Creutzfeldt-Jacob
Disease, amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
43: Combination Therapy with a Hormonal Substance
[0322] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a hormonal
substance, are chosen from the group of diseases or disorders
consisting of premenstrual syndrome and sexual and gender identity
disorders.
[0323] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of premenstrual syndrome and
sexual and gender identity disorders, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a hormonal substance to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said hormonal substance, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0324] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said hormonal substance is
chosen from the group consisting of a testosterone transdermal
spray, a testosterone gel, a female testosterone patch, synthetic
conjugated estrogen A, methyltestosterone, a
estrogens/methyltestosterone and a drosiperone/ethinyl estradiol
composition, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. More preferably, said
hormonal substance is synthetic conjugated estrogen A and is to be
administered in a daily dose ranging between 0.075 and 0.6 mg of
the active ingredient. More preferably, said hormonal substance is
a drosiperone/ethinyl estradiol composition and is to be
administered as a daily dose in tablets, preferably comprising 3 mg
drosiperone and 0.02 mg ethinyl estradiol of the active
ingredients, respectively.
[0325] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and
(b) a hormonal substance, preferably chosen from the group
consisting of a testosterone transdermal spray, a testosterone gel,
a female testosterone patch, synthetic conjugated estrogen A,
methyltestosterone, a estrogens/methyltestosterone and a
drosiperone/ethinyl estradiol composition, or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
a cognitive mental disease or disorder which is chosen from the
group consisting of premenstrual syndrome and sexual and gender
identity disorders.
[0326] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
hormonal substance is synthetic conjugated estrogen A, preferably
provided in a unitary dose of between 0.075 and 0.6 mg of the
active ingredient.
[0327] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
hormonal substance is a drosiperone/ethinyl estradiol composition,
preferably provided in tablets comprising a unitary dose of 3 mg
drosiperone and 0.02 mg ethinyl estradiol of the active
ingredients, respectively.
44: Combination Therapy with a Compound which Increases Brain
Concentrations of 5-HT
[0328] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
which increases brain concentrations of 5-HT (serotonin), are
chosen from the group of diseases or disorders consisting of mood
disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, substance-related disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0329] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a compound which
increases brain concentrations of 5-HT (serotonin) to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said compound which increases brain concentrations of
5-HT (serotonin), further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0330] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a compound which
increases brain concentrations of 5-HT (serotonin) to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said compound which increases brain concentrations of
5-HT (serotonin), further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0331] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said compound which
increases brain concentrations of 5-HT (serotonin) is chosen from
the group consisting of triptosine, SP 186, PMD 145 and KW 6055, or
a pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof.
[0332] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound which increases brain
concentrations of 5-HT (serotonin), preferably chosen from the
group consisting of triptosine, SP 186, PMD 145 and KW 6055, or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group of diseases and disorders consisting
of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
45: Combination Therapy with a Compound which Increases Insulin
Sensitivity
[0333] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
which increases insulin sensitivity, are chosen from the group of
diseases or disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0334] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a compound which increases insulin sensitivity to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said compound which increases insulin
sensitivity, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0335] According to a preferred embodiment, the invention relates
to the use as described above, wherein said compound which
increases insulin sensitivity is rosiglitazone maleate, or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof.
[0336] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound which increases
insulin sensitivity, preferably rosiglitazone maleate or a pro-drug
or an active metabolite thereof, or a pharmaceutically acceptable
salt thereof, as a combined preparation for simultaneous, separate
or sequential use for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder which is chosen from the
group consisting of Alzheimer Disease, substance-induced persisting
dementia, vascular dementia, dementia due to HIV disease, dementia
due to head trauma, dementia due to Parkinson Disease, dementia due
to Huntington Disease, dementia due to Pick Disease, dementia due
to Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
46: Combination Therapy with a Compound Inhibiting the Mixed
Lineage Kinase Family
[0337] The mental disorder which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
which is an inhibitor of the mixed lineage kinase family is
Parkinson Disease.
[0338] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a compound which is an inhibitor of the mixed lineage kinase
family to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said compound which is an
inhibitor of the mixed lineage kinase family, further characterized
in that pipamperon is to be administered to a patient in a daily
dose ranging between 5 and 15 mg of the active ingredient.
[0339] According to a preferred embodiment, the invention relates
to the use as described above, wherein said compound which is an
inhibitor of the mixed lineage kinase family is CEP-1347 or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof.
[0340] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound which is an inhibitor
of the mixed lineage kinase family, preferably CEP-1347 or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of Parkinson Disease.
47: Combination Therapy with an Interleukin-1 Beta Converting
Enzyme Inhibitor Compound
[0341] The mental disorder which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an
interleukin-1 beta converting enzyme inhibitor compound, is a pain
disorder.
[0342] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a pain disorder, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an interleukin-1 beta converting enzyme inhibitor compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said interleukin-1 beta converting enzyme
inhibitor compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0343] According to a preferred embodiment, the invention relates
to the use as described above, wherein said interleukin-1 beta
converting enzyme inhibitor is pralnacasan or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0344] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an interleukin-1 beta converting
enzyme inhibitor, preferably pralnacasan or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a pain
disorder.
48: Combination Therapy with a Levodopa/Decarboxylase Inhibitor
Compound
[0345] The mental disorder which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
levodopa/decarboxylase inhibitor compound, is Parkinson
Disease.
[0346] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a levodopa/decarboxylase inhibitor compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said levodopa/decarboxylase inhibitor compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0347] According to a preferred embodiment, the invention relates
to the use as described above, wherein said levodopa/decarboxylase
inhibitor compound is chosen from the group consisting of
levodopa/carbidopa, levodopa/benserazide, etilevodopa/carbidopa or
etilevodopa/benserazide, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. Preferably,
levodopa/carbidopa is to be administered in a daily dose between
250 to 600 mg/25 to 150 mg of the active ingredients. Preferably,
levodopa/benserazide is to be administered in a daily dose between
100 to 600 mg/25 to 150 mg of the active ingredients.
[0348] According to a further preferred embodiment, the invention
relates to the use as described above, wherein said
levodopa/decarboxylase inhibitor compound is
(eti)levodopa/carbidopa, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof in
combination with entacapone, which is an inhibitor of
catechol-O-methyltransferase (COMT), or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Preferably, said levodopa/decarboxylase inhibitor compound is
levodopa/carbidopa and is to be administered in a dose ranging
between 2000 mg/50 mg and 100 mg/10 mg of the active ingredients.
Preferably said entacapone is to be administered in a dose ranging
between 1000 mg/50 mg, more preferably between 500 mg/100 mg, and
most preferably 200 mg of the active ingredients per day.
[0349] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a levodopa/decarboxylase
inhibitor compound, preferably levodopa/carbidopa,
levodopa/benserazide, etilevodopa/carbidopa or
etilevodopa/benserazide, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of Parkinson
Disease. The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a levodopa/decarboxylase
inhibitor compound, preferably is (eti)levodopa/carbidopa, or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof in combination with entacapone, which is an
inhibitor of catechol-O-methyltransferase (COMT), or a pro-drug or
an active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
Parkinson Disease.
[0350] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
levodopa/decarboxylase inhibitor compound is levodopa/carbidopa,
preferably provided in a unitary dose of between 250 to 600 mg and
25 to 150 mg of the active ingredients.
[0351] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
levodopa/decarboxylase inhibitor compound is levodopa/benserazide,
preferably provided in a unitary dose of between 100 to 600 mg and
25 to 150 mg of the active ingredients.
[0352] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
levodopa/decarboxylase inhibitor compound is levodopa/carbidopa or
etilevodopa/carbidopa in combination with entacapone, of which the
latter is preferably provided in a unitary dose of between 500 mg
and 100 mg of the active ingredient.
49: Combination Therapy with a Lipid-DNA Complex
[0353] The mental disorder which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a lipid-DNA
complex, is Parkinson Disease.
[0354] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of lipid-DNA complex to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said lipid-DNA
complex, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0355] According to a preferred embodiment, the invention relates
to the use as described above, wherein said lipid-DNA complex is
GR213487B or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof.
[0356] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a lipid-DNA complex, preferably
GR213487B or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of Parkinson Disease.
50: Combination Therapy with a Monoamine Oxidase (MAO) Reuptake
Inhibitor
[0357] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a monoamine
oxidase (MAO) reuptake inhibitor, are chosen from the group of
diseases or disorders consisting of substance related disorders and
attention-deficit disorders (ADHD).
[0358] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of non-cognitive mental disease or disorder which are substance
related disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a monoamine oxidase (MAO) reuptake inhibitor compound to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said monoamine oxidase (MAO) reuptake
inhibitor compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0359] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of attention-deficit disorders (ADHD), characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a monoamine oxidase (MAO) reuptake inhibitor
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said monoamine oxidase (MAO)
reuptake inhibitor compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0360] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said monoamine oxidase
(MAO) reuptake inhibitor compound is NS 2359 or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0361] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a monoamine oxidase (MAO)
reuptake inhibitor, preferably NS 2359 or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group consisting of
substance related disorders and attention-deficit disorders
(ADHD).
51: Combination Therapy with a MAO-A and a MAO-B Reuptake
Inhibitor
[0362] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a monoamine
oxidase A (MAO-A) and a monoamine oxidase B (MAO-B) reuptake
inhibitor, wherein said disorders are attention-deficit
disorders.
[0363] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of attention-deficit disorders, characterized in that pipamperon or
said pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a monoamine oxidase A (MAO-A) and a monoamine oxidase B (MAO-B)
reuptake inhibitor compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said monoamine
oxidase A (MAO-A) and a monoamine oxidase B (MAO-B) reuptake
inhibitor compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0364] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said monoamine oxidase A
(MAO-A) and a monoamine oxidase B (MAO-B) reuptake inhibitor
compound is SPD473 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof.
[0365] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a monoamine oxidase A (MAO-A)
and a monoamine oxidase B (MAO-B) reuptake inhibitor, preferably
SPD473 or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of attention-deficit
disorders.
52: Combination Therapy with a Monoamine Oxidase B (MAO-B)
Inhibitor
[0366] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a monoamine
oxidase B (MAO-B) inhibitor, are chosen from the group of diseases
or disorders consisting of mood disorders, anxiety disorders,
eating disorders, premenstrual syndrome, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, adjustment disorders, impulse control disorders,
attention-deficit disorders, substance-related disorders,
personality disorders, problems related to abuse or neglect, pain
disorder and Parkinson Disease.
[0367] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, adjustment disorders, impulse
control disorders, attention-deficit disorders, substance-related
disorders, personality disorders, problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a monoamine oxidase
B (MAO-B) inhibitor compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said
monoamine oxidase B (MAO-B) inhibitor compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0368] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a monoamine oxidase B (MAO-B) inhibitor compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said monoamine oxidase B (MAO-B) inhibitor compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0369] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a monoamine oxidase B (MAO-B) inhibitor compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said monoamine oxidase B (MAO-B) inhibitor compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0370] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said monoamine oxidase B
(MAO-B) inhibitor compound is chosen from the group consisting of
selegiline, rasagiline (TVP-1012) and EmSam (transdermal
selegiline), or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. More preferably, said
monoamine oxidase B (MAO-B) inhibitor is selegiline and is to be
administered in a daily dose ranging between 5 and 60 mg or
possibly between 5 and 10 mg of the active ingredient. In a further
preferred embodiment, selegiline is to be administered in a
transdermal application in a daily dose ranging between 5 and 60 mg
of the active ingredient. In another preferred embodiment,
selegiline is to be administered orally in a daily dose ranging
between 5 and 10 mg of the active ingredient. More preferably, said
monoamine oxidase B (MAO-B) inhibitor is rasagiline (TVP-1012) and
is to be administered in a daily dose ranging between 1 and 2 mg of
the active ingredient.
[0371] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a monoamine oxidase B (MAO-B)
inhibitor, preferably chosen from the group consisting of
selegiline, rasagiline (TVP-1012) and EmSam (transdermal
selegiline), or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, adjustment disorders, impulse
control disorders, attention-deficit disorders, substance-related
disorders, personality disorders, problems related to abuse or
neglect, pain disorder and Parkinson Disease.
[0372] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
monoamine oxidase B (MAO-B) inhibitor is selegiline, preferably
provided in a unitary dose of between 5 and 10 mg or between 5 and
60 mg of the active ingredient.
[0373] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
monoamine oxidase B (MAO-B) inhibitor is rasagiline (TVP-1012),
preferably provided in a unitary dose of between 1 and 2 mg of the
active ingredient.
53: Combination Therapy with a Monoamine Oxidase B (MAO-B) Reuptake
Inhibitor
[0374] The mental disorder which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a monoamine
oxidase B (MAO-B) reuptake inhibitor, is Parkinson Disease.
[0375] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a monoamine oxidase B (MAO-B) reuptake inhibitor to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said monoamine oxidase B (MAO-B) reuptake inhibitor,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0376] According to a preferred embodiment, the invention relates
to the use as described above, wherein said monoamine oxidase B
(MAO-B) reuptake inhibitor is safinamide or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0377] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a monoamine oxidase B (MAO-B)
reuptake inhibitor, preferably safinamide or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
Parkinson Disease.
54: Combination Therapy with a Melanocortin-4 (MC4) Receptor
Antagonist Compound
[0378] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
melanocortin-4 (MC4) receptor antagonist compound, are chosen from
the group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
[0379] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a melanocortin-4
(MC4) receptor antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said melanocortin-4 (MC4) receptor antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0380] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a melanocortin-4 (MC4) receptor antagonist compound to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said melanocortin-4 (MC4) receptor antagonist
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0381] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said melanocortin-4 (MC4)
receptor antagonist compound is MCL0129, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0382] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a melanocortin-4 (MC4) receptor
antagonist compound, preferably MCL0129 or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group consisting of
mood disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, substance-related disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
55: Combination Therapy with a MCH Receptor Antagonist Compound
[0383] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a melanin
concentrating hormone (MCH) receptor antagonist compound, are
chosen from the group of diseases or disorders consisting of mood
disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, substance-related disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0384] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a melanin
concentrating hormone (MCH) receptor antagonist compound to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said melanin concentrating hormone (MCH)
receptor antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0385] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a melanin concentrating hormone (MCH) receptor antagonist
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said melanin concentrating
hormone (MCH) receptor antagonist compound, further characterized
in that pipamperon is to be administered to a patient in a daily
dose ranging between 5 and 15 mg of the active ingredient.
[0386] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said melanin concentrating
hormone (MCH) receptor antagonist compound is SNAP-7941 or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof.
[0387] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a melanin concentrating hormone
(MCH) receptor antagonist compound, preferably SNAP-7941 or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
56: Combination Therapy with a Melatonin Receptor (MT) Agonist
Compound
[0388] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a melatonin
receptor (MT) agonist compound, are chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
substance-related disorders, personality disorders, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0389] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a melatonin
receptor (MT) agonist compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said
melatonin receptor (MT) agonist compound, further characterized in
that pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0390] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a melatonin receptor (MT) agonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said melatonin receptor (MT) agonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0391] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said melatonin receptor
(MT) agonist compound is chosen from the group consisting of
ramelteon and aglomelatine, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. More
preferably, said melatonin receptor (MT) agonist compound is
aglomelatine and is to be administered in a daily dose ranging
between 25 and 50 mg of the active ingredient.
[0392] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a melatonin receptor (MT)
agonist compound, preferably ramelteon or aglomelatine or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
[0393] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
melatonin receptor (MT) agonist compound is aglomelatine,
preferably provided in a unitary dose of between 25 and 50 mg of
the active ingredient.
57: Combination Therapy with a Metabotropic Glutamate Receptor
(MgluR) Agonist Compound
[0394] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
metabotropic glutamate receptor (MgluR) agonist compound, are
chosen from the group of diseases or disorders consisting of
anxiety disorders, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, adjustment disorders,
impulse control disorders, substance-related disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0395] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of anxiety disorders,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, adjustment disorders, impulse
control disorders, substance-related disorders, personality
disorders, bereavement, occupational problem and problems related
to abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a metabotropic glutamate receptor (MgluR) agonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said metabotropic glutamate receptor (MgluR)
agonist compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0396] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a metabotropic glutamate receptor (MgluR) agonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said metabotropic glutamate receptor (MgluR)
agonist compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0397] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said metabotropic glutamate
receptor (MgluR) agonist compound is PRE703 or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0398] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a metabotropic glutamate
receptor (MgluR) agonist, preferably PRE703 or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
a mental disease or disorder which is chosen from the group
consisting of anxiety disorders, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
adjustment disorders, impulse control disorders, substance-related
disorders, personality disorders, bereavement, occupational
problem, problems related to abuse or neglect and pain
disorders.
58: Combination Therapy with a Compound Mimicking the Effect of
Nerve Growth Factor (NGF)
[0399] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
which mimics the effect of nerve growth factor (NGF), are chosen
from the group of diseases or disorders consisting of Alzheimer
Disease, substance-induced persisting dementia, vascular dementia,
dementia due to HIV disease, dementia due to head trauma, dementia
due to Parkinson Disease, dementia due to Huntington Disease,
dementia due to Pick Disease, dementia due to Creutzfeldt-Jacob
Disease, amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder, other cognitive disorders and Parkinson
Disease.
[0400] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a compound which mimics the effect of nerve
growth factor (NGF) to augment the therapeutic effect or to provide
a faster onset of the therapeutic effect of said compound which
mimics the effect of nerve growth factor (NGF), further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0401] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a compound which mimics the effect of nerve growth factor (NGF)
to augment the therapeutic effect or to provide a faster onset of
the therapeutic effect of said compound which mimics the effect of
nerve growth factor (NGF), further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0402] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said compound which mimics
the effect of nerve growth factor (NGF) is xaliproden or a pro-drug
or an active metabolite thereof, or a pharmaceutically acceptable
salt thereof. More preferably, said compound which mimics the
effect of nerve growth factor (NGF) is xaliproden and is to be
administered in a daily dose ranging between 1 and 2 mg of the
active ingredient.
[0403] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound which mimics the
effect of nerve growth factor (NGF), preferably xaliproden or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder, other cognitive disorders and Parkinson
Disease.
[0404] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
compound which mimics the effect of nerve growth factor (NGF) is
xaliproden, preferably provided in a unitary dose of between 1 and
2 mg of the active ingredient.
59: Combination Therapy with a Muscarinic Receptor Partial Agonist
Compound
[0405] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a muscarinic
receptor partial agonist compound, are chosen from the group of
diseases or disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0406] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a muscarinic receptor partial agonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said muscarinic receptor partial agonist
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0407] According to a preferred embodiment, the invention relates
to the use as described above, wherein said muscarinic receptor
partial agonist compound is sevimeline or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0408] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a muscarinic receptor partial
agonist compound, preferably sevimeline or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group consisting of
Alzheimer Disease, substance-induced persisting dementia, vascular
dementia, dementia due to HIV disease, dementia due to head trauma,
dementia due to Parkinson Disease, dementia due to Huntington
Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
60: Combination Therapy with a Selective Nor-Adrenaline Re-Uptake
Inhibitor (NARI) Compound
[0409] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a selective
nor-adrenaline re-uptake inhibitor (NARI) compound, are chosen from
the group of diseases or disorders consisting of mood disorders,
anxiety disorders, adjustment disorders, attention-deficit
disorders, personality disorders, antisocial behaviour,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
[0410] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, adjustment disorders, attention-deficit
disorders, personality disorders, antisocial behaviour,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a selective
nor-adrenaline re-uptake inhibitor (NARI) compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said selective nor-adrenaline re-uptake inhibitor (NARI)
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0411] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a selective nor-adrenaline re-uptake inhibitor (NARI) compound
to augment the therapeutic effect or to provide a faster onset of
the therapeutic effect of said selective nor-adrenaline re-uptake
inhibitor (NARI) compound, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0412] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said selective
nor-adrenaline re-uptake inhibitor (NARI) compound is chosen from
the group consisting of reboxetine, atomoxetine hydrochloride, A
75200, 155U88, (S)-A 75200, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. More
preferably, said selective nor-adrenaline re-uptake inhibitor
(NARI) compound is reboxetine and is to be administered in a daily
dose ranging between 8 and 12 mg of the active ingredient. More
preferably, said selective nor-adrenaline re-uptake inhibitor
(NARI) compound is atomoxetine hydrochloride and is to be
administered in a daily dose ranging between 40 and 100 mg of the
active ingredient.
[0413] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a selective nor-adrenaline
re-uptake inhibitor (NARI) compound, preferably chosen from the
group consisting of reboxetine, atomoxetine hydrochloride, A 75200,
155U88, (S)-A 75200, or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of mental disease or
disorder which is chosen from the group consisting of mood
disorders, anxiety disorders, adjustment disorders,
attention-deficit disorders, personality disorders, antisocial
behaviour, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0414] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
selective nor-adrenaline re-uptake inhibitor (NARI) compound is
reboxetine, preferably provided in a unitary dose of between 8 and
12 mg of the active ingredient.
[0415] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
selective nor-adrenaline re-uptake inhibitor (NARI) compound is
atomoxetine hydrochloride, preferably provided in a unitary dose of
between 40 and 100 mg of the active ingredient.
61: Combination Therapy with a NaSSA Compound
[0416] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
noradrenergic/specific serotonergic antidepressant (NaSSA)
compound, are chosen from the group of diseases or disorders
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, personality disorders,
antisocial behaviour, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0417] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, personality disorders, antisocial behaviour,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a
noradrenergic/specific serotonergic antidepressant (NaSSA) compound
to augment the therapeutic effect or to provide a faster onset of
the therapeutic effect of said noradrenergic/specific serotonergic
antidepressant (NaSSA) compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0418] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a noradrenergic/specific serotonergic antidepressant (NaSSA)
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said noradrenergic/specific
serotonergic antidepressant (NaSSA) compound, further characterized
in that pipamperon is to be administered to a patient in a daily
dose ranging between 5 and 15 mg of the active ingredient.
[0419] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said noradrenergic/specific
serotonergic antidepressant (NaSSA) compound is ORG 4420 or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof.
[0420] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a noradrenergic/specific
serotonergic antidepressant (NaSSA) compound, preferably ORG 4420
or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of mental disease or disorder
which is chosen from the group consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, personality disorders, antisocial behaviour,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
62: Combination Therapy with a Selective NDRI Compound
[0421] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a selective
nor-adrenaline and dopamine re-uptake inhibitor (NDRI) compound,
are chosen from the group of diseases or disorders consisting of
mood disorders, anxiety disorders, adjustment disorders,
attention-deficit disorders, personality disorders, antisocial
behaviour, bereavement, occupational problem, problems related to
abuse or neglect, pain disorders, delirium, Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0422] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, adjustment disorders, attention-deficit
disorders, personality disorders, antisocial behaviour,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a selective
nor-adrenaline and dopamine re-uptake inhibitor (NDRI) compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said selective nor-adrenaline and dopamine
re-uptake inhibitor (NDRI) compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0423] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a selective nor-adrenaline and dopamine re-uptake inhibitor
(NDRI) compound to augment the therapeutic effect or to provide a
faster onset of the therapeutic effect of said selective
nor-adrenaline and dopamine re-uptake inhibitor (NDRI) compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0424] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of delirium, Alzheimer
Disease, substance-induced persisting dementia, vascular dementia,
dementia due to HIV disease, dementia due to head trauma, dementia
due to Parkinson Disease, dementia due to Huntington Disease,
dementia due to Pick Disease, dementia due to Creutzfeldt-Jacob
Disease, amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a selective nor-adrenaline and dopamine re-uptake
inhibitor (NDRI) compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said selective
nor-adrenaline and dopamine re-uptake inhibitor (NDRI) compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0425] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said selective
nor-adrenaline and dopamine re-uptake inhibitor (NDRI) compound is
GW353162 or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. More preferably, said
selective nor-adrenaline and dopamine re-uptake inhibitor (NDRI)
compound is GW353162 and is to be administered in a daily dose
ranging between 20 and 60 mg of the active ingredient.
[0426] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a selective nor-adrenaline and
dopamine re-uptake inhibitor (NDRI) compound, preferably GW353162
or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of mental disease or disorder
which is chosen from the group consisting of mood disorders,
anxiety disorders, adjustment disorders, attention-deficit
disorders, personality disorders, antisocial behaviour,
bereavement, occupational problem, problems related to abuse or
neglect, pain disorders, delirium, Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0427] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
selective nor-adrenaline and dopamine re-uptake inhibitor (NDRI)
compound is GW353162, preferably provided in a unitary dose of
between 20 and 60 mg of the active ingredient.
63: Combination Therapy with a Compound which is a
Neuroimmunophilin Ligand
[0428] The mental disorder which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
which is a neuroimmunophilin ligand, is Parkinson Disease.
[0429] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a compound which is a neuroimmunophilin ligand to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said compound which is a neuroimmunophilin ligand,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0430] According to a preferred embodiment, the invention relates
to the use as described above, wherein said a compound which is a
neuroimmunophilin ligand is GPI 1485 or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
More preferably, said a compound which is a neuroimmunophilin
ligand is GPI 1485 and is to be administered in a daily dose
ranging between 200 and 1000 mg of the active ingredient.
[0431] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound which is a
neuroimmunophilin ligand, preferably GPI 1485 or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
Parkinson Disease.
[0432] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said a
compound which is a neuroimmunophilin ligand is GPI 1485,
preferably provided in a unitary dose of between 200 and 1000 mg of
the active ingredient.
64: Combination Therapy with a Neuromodulator Compound
[0433] The mental disorder which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
neuromodulator compound, is Parkinson Disease.
[0434] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a neuromodulator compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said
neuromodulator compound, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0435] According to a preferred embodiment, the invention relates
to the use as described above, wherein said neuromodulator compound
is adenosine or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof.
[0436] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a neuromodulator compound,
preferably adenosine or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of Parkinson
Disease.
65: Combination Therapy with a Neurotensin Receptor Antagonist
Compound
[0437] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
neurotensin receptor antagonist compound, are chosen from the group
of diseases or disorders consisting of mood disorders, anxiety
disorders, psychotic disorders, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sleep disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem,
problems related to abuse or neglect, pain disorders and
delirium.
[0438] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, psychotic disorders, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, sleep disorders, adjustment disorders, impulse control
disorders, pervasive development disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
psychological factors affecting medical conditions, malingering,
antisocial behaviour, bereavement, occupational problem, identity
problem and problems related to abuse or neglect, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a neurotensin receptor antagonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said neurotensin receptor antagonist
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0439] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a neurotensin receptor antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said neurotensin receptor antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0440] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder which is delirium,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a neurotensin
receptor antagonist compound to augment the therapeutic effect or
to provide a faster onset of the therapeutic effect of said
neurotensin receptor antagonist compound, further characterized in
that pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0441] According to a preferred embodiment, the invention relates
to the use as described above, wherein said neurotensin receptor
antagonist compound is SR 48692 or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
More preferably, said neurotensin receptor antagonist compound is
SR 48692 and is to be administered in a daily dose ranging between
90 and 300 mg of the active ingredient.
[0442] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a neurotensin receptor
antagonist compound, preferably SR 48692 or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group consisting mood
disorders, anxiety disorders, psychotic disorders, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sleep disorders, adjustment disorders,
impulse control disorders, pervasive development disorders,
disruptive behaviour disorders, substance-related disorders,
personality disorders, psychological factors affecting medical
conditions, malingering, antisocial behaviour, bereavement,
occupational problem, identity problem, problems related to abuse
or neglect, pain disorders and delirium.
[0443] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
neurotensin receptor antagonist compound is SR 48692, preferably
provided in a unitary dose of between 90 and 300 mg of the active
ingredient.
66: Combination Therapy with Nerve Growth Factor (NGF) Gene
Therapy
[0444] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with nerve growth
factor (NGF) gene therapy, are chosen from the group of diseases or
disorders consisting of Alzheimer Disease, substance-induced
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder,
other cognitive disorders and Parkinson Disease.
[0445] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from nerve growth factor
(NGF) gene therapy, to augment the therapeutic effect or to provide
a faster onset of the therapeutic effect of said nerve growth
factor (NGF) gene therapy, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0446] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to nerve growth factor
(NGF) gene therapy, to augment the therapeutic effect or to provide
a faster onset of nerve growth factor (NGF) gene therapy, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0447] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound useful in nerve
growth factor (NGF) gene therapy, preferably xaliproden or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder, other cognitive disorders and Parkinson
Disease.
[0448] It should be understood that "nerve growth factor gene
therapy" is well known in the art, and the compounds, for instance
nucleic acids used in nerve growth factor gene therapy are well
described (see e.g. Tuszynski et al., (2002) Journal of Molecular
Neuroscience Volume 19, Issue 1-2, pps. 207-208).
67: Combination Therapy with a Nicotinic Acetylcholine Receptor
Antagonist Compound
[0449] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a nicotinic
acetylcholine receptor antagonist compound, are chosen from the
group of diseases or disorders consisting of anxiety disorders,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, adjustment disorders, impulse
control disorders, substance-related disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
[0450] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of anxiety disorders,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, adjustment disorders, impulse
control disorders, substance-related disorders, personality
disorders, bereavement, occupational problem and problems related
to abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a nicotinic acetylcholine receptor antagonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said nicotinic acetylcholine receptor
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0451] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a nicotinic acetylcholine receptor antagonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said nicotinic acetylcholine receptor
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0452] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said nicotinic
acetylcholine receptor antagonist compound is SEP174559 or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof.
[0453] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a nicotinic acetylcholine
receptor antagonist compound, preferably SEP174559 or a pro-drug or
an active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
a mental disease or disorder which is chosen from the group
consisting of anxiety disorders, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
adjustment disorders, impulse control disorders, substance-related
disorders, personality disorders, bereavement, occupational
problem, problems related to abuse or neglect and pain
disorders.
68: Combination Therapy with a Nicotinic Receptor Agonist
Compound
[0454] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a nicotinic
receptor agonist compound, are chosen from the group of diseases or
disorders consisting of Alzheimer Disease, substance-induced
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder
and other cognitive disorders.
[0455] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a nicotinic receptor agonist compound to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said nicotinic receptor agonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0456] According to a preferred embodiment, the invention relates
to the use as described above, wherein said nicotinic receptor
agonist compound is ABT-089, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. More
preferably, said nicotinic receptor agonist compound is ABT-089 and
is to be administered in a daily dose ranging between 4 and 40 mg
of the active ingredient.
[0457] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a nicotinic receptor agonist
compound, preferably ABT-089 or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a cognitive
mental disease or disorder which is chosen from the group
consisting of Alzheimer Disease, substance-induced persisting
dementia, vascular dementia, dementia due to HIV disease, dementia
due to head trauma, dementia due to Parkinson Disease, dementia due
to Huntington Disease, dementia due to Pick Disease, dementia due
to Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
[0458] The invention also relates to a pharmaceutical composition
as described above, wherein pipamperon is provided in a unitary
dose of between 5 and 15 mg of the active ingredient and wherein
said nicotinic receptor agonist compound is ABT-089, preferably
provided in a unitary dose of between 4 and 40 mg of the active
ingredient.
69: Combination Therapy with a Neurokinin 2 Receptor (NK2)
Antagonist Compound
[0459] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a neurokinin
2 receptor (NK2) antagonist compound, are chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
substance-related disorders, personality disorders, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0460] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a neurokinin 2
receptor (NK2) antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said neurokinin 2 receptor (NK2) antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0461] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a neurokinin 2 receptor (NK2) antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said neurokinin 2 receptor (NK2) antagonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0462] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said neurokinin 2 receptor
(NK2) antagonist compound is saredutant or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
More preferably, said neurokinin 2 receptor (NK2) antagonist
compound is saredutant and is to be administered in a daily dose
ranging between 25 and 200 mg of the active ingredient.
[0463] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a neurokinin 2 receptor (NK2)
antagonist compound, preferably saredutant or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
a mental disease or disorder which is chosen from the group
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0464] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
neurokinin 2 receptor (NK2) antagonist compound is saredutant,
preferably provided in a unitary dose of between 25 and 200 mg of
the active ingredient.
70: Combination Therapy with a Neurokinin 3 Receptor (NK3)
Antagonist Compound
[0465] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a neurokinin
3 receptor (NK3) antagonist compound, are chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, psychotic disorders, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sleep disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem,
problems related to abuse or neglect, pain disorders and
delirium.
[0466] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, psychotic disorders, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, sleep disorders, adjustment disorders, impulse control
disorders, pervasive development disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
psychological factors affecting medical conditions, malingering,
antisocial behaviour, bereavement, occupational problem, identity
problem and problems related to abuse or neglect, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a neurokinin 3 receptor (NK3) antagonist compound
to augment the therapeutic effect or to provide a faster onset of
the therapeutic effect of said neurokinin 3 receptor (NK3)
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0467] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a neurokinin 3 receptor (NK3) antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said neurokinin 3 receptor (NK3) antagonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0468] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder which is delirium,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a neurokinin 3
receptor (NK3) antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said neurokinin 3 receptor (NK3) antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0469] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said neurokinin 3 receptor
(NK3) antagonist compound is talnetant or osanetant, or a pro-drug
or an active metabolite thereof, or a pharmaceutically acceptable
salt thereof. More preferably, said neurokinin 3 receptor (NK3)
antagonist compound is talnetant and is to be administered in a
daily dose ranging between 1.5 and 12 mg of the active
ingredient.
[0470] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a neurokinin 3 receptor (NK3)
antagonist compound, preferably talnetant or osanetant, or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group consisting mood disorders, anxiety
disorders, psychotic disorders, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sleep disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem,
problems related to abuse or neglect, pain disorders and
delirium.
[0471] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
neurokinin 3 receptor (NK3) antagonist compound is talnetant,
preferably provided in a unitary dose of between 1.5 and 12 mg of
the active ingredient.
71: Combination Therapy with an N-Methyl-D-aspartate (NMDA)
Antagonist Compound
[0472] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an
N-Methyl-D-aspartate (NMDA) antagonist compound, are chosen from
the group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, adjustment disorders, impulse control disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect, pain disorders, Alzheimer Disease,
substance-related persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0473] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, adjustment disorders, impulse control disorders,
personality disorders, bereavement, occupational problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of an N-Methyl-D-aspartate (NMDA) antagonist
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said N-Methyl-D-aspartate (NMDA)
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0474] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of an N-Methyl-D-aspartate (NMDA) antagonist compound to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said N-Methyl-D-aspartate (NMDA) antagonist
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0475] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-related persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of an N-Methyl-D-aspartate (NMDA) antagonist
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said N-Methyl-D-aspartate (NMDA)
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0476] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said N-Methyl-D-aspartate
(NMDA) antagonist compound is chosen from the group consisting of
SEP174559, memantine, delucemine, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
More preferably, said N-Methyl-D-aspartate (NMDA) antagonist
compound is memantine and is to be administered in a daily dose
ranging between 5 and 40 mg of the active ingredient.
[0477] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an N-Methyl-D-aspartate (NMDA)
antagonist compound, preferably chosen from the group consisting of
SEP174559, memantine, delucemine or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of mental
disease or disorder which is chosen from the group consisting of
mood disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, adjustment disorders, impulse control
disorders, personality disorders, bereavement, occupational
problem, problems related to abuse or neglect, pain disorders,
Alzheimer Disease, substance-related persisting dementia, vascular
dementia, dementia due to HIV disease, dementia due to head trauma,
dementia due to Parkinson Disease, dementia due to Huntington
Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
[0478] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
N-Methyl-D-aspartate (NMDA) antagonist compound is memantine,
preferably provided in a unitary dose of between 5 and 40 mg of the
active ingredient.
72: Combination Therapy with a Non-Steroidal Anti-Inflammatory
Drug
[0479] The mental disorder which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
non-steroidal anti-inflammatory drug, is a pain disorder or
Alzheimer Disease.
[0480] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a pain disorder, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a non-steroidal anti-inflammatory drug to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said a non-steroidal anti-inflammatory drug, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0481] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive disease, such as Alzheimer Disease, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a non-steroidal anti-inflammatory drug to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said a non-steroidal anti-inflammatory drug,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0482] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said a non-steroidal
anti-inflammatory drug is chosen from the group consisting of
piroxicam, MX-1094, meloxicam and flurizan (pure R-enantiomer form
of flurbiprofen), or a pro-drug or an active metabolite thereof, or
a pharmaceutically acceptable salt thereof.
[0483] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a non-steroidal
anti-inflammatory drug, preferably chosen from the group consisting
of piroxicam, MX-1094, meloxicam and flurizan (pure R-enantiomer
form of flurbiprofen), or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a pain
disorder or Alzheimer Disease.
73: Combination Therapy with an Opoid Receptor Antagonist
Compound
[0484] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an opoid
receptor antagonist compound, are substance related disorders.
[0485] It will be appreciated that the terms "opoid" and "opioid"
may be used interchangeably.
[0486] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of substance related disorders, characterized in that pipamperon or
said pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a opoid receptor antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said opoid receptor antagonist compound, further characterized in
that pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0487] According to a preferred embodiment, the invention relates
to the use as described above, wherein said opoid receptor
antagonist compound is naltrexone, preferably as a depot
formulation, more preferably in the form of microcapsules, or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof. Preferably, said naltrexone is to be
administered in the form of a depot, preferably a depot of
microcapsules comprising a daily dose of between 192 and 384
mg.
[0488] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an opoid receptor antagonist,
preferably naltrexone, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of substance
related disorders.
[0489] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
opoid receptor antagonist compound is naltrexone, preferably
provided in a unitary dose of between 192 and 384 mg of the active
ingredient.
74: Combination Therapy with an Opoid Agonist Compound
[0490] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with an opoid
agonist compound, are chosen from the group of diseases or
disorders consisting of anxiety disorders, psychotic disorders,
eating disorders, premenstrual syndrome, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, sexual and gender identity disorders, sleep disorders,
adjustment disorders, impulse control disorders, substance-related
disorders, personality disorders, bereavement, occupational problem
and problems related to abuse or neglect.
[0491] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of anxiety disorders,
psychotic disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of an opoid agonist
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said opoid agonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0492] According to a preferred embodiment, the invention relates
to the use as described above, wherein said opoid agonist compound
is chosen from the group consisting of siramesine, E-5842 and
cyclazocine, preferably siramesine, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0493] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) an opoid agonist compound,
preferably chosen from the group consisting of siramesine, E-5842
and cyclazocine, preferably siramesine, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of a
non-cognitive mental disease or disorder which is chosen from the
group consisting of anxiety disorders, psychotic disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, bereavement, occupational problem and
problems related to abuse or neglect.
75: Combination Therapy with a Phosphodiesterase-4 (PDE4) Inhibitor
Compound
[0494] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
phosphodiesterase-4 (PDE4) inhibitor compound, are chosen from the
group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, adjustment disorders, impulse control disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect, pain disorders, Alzheimer Disease,
substance-related persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0495] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, adjustment disorders, impulse control disorders,
personality disorders, bereavement, occupational problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of phosphodiesterase-4 (PDE4) inhibitor compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said phosphodiesterase-4 (PDE4) inhibitor
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0496] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a phosphodiesterase-4 (PDE4) inhibitor compound d to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said phosphodiesterase-4 (PDE4) inhibitor compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0497] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-related persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a phosphodiesterase-4 (PDE4) inhibitor compound
to augment the therapeutic effect or to provide a faster onset of
the therapeutic effect of said phosphodiesterase-4 (PDE4) inhibitor
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0498] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said phosphodiesterase-4
(PDE4) inhibitor compound is chosen from the group consisting of
ND1251 and MEM 1917 (R1497), or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof.
[0499] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a phosphodiesterase-4 (PDE4)
inhibitor antagonist compound, preferably chosen from the group
consisting of ND1251 and MEM 1917 (R1497), or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
mental disease or disorder which is chosen from the group
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, adjustment disorders, impulse
control disorders, personality disorders, bereavement, occupational
problem, problems related to abuse or neglect, pain disorders,
Alzheimer Disease, substance-related persisting dementia, vascular
dementia, dementia due to HIV disease, dementia due to head trauma,
dementia due to Parkinson Disease, dementia due to Huntington
Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
76: Combination Therapy with a Peptidic Compound
[0500] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a peptidic
compound, are chosen from the group of diseases or disorders
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, disruptive behaviour disorders, substance related
disorders, personality disorders, bereavement, occupational
problem, problems related to abuse or neglect, pain disorders,
Alzheimer Disease, substance-induced persisting dementia, vascular
dementia, dementia due to HIV disease, dementia due to head trauma,
dementia due to Parkinson Disease, dementia due to Huntington
Disease, dementia due to Pick Disease, dementia due to
Creutzfeldt-Jacob Disease, amnestic disorders due to a general
medical condition, substance-induced persisting amnestic disorder,
mild cognitive impairment disorder and other cognitive
disorders.
[0501] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, pervasive development disorders, disruptive behaviour
disorders, substance related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a peptidic compound
to augment the therapeutic effect or to provide a faster onset of
the therapeutic effect of said peptidic compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0502] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a peptidic compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said peptidic
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0503] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a peptidic compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said peptidic compound, further characterized in that pipamperon is
to be administered to a patient in a daily dose ranging between 5
and 15 mg of the active ingredient.
[0504] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said peptidic compound is
chosen from the group consisting of secretin, PT-141, INN 00835 and
beta sheet breaker peptide, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. More
preferably, said peptidic compound is secretin and is to be
administered in a daily dose ranging between 0.2 and 0.4 mg/kg of
the active ingredient. More preferably, said peptidic compound is
INN 00835 and is to be administered in a daily dose ranging between
18 and 160 mg of the active ingredient.
[0505] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a peptidic compound, preferably
chosen from the group consisting of secretin, PT-141, INN 00835 and
beta sheet breaker peptide, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of mental disease
or disorder which is chosen from the group consisting of mood
disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, pervasive development disorders, disruptive
behaviour disorders, substance related disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect, pain disorders, Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0506] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
peptidic compound is secretin, preferably provided in a unitary
dose of 0.2 and 0.4 mg/kg of the active ingredient.
[0507] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
peptidic compound is INN 00835, preferably provided in a unitary
dose of 18 and 160 mg of the active ingredient.
77: Combination Therapy with a Phospholipase A2 Inhibitor
Compound
[0508] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
phospholipase A2 inhibitor compound which has caspase inhibitor
activity, are chosen from the group of diseases or disorders
consisting of mood disorders, anxiety disorders, psychotic
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, bereavement,
occupational problem, problems related to abuse or neglect, pain
disorders and delirium.
[0509] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, psychotic disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, disruptive behaviour disorders, substance-related
disorders, personality disorders, bereavement, occupational problem
and problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a phospholipase A2 inhibitor compound which has
caspase inhibitor activity to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said
phospholipase A2 inhibitor compound which has caspase inhibitor
activity, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0510] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a phospholipase A2 inhibitor compound which has caspase
inhibitor activity to augment the therapeutic effect or to provide
a faster onset of the therapeutic effect of said phospholipase A2
inhibitor compound which has caspase inhibitor activity, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0511] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder which is delirium,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a phospholipase A2
inhibitor compound which has caspase inhibitor activity to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said phospholipase A2 inhibitor compound
which has caspase inhibitor activity, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0512] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said phospholipase A2
inhibitor compound which has caspase inhibitor activity is chosen
from the group consisting of LAX-101a, LAX-101b and LAX-101c,
preferably LAX-101c, or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof.
[0513] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a phospholipase A2 inhibitor
compound which has caspase inhibitor activity, preferably chosen
from the group consisting of LAX-101a, LAX-101b and LAX-101c, more
preferably LAX-101c, or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of a mental disease
or disorder which is chosen from the group consisting mood
disorders, anxiety disorders, psychotic disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, disruptive behaviour disorders, substance-related
disorders, personality disorders, bereavement, occupational
problem, problems related to abuse or neglect, pain disorders and
delirium.
78: Combination Therapy with a Compound which is a Prodrug of
Uridine
[0514] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
which is a prodrug of uridine, are chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0515] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, personality disorders, bereavement, occupational problem
and problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a compound which is a prodrug of uridine to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said compound which is a prodrug of uridine,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0516] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a compound which is a prodrug of uridine to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said compound which is a prodrug of uridine, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0517] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said compound which is a
prodrug of uridine is RG2133 (triacetyluridine) or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0518] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound which is a prodrug of
uridine, preferably RG2133 (triacetyluridine) or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
a mental disease or disorder which is chosen from the group
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
79: Combination Therapy with Prostaglandin E1 Compound
[0519] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with
prostaglandin E1 compound, are sexual and gender identity
disorders.
[0520] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of sexual and gender identity disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a prostaglandin E1 compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said prostaglandin E1 compound, further characterized in
that pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0521] According to a preferred embodiment, the invention relates
to the use as described above, wherein said prostaglandin E1 is
alprostadil or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. More preferably, said
prostaglandin E1 compound is alprostadil, preferably in the form of
cream or gel, preferably a topical gel, and is to be administered
in a daily dose ranging between 50 and 300 microgram per
application of the active ingredient.
[0522] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a prostaglandin E1 compound,
preferably alprostadil or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of sexual and
gender identity disorders.
[0523] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
prostaglandin E1 compound is alprostadil, preferably provided in
the form of a cream or gel, preferably a topical gel, wherein a
unitary dose comprises between 50 and 300 microgram of the active
ingredient per application.
80: Combination Therapy with a Compound Protecting Dopaminergic and
Cholinergic Neurons
[0524] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
which protects dopaminergic and cholinergic neurons, are chosen
from the group of diseases or disorders consisting of Alzheimer
Disease, substance-induced persisting dementia, vascular dementia,
dementia due to HIV disease, dementia due to head trauma, dementia
due to Parkinson Disease, dementia due to Huntington Disease,
dementia due to Pick Disease, dementia due to Creutzfeldt-Jacob
Disease, amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder, other cognitive disorders and Parkinson
Disease.
[0525] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a compound which protects dopaminergic and
cholinergic neurons to augment the therapeutic effect or to provide
a faster onset of the therapeutic effect of said compound which
protects dopaminergic and cholinergic neurons, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0526] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a compound which protects dopaminergic and cholinergic neurons
to augment the therapeutic effect or to provide a faster onset of
the therapeutic effect of said compound which protects dopaminergic
and cholinergic neurons, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0527] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said compound which
protects dopaminergic and cholinergic neurons is SR 57667 or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof.
[0528] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound which protects
dopaminergic and cholinergic neurons, preferably SR 57667 or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group consisting of Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder, other cognitive disorders and Parkinson
Disease.
81: Combination Therapy with a Psycho Stimulant
[0529] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a psycho
stimulant, are chosen from the group of diseases or disorders
consisting of sleep disorders, attention-deficit disorders and
substance-related disorders.
[0530] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of sleep disorders,
attention-deficit disorders and substance-related disorders,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a psycho stimulant
to augment the therapeutic effect or to provide a faster onset of
the therapeutic effect of said psycho stimulant, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0531] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said psycho stimulant is
chosen from the group consisting of SPD 503, r-modafinil and
modafinil, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. More preferably, said
psycho stimulant is SPE 503, more preferably said psycho stimulant
is modafinil and is to be administered in a daily dose ranging
between 200 and 600 mg of the active ingredient.
[0532] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a psycho stimulant, preferably
chosen from the group consisting of SPD 503, r-modafinil and
modafinil, more preferably said SPC 503 or modafinil or a pro-drug
or an active metabolite thereof, or a pharmaceutically acceptable
salt thereof, as a combined preparation for simultaneous, separate
or sequential use for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder which is chosen from
the group consisting of sleep disorders, attention-deficit
disorders and substance-related disorders.
[0533] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
psycho stimulant is modafinil, preferably provided in a unitary
dose of between 200 and 600 mg of the active ingredient.
82: Combination Therapy with a Compound which is a Reversible
Inhibitor of Mono-Amine Oxydase A (RIMA)
[0534] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
which is a reversible inhibitor of mono-amine oxydase A (RIMA), are
chosen from the group of diseases or disorders consisting of mood
disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, adjustment disorders, impulse control
disorders, personality disorders, antisocial behaviour,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
[0535] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders; dissociative disorders, sexual and gender identity
disorders, adjustment disorders, impulse control disorders,
personality disorders, antisocial behaviour, bereavement,
occupational problem and problems related to abuse or neglect,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a compound which is
a reversible inhibitor of mono-amine oxydase A (RIMA) to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said compound which is a reversible inhibitor
of mono-amine oxydase A (RIMA), further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0536] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a compound which is a reversible inhibitor of mono-amine oxydase
A (RIMA) to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said compound which is a
reversible inhibitor of mono-amine oxydase A (RIMA), further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0537] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said compound which is a
reversible inhibitor of mono-amine oxydase A (RIMA) is chosen from
the group consisting of toloxatone, RS 8359, moclobemide,
cimoxatone, caroxazone (F.I 6654) and befloxatone, or a pro-drug or
an active metabolite thereof, or a pharmaceutically acceptable salt
thereof. More preferably, said compound which is a reversible
inhibitor of mono-amine oxydase A (RIMA) is befloxatone and is to
be administered in a daily dose ranging between 2.5 and 20 mg of
the active ingredient.
[0538] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound which is a reversible
inhibitor of mono-amine oxydase A (RIMA), preferably chosen from
the group consisting of toloxatone, RS 8359, moclobemide,
cimoxatone, caroxazone (F.I 6654) and befloxatone, or a pro-drug or
an active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
mental disease or disorder which is chosen from the group
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, adjustment disorders, impulse
control disorders, personality disorders, antisocial behaviour,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
[0539] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
compound which is a reversible inhibitor of mono-amine oxydase A
(RIMA) is befloxatone, preferably provided in a unitary dose of
between 2.5 and 20 mg of the active ingredient.
83: Combination Therapy with a Compound which Modulates SCT-11
[0540] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
which modulates SCT-11 (i.e. SCT-11 is a G protein-coupled
receptor), are chosen from the group of diseases or disorders
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
[0541] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders adjustment disorders, impulse control
disorders, personality disorders, bereavement, occupational problem
and problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a compound which modulates SCT-11 to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said compound which modulates SCT-11, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0542] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a compound which modulates SCT-11 to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said compound which modulates SCT-11, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0543] According to a preferred embodiment, the invention relates
to the use as described above, wherein said compound which
modulates SCT-11 is SNEC-2 or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof.
[0544] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound which modulates
SCT-11, preferably SNE-2 or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group consisting of
mood disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, personality disorders, bereavement, occupational
problem, problems related to abuse or neglect and pain
disorders.
84: Combination Therapy with a Serotonin/Dopamine Antagonist
Compound (SDA)
[0545] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
serotonin/dopamine antagonist compound (SDA), are chosen from the
group of diseases or disorders consisting of mood disorders,
anxiety disorders, psychotic disorders, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, sleep disorders, adjustment disorders, impulse control
disorders, pervasive development disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
psychological factors affecting medical conditions, malingering,
antisocial behaviour, bereavement, occupational problem, identity
problem, problems related to abuse or neglect, pain disorders and
delirium.
[0546] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, psychotic disorders, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, sleep disorders, adjustment disorders, impulse control
disorders, pervasive development disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
psychological factors affecting medical conditions, malingering,
antisocial behaviour, bereavement, occupational problem, identity
problem and problems related to abuse or neglect, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a serotonin/dopamine antagonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said serotonin/dopamine antagonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0547] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a serotonin/dopamine antagonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said serotonin/dopamine antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0548] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder which is delirium,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a
serotonin/dopamine antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said serotonin/dopamine antagonist compound, further characterized
in that pipamperon is to be administered to a patient in a daily
dose ranging between 5 and 15 mg of the active ingredient.
[0549] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said serotonin/dopamine
antagonist compound is chosen from the group consisting of
zotepine, ziprasidone, SM-13496, SL 91.0177, sertindole, S-18327,
risperidone, quetiapine fumarate (preferably sustained release
formulation), quetiapine fumarate (preferably granules),
quetiapine, perospirone, paliperidone, olanzapine, ocaperidone, LU
31-131, iloperidone, clozapine, BSF-190555, blonanserin,
bifeprunox, asenapine and aripiprazole, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Even more preferably, said serotonin/dopamine antagonist compound
is chosen from the group consisting of SL 91.0177, sertindole,
perospirone, paliperidone, blonanserin, bifeprunox and asenapine,
or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. More preferably, said
serotonin/dopamine antagonist compound is sertindole and is to be
administered in a daily dose ranging between 12 and 24 mg of the
active ingredient. More preferably, said serotonin/dopamine
antagonist compound is paliperidone and is to be administered in a
daily dose ranging between 3 and 15 mg of the active ingredient.
More preferably, said serotonin/dopamine antagonist compound is
asenapine and is to be administered in a daily dose ranging between
2.5 and 20 mg of the active ingredient.
[0550] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a serotonin/dopamine antagonist
compound, preferably chosen from the group consisting of SL
91.0177, sertindole, perospirone, paliperidone, blonanserin,
bifeprunox and asenapine, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group consisting mood
disorders, anxiety disorders, psychotic disorders, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sleep disorders, adjustment disorders,
impulse control disorders, pervasive development disorders,
disruptive behaviour disorders, substance-related disorders,
personality disorders, psychological factors affecting medical
conditions, malingering, antisocial behaviour, bereavement,
occupational problem, identity problem, problems related to abuse
or neglect, pain disorders and delirium.
[0551] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
serotonin/dopamine antagonist compound is sertindole, preferably
provided in a unitary dose of between 12 and 24 mg of the active
ingredient.
[0552] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
serotonin/dopamine antagonist compound is paliperidone, preferably
provided in a unitary dose of between 3 and 15 mg of the active
ingredient.
[0553] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
serotonin/dopamine antagonist compound is asenapine, preferably
provided in a unitary dose of between 2.5 and 20 mg of the active
ingredient.
85: Combination Therapy with a Selective SDRI Compound
[0554] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a selective
serotonin and dopamine re-uptake inhibitor (SDRI) compound, are
chosen from the group of diseases or disorders consisting of mood
disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sleep disorders,
adjustment disorders, impulse control disorders, substance-related
disorders, personality disorders, antisocial behaviour,
bereavement, occupational problem, problems related to abuse or
neglect, pain disorders, delirium, Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
[0555] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, antisocial behaviour, bereavement,
occupational problem and problems related to abuse or neglect,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a selective
serotonin and dopamine reuptake inhibitor (SDRI) compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said selective serotonin and dopamine
reuptake inhibitor (SDRI) compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0556] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a selective serotonin and dopamine reuptake inhibitor (SDRI)
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said selective serotonin and
dopamine reuptake inhibitor (SDRI) compound, further characterized
in that pipamperon is to be administered to a patient in a daily
dose ranging between 5 and 15 mg of the active ingredient.
[0557] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of delirium, Alzheimer
Disease, substance-induced persisting dementia, vascular dementia,
dementia due to HIV disease, dementia due to head trauma, dementia
due to Parkinson Disease, dementia due to Huntington Disease,
dementia due to Pick Disease, dementia due to Creutzfeldt-Jacob
Disease, amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a selective serotonin and dopamine reuptake
inhibitor (SDRI) compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said selective
serotonin and dopamine reuptake inhibitor (SDRI) compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0558] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said selective serotonin
and dopamine reuptake inhibitor (SDRI) compound is bazinaprine, or
a pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof.
[0559] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a selective serotonin and
dopamine reuptake inhibitor (SDRI) compound, preferably bazinaprine
or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of mental disease or disorder
which is chosen from the group consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, antisocial behaviour, bereavement,
occupational problem, problems related to abuse or neglect, pain
disorders, delirium, Alzheimer Disease, substance-induced
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder
and other cognitive disorders.
86: Combination Therapy with a Second Messenger Beta Agonist
Compound
[0560] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a second
messenger beta agonist compound, are chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0561] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, personality disorders, bereavement, occupational problem
and problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a second messenger beta agonist compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said second messenger beta agonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0562] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a second messenger beta agonist compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said second messenger beta agonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0563] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said second messenger beta
agonist compound is chosen from the group consisting of SR 57227,
rolipram and eplivanserin, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. More
preferably, said second messenger beta agonist compound is rolipram
and is to be administered in a daily dose ranging between 1.5 and 3
mg of the active ingredient.
[0564] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a second messenger beta agonist
compound, preferably chosen from the group consisting of SR 57227,
rolipram and eplivanserin or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group consisting of
mood disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, personality disorders, bereavement, occupational
problem, problems related to abuse or neglect and pain
disorders.
[0565] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
second messenger beta agonist compound is rolipram, preferably
provided in a unitary dose of between 1.5 and 3 mg of the active
ingredient.
87: Combination Therapy with a Secretin Pancreatic Hormone
[0566] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a secretin
pancreatic hormone, are chosen from the group of diseases or
disorders consisting of anxiety disorders, psychotic disorders,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, disruptive behaviour disorders, substance-related
disorders, personality disorders, psychological factors affecting
medical conditions, malingering, antisocial behaviour, bereavement,
occupational problem, identity problem, problems related to abuse
or neglect, pain disorders and delirium.
[0567] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of anxiety disorders,
psychotic disorders, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sleep
disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a secretin pancreatic hormone to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said secretin pancreatic hormone, further characterized
in that pipamperon is to be administered to a patient in a daily
dose ranging between 5 and 15 mg of the active ingredient.
[0568] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a secretin pancreatic hormone to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said
secretin pancreatic hormone, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0569] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder which is delirium,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a secretin
pancreatic hormone to augment the therapeutic effect or to provide
a faster onset of the therapeutic effect of said secretin
pancreatic hormone, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0570] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said secretin pancreatic
hormone is RG1068 or a pro-drug or an active metabolite thereof, or
a pharmaceutically acceptable salt thereof.
[0571] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a secretin pancreatic hormone,
preferably RG1068, or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of a mental disease
or disorder which is chosen from the group consisting of anxiety
disorders, psychotic disorders, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sleep disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem,
problems related to abuse or neglect, pain disorders and
delirium.
88: Combination Therapy with a Sigma Receptor Agonist Compound
[0572] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a sigma
receptor agonist compound, are chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, attention-deficit disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0573] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, attention-deficit disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a sigma receptor
agonist compound to augment the therapeutic effect or to provide a
faster onset of the therapeutic effect of said sigma receptor
agonist compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0574] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a sigma receptor agonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said sigma receptor agonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0575] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said sigma receptor agonist
compound is VPI-013 (also known as OPC-14523) or PRX-00023,
preferably VPI-013 (also known as OPC-14523), or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0576] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a sigma receptor agonist
compound, preferably VPI-013 (also known as OPC-14523) or
PRX-00023, preferably VPI-013 (also known as OPC-14523), or a
pro-drug or an active metabolite thereof, or a pharmaceutically
acceptable salt thereof, as a combined preparation for
simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder,
which is chosen from the group consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, attention-deficit disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
89: Combination Therapy with a Sigma Receptor Antagonist
Compound
[0577] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a sigma
receptor antagonist compound, are chosen from the group of diseases
or disorders consisting of mood disorders, anxiety disorders,
psychotic disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, pervasive development disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect, pain disorders and delirium.
[0578] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, psychotic disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, disruptive behaviour disorders, substance-related
disorders, personality disorders, bereavement, occupational problem
and problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a sigma receptor antagonist compound to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said sigma receptor antagonist compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0579] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a sigma receptor antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said sigma receptor antagonist compound, further characterized in
that pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0580] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder which is delirium,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a sigma receptor
antagonist compound to augment the therapeutic effect or to provide
a faster onset of the therapeutic effect of said sigma receptor
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0581] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said sigma receptor
antagonist compound is chosen from the group consisting of SR 31742
and EMD 68843, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. More preferably, said
sigma receptor antagonist compound is EMD 68843 and is to be
administered in a daily dose ranging between 5 and 40 mg of the
active ingredient.
[0582] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a sigma receptor antagonist
compound, preferably chosen from the group consisting of SR 31742
and EMD 68843, or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group consisting mood disorders, anxiety
disorders, psychotic disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, pervasive development disorders, disruptive
behaviour disorders, substance-related disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect, pain disorders and delirium.
[0583] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
sigma receptor antagonist compound is EMD 68843, preferably
provided in a unitary dose of between 5 and 40 mg of the active
ingredient.
90: Combination Therapy with a Selective SNDRI Compound
[0584] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a selective
serotonin, nor-adrenaline and dopamine re-uptake inhibitor (SNDRI)
compound, are chosen from the group of diseases or disorders
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sleep
disorders, adjustment disorders, impulse control disorders,
attention-deficit disorders, substance-related disorders,
personality disorders, antisocial behaviour, bereavement,
occupational problem, problems related to abuse or neglect, pain
disorders, delirium, Alzheimer Disease, substance-induced
persisting dementia, vascular dementia, dementia due to HIV
disease, dementia due to head trauma, dementia due to Parkinson
Disease, dementia due to Huntington Disease, dementia due to Pick
Disease, dementia due to Creutzfeldt-Jacob Disease, amnestic
disorders due to a general medical condition, substance-induced
persisting amnestic disorder, mild cognitive impairment disorder
and other cognitive disorders.
[0585] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, attention-deficit disorders,
substance-related disorders, personality disorders, antisocial
behaviour, bereavement, occupational problem and problems related
to abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a selective serotonin, nor-adrenaline and dopamine re-uptake
inhibitor (SNDRI) compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said selective
serotonin, nor-adrenaline and dopamine re-uptake inhibitor (SNDRI)
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0586] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a selective serotonin, nor-adrenaline and dopamine re-uptake
inhibitor (SNDRI) compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said selective
serotonin, nor-adrenaline and dopamine re-uptake inhibitor (SNDRI)
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0587] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder selected from the group
of diseases and disorders consisting of delirium, Alzheimer
Disease, substance-induced persisting dementia, vascular dementia,
dementia due to HIV disease, dementia due to head trauma, dementia
due to Parkinson Disease, dementia due to Huntington Disease,
dementia due to Pick Disease, dementia due to Creutzfeldt-Jacob
Disease, amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a selective serotonin, nor-adrenaline and
dopamine re-uptake inhibitor (SNDRI) compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said selective serotonin, nor-adrenaline and dopamine
re-uptake inhibitor (SNDRI) compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0588] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said selective serotonin,
nor-adrenaline and dopamine re-uptake inhibitor (SNDRI) compound is
selected from the group consisting of NS 2330; McN 5652; DOV
216,303 and DOV 21,947; more preferably NS 2330 or DOV 216,303; or
a pro-drug or an active metabolite thereof; or a pharmaceutically
acceptable salt thereof.
[0589] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a selective serotonin,
nor-adrenaline and dopamine re-uptake inhibitor (SNDRI) compound,
preferably selected from the group consisting of NS 2330; McN 5652;
DOV 216,303 and DOV 21,947, more preferably NS 2330 or DOV 216,303,
or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of mental disease or disorder
which is chosen from the group consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, attention-deficit disorders,
substance-related disorders, personality disorders, antisocial
behaviour, bereavement, occupational problem, problems related to
abuse or neglect, pain disorders, delirium, Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders.
91: Combination Therapy with a Selective SNRI Compound
[0590] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a selective
serotonin and nor-adrenaline re-uptake inhibitor (SNRI) compound,
are chosen from the group of diseases or disorders consisting of
mood disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sleep disorders,
adjustment disorders, impulse control disorders, attention-deficit
disorders, substance-related disorders, personality disorders,
antisocial behaviour, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0591] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, attention-deficit disorders,
substance-related disorders, personality disorders, antisocial
behaviour, bereavement, occupational problem and problems related
to abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a selective serotonin and nor-adrenaline re-uptake inhibitor
(SNRI) compound to augment the therapeutic effect or to provide a
faster onset of the therapeutic effect of said selective serotonin
and nor-adrenaline re-uptake inhibitor (SNRI) compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0592] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a selective serotonin and nor-adrenaline re-uptake inhibitor
(SNRI) compound to augment the therapeutic effect or to provide a
faster onset of the therapeutic effect of said selective serotonin
and nor-adrenaline re-uptake inhibitor (SNRI) compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0593] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said selective serotonin
and nor-adrenaline re-uptake inhibitor (SNRI) compound is selected
from the group consisting of venlafaxine, tomoxetine, tandamine,
talsupram, talopram, nefazodone, milnacipran, LY 113.821,
duloxetine, desvenlafaxine and amoxapine, or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof. Even more preferably, said selective serotonin and
nor-adrenaline re-uptake inhibitor (SNRI) compound is chosen from
the group consisting of venlafaxine, tomoxetine, milnacipran,
duloxetine and desvenlafaxine, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
More preferably, said selective serotonin and nor-adrenaline
re-uptake inhibitor (SNRI) compound is venlafaxine and is to be
administered in a daily dose ranging between 75 and 300 mg of the
active ingredient. More preferably, said selective serotonin and
nor-adrenaline re-uptake inhibitor (SNRI) compound is tomoxetine
and is to be administered in a daily dose ranging between 0.475 and
3.8 mg/kg of the active ingredient. More preferably, said selective
serotonin and nor-adrenaline re-uptake inhibitor (SNRI) compound is
milnacipran and is to be administered in a daily dose ranging
between 50 and 200 mg of the active ingredient. More preferably,
said selective serotonin and nor-adrenaline re-uptake inhibitor
(SNRI) compound is duloxetine and is to be administered in a daily
dose ranging between 40 and 60 mg of the active ingredient.
[0594] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a selective serotonin and
nor-adrenaline re-uptake inhibitor (SNRI) compound, preferably
selected from the group consisting of venlafaxine, tomoxetine,
tandamine, talsupram, talopram, nefazodone, milnacipran, LY
113.821, duloxetine, desvenlafaxine and amoxapine, or a pro-drug or
an active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
mental disease or disorder which is chosen from the group
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sleep
disorders, adjustment disorders, impulse control disorders,
attention-deficit disorders, substance-related disorders,
personality disorders, antisocial behaviour, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0595] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
selective serotonin and nor-adrenaline re-uptake inhibitor (SNRI)
compound is venlafaxine, preferably provided in a unitary dose of
between 75 and 300 mg of the active ingredient.
[0596] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
selective serotonin and nor-adrenaline re-uptake inhibitor (SNRI)
compound is tomoxetine, preferably provided in a unitary dose of
between 0.475 and 3.8 mg/kg of the active ingredient.
[0597] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
selective serotonin and nor-adrenaline re-uptake inhibitor (SNRI)
compound is milnacipran, preferably provided in a unitary dose of
between 50 and 200 mg of the active ingredient.
[0598] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
selective serotonin and nor-adrenaline re-uptake inhibitor (SNRI)
compound is duloxetine, preferably provided in a unitary dose of
between 40 and 60 mg of the active ingredient.
92: Combination Therapy with a Selective Serotonin Re-Uptake
Inhibitor (SSRI) Compound
[0599] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a selective
serotonin re-uptake inhibitor (SSRI) compound, are chosen from the
group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, antisocial behaviour, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0600] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, antisocial behaviour, bereavement,
occupational problem and problems related to abuse or neglect,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a selective
serotonin re-uptake inhibitor (SSRI) compound to augment the
therapeutic effect or to provide a faster onset of the therapeutic
effect of said selective serotonin re-uptake inhibitor (SSRI)
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0601] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a selective serotonin re-uptake inhibitor (SSRI) compound to
augment the therapeutic effect or to provide a faster onset of the
therapeutic effect of said selective serotonin re-uptake inhibitor
(SSRI) compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0602] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said selective serotonin
re-uptake inhibitor (SSRI) compound is selected from the group
consisting of YM 992, VPI-013 (also known as OPC-14523),
sertraline, paroxetine, LY 214.281, LU AA 21-004, Lu 35-138,
litoxetine, ifoxetine, fluvoxamine (controlled release
formulation), fluvoxamine, fluoxetine, femoxetine, escitalopram,
EMD 68843, cyanodothepine, citalopram, cericlamine and
ademethionine (preferably s-adenosylmethionine), or a pro-drug or
an active metabolite thereof, or a pharmaceutically acceptable salt
thereof. Even more preferably, said selective serotonin re-uptake
inhibitor (SSRI) compound is chosen from the group consisting of
litoxetine, fluvoxamine (controlled release formulation),
citalopram and escitalopram, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof. More
preferably, said selective serotonin re-uptake inhibitor (SSRI)
compound is fluvoxamine (controlled release formulation) and is to
be administered in a daily dose ranging between 100 and 300 mg of
the active ingredient. More preferably, said selective serotonin
re-uptake inhibitor (SSRI) compound is escitalopram and is to be
administered in a daily dose ranging between 10 and 20 mg of the
active ingredient. More preferably, said selective serotonin
re-uptake inhibitor (SSRI) compound is citalopram and is to be
administered in a daily dose ranging between 10 and 40 mg of the
active ingredient.
[0603] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a selective serotonin re-uptake
inhibitor (SSRI) compound, preferably selected from the group
consisting of YM 992, VPI-013 (also known as OPC-14523),
sertraline, paroxetine, LY 214.281, LU AA 21-004, Lu 35-138,
litoxetine, ifoxetine, fluvoxamine (controlled release
formulation), fluvoxamine, fluoxetine, femoxetine, escitalopram,
EMD 68843, cyanodothepine, citalopram, venlafaxine, milnacipran,
duloxetine, cericlamine and ademethionine (preferably
s-adenosylmethionine), or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of mental disease
or disorder which is chosen from the group consisting of mood
disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sleep disorders,
adjustment disorders, impulse control disorders, substance-related
disorders, personality disorders, antisocial behaviour,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
[0604] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
selective serotonin re-uptake inhibitor (SSRI) compound is
fluvoxamine (controlled release formulation), preferably provided
in a unitary dose of between 100 and 300 mg of the active
ingredient.
[0605] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
selective serotonin re-uptake inhibitor (SSRI) compound is
escitalopram, preferably provided in a unitary dose of between 10
and 20 mg of the active ingredient.
[0606] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
selective serotonin re-uptake inhibitor (SSRI) compound is
citalopram, preferably provided in a unitary dose of between 10 and
40 mg of the active ingredient.
[0607] Citalopram or citalopram hydrobromide is a selective
serotonin (5-hydroxytryptamine/5-HT) re-uptake inhibitor (SSRI) and
is the conventional name given for the compound of the formula
(RS)-1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitril-
e-hydro-bromide. According to an embodiment, a daily doses of
active ingredient of SSRI, preferably citalopram, ranges between 10
and 40 mg per day. Preferably, daily doses of active ingredient
ranging between 20 and 30 mg per day are administered. More
preferably, a daily dose of 10, 15, 20, 25, 30, 35 or 40 mg per day
is administered.
[0608] Fluvoxamine or fluvoxamine maleate (luvox, fevarin) is a
selective serotonin (5-HT) re-uptake inhibitor (SSRI) belonging to
a new chemical series, the 2-aminoethyl oxime ethers of
aralkylketones. It is chemically unrelated to other SSRIs and
clomipramine. It is chemically designated as
5-methoxy-4'-(trifluoromethyl)valerophenone
(E)-O-(2-aminoethyl)oxime maleate (1:1).
[0609] According to an embodiment, a daily dose of active
ingredient of fluvoxamine in a controlled release mode ranges
between 100 and 300 mg per day. Preferably, daily doses of active
ingredient ranging between 150 and 200 mg per day are administered
in a controlled release mode. More preferably, a daily dose of 100,
150, 200, 250 or 300 mg per day is administered by controlled
release.
93: Combination Therapy with a Substance P Receptor (NK1)
Antagonist Compound
[0610] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a substance
P receptor (NK1) antagonist compound, are chosen from the group of
diseases or disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
substance-related disorders, personality disorders, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0611] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a substance P
receptor (NK1) antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said substance P receptor (NK1) antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0612] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a substance P
receptor (NK1) antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said substance P receptor (NK1) antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0613] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said substance P receptor
(NK1) antagonist compound is chosen from the group consisting of
vestipitant, TAK-637, R673, GW823296, GW679769, GW597599,
CP-122.721, aprepitant, 823296 and 679769, or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof. More preferably, said substance P receptor (NK1)
antagonist compound is aprepitant and is to be administered in a
daily dose ranging between 40 and 160 mg of the active
ingredient.
[0614] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a substance P receptor (NK1)
antagonist compound, preferably chosen from the group consisting of
vestipitant, TAK-637, R673, GW823296, GW679769, GW597599,
CP-122.721, aprepitant, 823296 and 679769, or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
a mental disease or disorder which is chosen from the group of
diseases and disorders consisting of mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, sexual and gender identity disorders, sleep
disorders, adjustment disorders, impulse control disorders,
substance-related disorders, personality disorders, bereavement,
occupational problem, problems related to abuse or neglect and pain
disorders.
[0615] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
substance P receptor (NK1) antagonist compound is aprepitant,
preferably provided in a unitary dose of between 40 and 160 mg of
the active ingredient.
94: Combination Therapy with a Sulfonamide Compound
[0616] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
sulfonamide compound, are chosen from the group of diseases or
disorders consisting of mood disorders, psychotic disorders,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, disruptive behaviour disorders, substance-related
disorders, personality disorders, psychological factors affecting
medical conditions, malingering, antisocial behaviour, bereavement,
occupational problem, identity problem, problems related to abuse
or neglect, pain disorders and delirium.
[0617] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
psychotic disorders, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sleep
disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem and
problems related to abuse or neglect, characterized in that
pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a sulfonamide compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said sulfonamide compound, further characterized in that pipamperon
is to be administered to a patient in a daily dose ranging between
5 and 15 mg of the active ingredient.
[0618] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a sulfonamide compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said
sulfonamide compound, further characterized in that pipamperon is
to be administered to a patient in a daily dose ranging between 5
and 15 mg of the active ingredient.
[0619] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a cognitive mental disease or disorder which is delirium,
characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a sulfonamide
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said sulfonamide compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0620] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said sulfonamide compound
is zonisamide or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. More preferably, said
sulfonamide compound is zonisamide and is to be administered in a
daily dose ranging between 100 and 600 mg of the active
ingredient.
[0621] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a sulfonamide compound,
preferably zonisamide, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group consisting mood
disorders, psychotic disorders, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sleep disorders, adjustment disorders, impulse control disorders,
pervasive development disorders, disruptive behaviour disorders,
substance-related disorders, personality disorders, psychological
factors affecting medical conditions, malingering, antisocial
behaviour, bereavement, occupational problem, identity problem,
problems related to abuse or neglect, pain disorders and
delirium.
[0622] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
sulfonamide compound is zonisamide, preferably provided in a
unitary dose of between 100 and 600 mg of the active
ingredient.
95: Combination Therapy with a Tachykinin Antagonist Compound
[0623] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a tachykinin
antagonist compound, are chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0624] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a tachykinin
antagonist compound to augment the therapeutic effect or to provide
a faster onset of the therapeutic effect of said tachykinin
antagonist compound, further characterized in that pipamperon is to
be administered to a patient in a daily dose ranging between 5 and
15 mg of the active ingredient.
[0625] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a tachykinin antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said tachykinin antagonist compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0626] According to a preferred embodiment, the invention relates
to the use as described above, wherein said tachykinin antagonist
compound is SR 48968 or a pro-drug or an active metabolite thereof,
or a pharmaceutically acceptable salt thereof.
[0627] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a tachykinin antagonist
compound, preferably SR 48968 or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group consisting of
mood disorders, anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, substance-related disorders, personality
disorders, bereavement, occupational problem, problems related to
abuse or neglect and pain disorders.
96: Combination Therapy with a Compound Selected from the Group
Consisting of R228060 (YKP-10A), Palanpanel, ORG 39479/PH80, ORG
34167, DP 543 and CJ-017.493
[0628] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a compound
selected from the group consisting of R228060 (YKP-10A),
palanpanel, ORG 39479/PH80, ORG 34167, DP 543 and CJ-017.493, are
chosen from the group of diseases or disorders consisting of mood
disorders, anxiety disorders, psychotic disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, attention-deficit disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
psychological factors affecting medical conditions, malingering,
antisocial behaviour, bereavement, occupational problem, identity
problem, phase of life problem, academic problem, problems related
to abuse or neglect, pain disorders, delirium, Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder, other cognitive disorders and Parkinson
Disease.
[0629] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, psychotic disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, attention-deficit disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
psychological factors affecting medical conditions, malingering,
antisocial behaviour, bereavement, occupational problem, identity
problem, phase of life problem, academic problem and problems
related to abuse or neglect, characterized in that pipamperon or
said pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a compound selected from the group consisting of R228060
(YKP-10A), palanpanel, ORG 39479/PH80, ORG 34167, DP 543 and
CJ-017.493, to augment the therapeutic effect or to provide a
faster onset of the therapeutic effect of said compound selected
from the group consisting of R228060 (YKP-10A), palanpanel, ORG
39479/PH80, ORG 34167, DP 543 and CJ-017.493, further characterized
in that pipamperon is to be administered to a patient in a daily
dose ranging between 5 and 15 mg of the active ingredient.
[0630] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a compound selected from the group consisting of R228060
(YKP-10A), palanpanel, ORG 39479/PH80, ORG 34167, DP 543 and
CJ-017.493, to augment the therapeutic effect or to provide a
faster onset of the therapeutic effect of said compound selected
from the group consisting of R228060 (YKP-10A), palanpanel, ORG
39479/PH80, ORG 34167, DP 543 and CJ-017.493, further characterized
in that pipamperon is to be administered to a patient in a daily
dose ranging between 5 and 15 mg of the active ingredient.
[0631] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of delirium, Alzheimer
Disease, substance-induced persisting dementia, vascular dementia,
dementia due to HIV disease, dementia due to head trauma, dementia
due to Parkinson Disease, dementia due to Huntington Disease,
dementia due to Pick Disease, dementia due to Creutzfeldt-Jacob
Disease, amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder and other cognitive disorders, characterized in
that pipamperon or said pharmaceutically acceptable salt thereof is
administered simultaneously with, separate from or prior to the
administration of a compound selected from the group consisting of
R228060 (YKP-10A), palanpanel, ORG 39479/PH80, ORG 34167, DP 543
and CJ-017.493, to augment the therapeutic effect or to provide a
faster onset of the therapeutic effect of said compound selected
from the group consisting of R228060 (YKP-10A), palanpanel, ORG
39479/PH80, ORG 34167, DP 543 and CJ-017.493, further characterized
in that pipamperon is to be administered to a patient in a daily
dose ranging between 5 and 15 mg of the active ingredient.
[0632] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson Disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a compound selected from the group consisting of R228060
(YKP-10A), palanpanel, ORG 39479/PH80, ORG 34167, DP 543 and
CJ-017.493, to augment the therapeutic effect or to provide a
faster onset of the therapeutic effect of said compound selected
from the group consisting of R228060 (YKP-10A), palanpanel, ORG
39479/PH80, ORG 34167, DP 543 and CJ-017.493, further characterized
in that pipamperon is to be administered to a patient in a daily
dose ranging between 5 and 15 mg of the active ingredient.
[0633] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a compound selected from the
group consisting of R228060 (YKP-10A), palanpanel, ORG 39479/PH80,
ORG 34167, DP 543 and CJ-017.493, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof,
as a combined preparation for simultaneous, separate or sequential
use for treating the underlying emotion dysregulation of mental
disease or disorder which is chosen from the group consisting of
mood disorders, anxiety disorders, psychotic disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
sexual and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, pervasive development
disorders, attention-deficit disorders, disruptive behaviour
disorders, substance-related disorders, personality disorders,
psychological factors affecting medical conditions, malingering,
antisocial behaviour, bereavement, occupational problem, identity
problem, phase of life problem, academic problem, problems related
to abuse or neglect, pain disorders, delirium, Alzheimer Disease,
substance-induced persisting dementia, vascular dementia, dementia
due to HIV disease, dementia due to head trauma, dementia due to
Parkinson Disease, dementia due to Huntington Disease, dementia due
to Pick Disease, dementia due to Creutzfeldt-Jacob Disease,
amnestic disorders due to a general medical condition,
substance-induced persisting amnestic disorder, mild cognitive
impairment disorder, other cognitive disorders and Parkinson
Disease.
97: Combination Therapy with a Vasopressin 1B Receptor (V1B)
Antagonist Compound
[0634] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
vasopressin 1B receptor (V1B) antagonist compound, are chosen from
the group of diseases or disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
[0635] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a vasopressin 1B
receptor (V1B) antagonist compound to augment the therapeutic
effect or to provide a faster onset of the therapeutic effect of
said vasopressin 1B receptor (V1B) antagonist compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0636] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a vasopressin 1B receptor (V1B) antagonist compound to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said vasopressin 1B receptor (V1B) antagonist
compound, further characterized in that pipamperon is to be
administered to a patient in a daily dose ranging between 5 and 15
mg of the active ingredient.
[0637] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said vasopressin 1B
receptor (V1B) antagonist compound is SSR149415 or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof.
[0638] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a vasopressin 1B receptor (V1B)
antagonist compound, preferably SSR149415 or a pro-drug or an
active metabolite thereof, or a pharmaceutically acceptable salt
thereof, as a combined preparation for simultaneous, separate or
sequential use for treating the underlying emotion dysregulation of
a mental disease or disorder which is chosen from the group
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
98: Combination Therapy with a Voltage-Gated Calcium Channel
.alpha.(2).delta. Subunit Modulator Compound
[0639] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
voltage-gated calcium channel alpha(2)delta subunit modulator
compound, are chosen from the group of diseases or disorders
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, substance-related disorders,
personality disorders, bereavement, occupational problem, problems
related to abuse or neglect and pain disorders.
[0640] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a voltage-gated
calcium channel alpha(2)delta subunit modulator compound to augment
the therapeutic effect or to provide a faster onset of the
therapeutic effect of said voltage-gated calcium channel
alpha(2)delta subunit modulator compound, further characterized in
that pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0641] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a voltage-gated calcium channel alpha(2)delta subunit modulator
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said voltage-gated calcium
channel alpha(2)delta subunit modulator compound, further
characterized in that pipamperon is to be administered to a patient
in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0642] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said voltage-gated calcium
channel alpha(2)delta subunit modulator compound is pregabalin or
PD-200,390; or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof. More preferably, said
voltage-gated calcium channel alpha(2)delta subunit modulator
compound is pregabalin, and is to be administered in a daily dose
ranging between 50 and 600 mg of the active ingredient.
[0643] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a voltage-gated calcium channel
alpha(2)delta subunit modulator compound, preferably pregabalin or
PD-200,390; or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof, as a combined preparation
for simultaneous, separate or sequential use for treating the
underlying emotion dysregulation of a mental disease or disorder
which is chosen from the group consisting of mood disorders,
anxiety disorders, eating disorders, premenstrual syndrome,
somatoform disorders (excluding pain disorders), factitious
disorders, dissociative disorders, sexual and gender identity
disorders, sleep disorders, adjustment disorders, impulse control
disorders, substance-related disorders, personality disorders,
bereavement, occupational problem, problems related to abuse or
neglect and pain disorders.
[0644] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
voltage-gated calcium channel alpha(2)delta subunit modulator
compound is pregabalin, preferably provided in a unitary dose of
between 50 and 600 mg of the active ingredient.
99: Combination Therapy with a Vomeropherin Compound
[0645] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a
vomeropherin compound, are chosen from the group of diseases or
disorders consisting of anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders, sexual
and gender identity disorders, sleep disorders, adjustment
disorders, impulse control disorders, personality disorders,
bereavement, occupational problem and problems related to abuse or
neglect.
[0646] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting of anxiety disorders,
eating disorders, premenstrual syndrome, somatoform disorders
(excluding pain disorders), factitious disorders, dissociative
disorders, sexual and gender identity disorders, sleep disorders,
adjustment disorders, impulse control disorders, personality
disorders, bereavement, occupational problem and problems related
to abuse or neglect, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of vomeropherin compound to augment the therapeutic effect or to
provide a faster onset of the therapeutic effect of said
vomeropherin compound, further characterized in that pipamperon is
to be administered to a patient in a daily dose ranging between 5
and 15 mg of the active ingredient.
[0647] According to a preferred embodiment, the invention relates
to the use as described above, wherein said vomeropherin compound
is PH94B or a pro-drug or an active metabolite thereof, or a
pharmaceutically acceptable salt thereof.
[0648] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) vomeropherin compound,
preferably PH94B or a pro-drug or an active metabolite thereof, or
a pharmaceutically acceptable salt thereof, as a combined
preparation for simultaneous, separate or sequential use for
treating the underlying emotion dysregulation of a non-cognitive
mental disease or disorder which is chosen from the group
consisting of anxiety disorders, eating disorders, premenstrual
syndrome, somatoform disorders (excluding pain disorders),
factitious disorders, dissociative disorders, sexual and gender
identity disorders, sleep disorders, adjustment disorders, impulse
control disorders, personality disorders, bereavement, occupational
problem and problems related to abuse or neglect.
[0649] Also, the invention relates in particular to the use as
described before, wherein said second compound is chosen from the
group consisting of fluvoxamine controlled release, phenserine
tartrate, atomoxetine hydrochloride, bupropion (controlled-release
formulation), ropinirole HCL (controlled-release formulation), INN
00835, galantamine (extended release formulation), paliperidone,
tomoxetine, aprepitant, rivastigmine tartrate, ORG 34517/34850,
sunepitron, sumanirole, milnacipran, idazoxan, xaliproden, SR
58611, befloxatone, litoxetine, tianeptine, aglomelatine, SPD 503,
flesinoxan, bifeprunox, ramelteon, etilevodopa, rasagiline
(TVP-1012) and desvenlafaxine.
[0650] Also, the invention relates in particular to the use as
described before, wherein said second compound is chosen from the
group consisting of galantamine (extended release formulation),
R121919, risperidone, paliperidone and R228060 (YKP-10A).
100: Combination Therapy with a Dopamine Releaser
[0651] The mental disorders which can be treated using compounds
having a high selective affinity for the 5-HT2A and D4 receptor,
for instance pipamperon, in a combination therapy with a dopamine
releaser, are chosen from the group of diseases or disorders
consisting of mood disorders, anxiety disorders, eating disorders,
premenstrual syndrome, somatoform disorders (excluding pain
disorders), factitious disorders, dissociative disorders,
adjustment disorders, impulse control disorders, attention-deficit
disorders, substance-related disorders, personality disorders,
problems related to abuse or neglect, pain disorders and Parkinson
disease.
[0652] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of a non-cognitive mental disease or disorder selected from the
group of diseases and disorders consisting mood disorders, anxiety
disorders, eating disorders, premenstrual syndrome, somatoform
disorders (excluding pain disorders), factitious disorders,
dissociative disorders, adjustment disorders, impulse control
disorders, attention-deficit disorders, substance-related
disorders, personality disorders and problems related to abuse or
neglect, characterized in that pipamperon or said pharmaceutically
acceptable salt thereof is administered simultaneously with,
separate from or prior to the administration of a dopamine releaser
compound to augment the therapeutic effect or to provide a faster
onset of the therapeutic effect of said dopamine releaser compound,
further characterized in that pipamperon is to be administered to a
patient in a daily dose ranging between 5 and 15 mg of the active
ingredient.
[0653] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of pain disorders, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a dopamine releaser compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said
dopamine releaser compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0654] The present invention thus relates to the use of pipamperon
or a pharmaceutically acceptable salt thereof for the preparation
of a medicament for treating the underlying emotion dysregulation
of Parkinson disease, characterized in that pipamperon or said
pharmaceutically acceptable salt thereof is administered
simultaneously with, separate from or prior to the administration
of a dopamine releaser compound to augment the therapeutic effect
or to provide a faster onset of the therapeutic effect of said
dopamine releaser compound, further characterized in that
pipamperon is to be administered to a patient in a daily dose
ranging between 5 and 15 mg of the active ingredient.
[0655] According to a preferred embodiment, the invention relates
to the uses as described above, wherein said dopamine (receptor)
agonist compound is amantadine, or a pro-drug or an active
metabolite thereof, or a pharmaceutically acceptable salt thereof.
Preferably, amantadine is to be administered in a daily dose of
between 100 and 300 mg of the active ingredient.
[0656] The invention also relates to a pharmaceutical composition
comprising (a) pipamperon, and (b) a dopamine (receptor) agonist,
preferably amantadine, or a pro-drug or an active metabolite
thereof, or a pharmaceutically acceptable salt thereof, as a
combined preparation for simultaneous, separate or sequential use
for treating the underlying emotion dysregulation of a mental
disease or disorder which is chosen from the group of diseases or
disorders consisting of mood disorders, anxiety disorders, eating
disorders, premenstrual syndrome, somatoform disorders (excluding
pain disorders), factitious disorders, dissociative disorders,
adjustment disorders, impulse control disorders, attention-deficit
disorders, substance-related disorders, personality disorders,
problems related to abuse or neglect, pain disorders and Parkinson
disease.
[0657] The invention also relates to a pharmaceutical composition
as described above wherein pipamperon is provided in a unitary dose
of between 5 and 15 mg of the active ingredient and wherein said
dopamine (receptor) agonist is amantadine, preferably provided in a
unitary dose of between 100 and 300 mg of the active
ingredient.
[0658] From the above it will be apparent that the numbering of the
grouping according to the action on the pathway or system
corresponds to the numbering of the columns in Table 5 and the
numbering of the pharmalogical profile in Table 6.
[0659] The disclosure of all patents, publications (including
published patent publications), and database accession numbers and
depository accession numbers referenced in this specification are
specifically incorporated herein by reference in their entirety to
the same extent as if each such individual patent, publication, and
database accession number, and depository accession number were
specifically and individually indicated to be incorporated by
reference.
[0660] The invention, now being generally described, will be more
readily understood by reference to the following tables and
examples, which are included merely for purposes of illustration of
certain aspects and embodiments of the present invention and are
not intended to limit the invention.
SHORT DESCRIPTION OF THE TABLES AND FIGURES
[0661] Table 1: In Table 1, the pKi values of test compounds are
given for each of the dopamine receptors, 5HT receptors, adrenergic
receptors and the histamine1 receptor.
[0662] Table 2: Set-up of a clinical trial comprising for treatment
groups.
[0663] Table 3: Overview of a placebo, active and period controlled
clinical trial in a fore-going pipamperon-citalopram treatment in
Major Depressive Disorder.
[0664] Table 4: POC process for major depressive disorder.
[0665] Table 5: Summary of diseases and disorders relative to known
psycho-tropics.
[0666] Table 6: Overview of Pharmacological grouping, indicating
pharmacological profile numbering (column 2), pharmacological
profile (column 3), main indication(s) (column 4), name of the
compound (column 4), the dose range (column 5), and the company
producing or selling said compound (column 6). Compounds indicated
by hatching are preferred.
[0667] FIG. 1: Add-on treatment with pipamperon after treatment
with citalopram.
[0668] FIG. 2: HDRS-17 change from baseline: combo treatment
pipamperon as add-on-citalopram vs SNRI (duloxetine) in Major
Depression.
[0669] FIG. 3: Remission rates (HDRS-17 <=7): combo treatment
pipamperon as add-on-citalopram vs SNRI (venlafaxine) vs SSRIs vs
placebo in Major Depression.
[0670] FIG. 4: Fore-going treatment during 1-5 days with pipamperon
followed with the combination treatment of pipamperon and
citalopram.
[0671] FIG. 5: HDRS-17 change from baseline: combo treatment
pipamperon-citalopram with a fore-going treatment of 4 days with
pipamperon vs SNRI (duloxetine) in Major Depression.
[0672] FIG. 6: Remission rates (HDRS-17 <=7): combo
pipamperon-citalopram with a fore-going treatment of 4 days with
pipamperon vs SNRI (venlafaxine) in Major Depression.
[0673] FIG. 7: Fore-going treatment during 6-8 days with pipamperon
followed with the combination treatment of pipamperon and
citalopram.
[0674] FIG. 8: HDRS-17 change from baseline: combo treatment
pipamperon-citalopram with a fore-going treatment of 7 days with
pipamperon vs SNRI (duloxetine) in Major Depression.
[0675] FIG. 9: Fore-going and add-on treatment with pipamperon in
MDD.
[0676] FIG. 10: HDRS-17 change from baseline: fore-going and add-on
treatment with pipamperon and citalopram in comparison with the
SNRI duloxetine in Major Depression.
[0677] FIG. 11: Remission rates (HDRS-17 <=7): fore-going and
add-on treatment with pipamperon and citalopram in comparison with
the SNRI venlafaxine in Major Depression.
[0678] FIG. 12: Y-BOCS total score: fore-going and add-on treatment
with pipamperon and citalopram in comparison with the SSRI
fluvoxamine in OCD.
[0679] FIG. 13: Y-BOCS obsession score: fore-going and add-on
treatment with pipamperon and citalopram in comparison with the
SSRI fluvoxamine in OCD.
[0680] FIG. 14: Y-BOCS compulsion score: fore-going and add-on
treatment with pipamperon and citalopram in comparison with the
SSRI fluvoxamine in OCD.
[0681] FIG. 15: CGI-severity score: fore-going and add-on treatment
with pipamperon and citalopram in comparison with the SSRI in panic
disorder.
TABLE-US-00001 TABLE 1 D 1 D 2 D 3 D 4 5HT.sub.1A 5HT.sub.1B
5HT.sub.1D 5HT.sub.1E 5HT.sub.1F 5HT.sub.2A 5HT.sub.2B 5HT.sub.2C
ORG5222 8-9 8-9 8-9 8-9 8-9 8-9 8-9 7-8 0 >9 >9 >9
Zotepine 0 8-9 8-9 7-8 6-7 7-8 7-8 6-7 0 8-9 0 0 Fluparoxan 0 <6
<6 0 6-7 <6 <6 0 0 <6 0 <6 Olanzapine 7-8 7-8 7-8
7-8 <6 6-7 6-7 <6 6-7 8-9 8-9 8-9 Clozapine 7-8 6-7 6-7 7-8
6-7 6-7 6-7 6-7 6-7 8-9 8-9 7-8 S16924 0 7-8 7-8 7-8 8-9 0 0 0 0
>9 8-9 7-8 S18327 7-8 7-8 6-7 8-9 7-8 0 0 0 0 8-9 0 6-7
Amperozide 6-7 6-7 6-7 <6 <6 0 0 0 0 8-9 0 <6 GGR218231
<6 7-8 >9 <6 6-7 <6 <6 0 0 <6 <6 <6
Sertindole 7-8 8-9 8-9 7-8 6-7 7-8 7-8 6-7 6-7 >9 0 8-9
MDL100.907 6-7 <6 <6 6-7 <6 0 0 0 0 >9 0 7-8
Haloperidol 8-9 >9 8-9 8-9 <6 6-7 <6 <6 <6 6-7 <6
<6 Tiospirone 7-8 8-9 8-9 8-9 8-9 0 0 0 0 >9 0 8-9 Raciopride
<6 8-9 8-9 <6 <6 0 0 0 0 6-7 0 <6 Fluspirilene 0 >9
8-9 8-9 7-8 <6 <6 <6 0 <6 0 0 Ocaperidone 7-8 >9 8-9
8-9 7-8 0 0 0 0 >9 0 7-8 Risperidone 7-8 8-9 7-8 8-9 6-7 8-9 6-7
<6 <6 >9 0 7-8 S33084 6-7 7-8 >9 <6 <6 6-7 6-7 0
0 6-7 6-7 7-8 L741626 6-7 8-9 7-8 6-7 <6 <6 <6 0 0 6-7 6-7
<6 Seroquel 6-7 6-7 6-7 <6 6-7 <6 <6 <6 <6 6-7
6-7 6-7 Yohimbine 0 6-7 <6 0 7-8 6-7 7-8 0 0 <6 0 <6
Ziprasidone 8-9 8-9 7-8 7-8 8-9 >9 8-9 6-7 0 >9 8-9 8-9
Pipamperon 0 6-7 6-7 8-9 <6 6-7 6-7 <6 <6 8-9 0 0
5HT.sub.6rat 5HT.sub.7rat Alpha1 Alpha2 Alpha2 Alpha2 Beta1 Beta2
H1 ORG5222 >9 >9 >9 8-9 >9 7-8 <6 <6 >9
Zotepine 0 0 0 6-7 8-9 6-7 <6 <6 >9 Fluparoxan 0 0 6-7 8-9
8-9 8-9 0 0 0 Olanzapine 7-8 6-7 7-8 6-7 6-7 6-7 <6 <6 >9
Clozapine 7-8 7-8 8-9 7-8 7-8 7-8 <6 <6 >9 S16924 7-8 7-8
8-9 6-7 7-8 6-7 <6 <6 0 S18327 0 0 >9 6-7 0 0 0 0 0
Amperozide 0 0 7-8 <6 0 0 0 0 0 GGR218231 0 0 <6 <6 0 0 0
0 0 Sertindole 0 0 >9 6-7 6-7 6-7 <6 <6 6-7 MDL100.907 0 0
<6 <6 0 0 0 0 0 Haloperidol <6 6-7 8-9 <6 6-7 <6
<6 <6 6-7 Tiospirone 0 0 >9 6-7 0 0 0 0 0 Raciopride 0 0
<6 <6 0 0 0 0 0 Fluspirilene 0 0 0 6-7 7-8 7-8 6-7 6-7 7-8
Ocaperidone 0 0 >9 0 0 0 0 0 0 Risperidone 0 0 >9 7-8 8-9 8-9
<6 <6 7-8 S33084 0 0 6-7 <6 0 0 0 0 0 L741626 0 0 6-7
<6 0 0 0 0 0 Seroquel 0 6-7 7-8 <6 7-8 6-7 <6 <6 8-9
Yohimbine 0 0 6-7 8-9 8-9 >9 <6 <6 0 Ziprasidone 7-8 8-9
8-9 6-7 7-8 7-8 <6 <6 7-8 Pipamperon 0 0 0 6-7 7-8 6-7 <6
<6 <6
TABLE-US-00002 TABLE 2 ACUTE PHASE** EXTENSION PHASE*** VISITS V1
V2 V3 V4 V5 V6 V7 V8 V9 V10 Day/Week/Month Screen Baseline minus D
7 D 0 D 4 D 7 W 2 W 3 W 4 W 6 W 8 W 10 TREATMENTGROUP Group
Pip-Active/D 7 A B B C Group Pip-Active/D 4 A B C Group
Pip-Active/D 0 A C Group Plc-Activc/D 0 A D Informed Consent x
NECT* x x x x x x x x x x Vital Signs/Weight x LAB x ECG x Phys
Exam x Alc/Drugs Screen x CGI-S**** x x x x x x x x x x
Q-LES-Q***** EXTENSION PHASE*** FOLLOW-UP PHASE VISITS V11 V12 V13
V14 V15 V16 V17 V18 V19 Day/Week/Month W 12 W 16 W 20 W 24 M 8 M 10
M 12 W 1 W 2 TREATMENTGROUP Group Pip-Active/D 7 A A Group
Pip-Active/D 4 A A Group Pip-Active/D 0 A A Group Plc-Activc/D 0 A
A Informed Consent NECT* x x x x x x x x x Vital Signs/Weight x x x
LAB x x x ECG x x x Phys Exam Alc/Drugs Screen x x x CGI-S**** x x
x x x x x x x Q-LES-Q***** Treatment regimen: A: PLC + PLC B:
2x(PLC + PIP(4 mg))/d C: 2x(CIT(10 mg) + PIP(4 mg))/d D: 2x(CIT(10
mg) + PLC)/d *Neuronal E-Clinical Trial = Vesalius Expert
Development for this Trial which includes the bottom-up measurement
of: **Entering Acute Phase: only NON-placebo responders as defined
by the DSM-IV criteria of efficacy ***Entering Extension Phase:
only remittors as defined by the DSM-IV criteria of efficacy
****CGI-S: Clinical Global Impressions-Improvement Scale
*****Q-LES-Q: Quality of Life, Enjoyment and Satisfaction
Questionnaire
TABLE-US-00003 TABLE 3 FOREGOING PIPAMPERON- CITALOPRAM TREATMENT
IN MAJOR DEPRESSIVE DISORDER A PLACEBO, ACTIVE AND PERIODE
CONTROLLED CLIINICAL TRIAL ACUTE PHASE** EXTENSION PHASE*** VISITS
V1 V2 V3 V4 V5 V6 V7 V8 V9 DAY/WEEK/MONTH SCREEN BASELINE minus D 7
D 0 D 4 D 7 W 2 W 3 W 4 W 6 W 8 TREATMENTGROUP Group Pip -
Active/Day 4 PLC + PLC 2x(PLC + PIP(4 mg))/d 2x(CIT(10 mg) + PIP(4
mg))/d Group Pip - Active/Day 0 PLC + PLC 2x(CIT(10 mg) + PIP(4
mg))/d Group Plc - Active/Day 0 PLC + PLC 2x(CIT(10 mg) + PLC)/d
Group Placebo PLC + PLC Informed Consent x NECT* x x x x x x x x x
Vital Signs/Weight x x x x x x x x x LAB x x ECG x Phys Exam x x
Alc/Drugs Screen x CGI-S x x x x x x x x x ****Q-LES-Q x x x x x x
x x EXTENSION PHASE*** FOLLOW-UP PHASE VISITS V10 V11 V12 V13 V14
V15 V16 V17 V18 V19 DAY/WEEK/MONTH W 10 W 12 W 16 W 20 W 24 M 8 M
10 M 12 W 1 W 2 TREATMENTGROUP Group Pip - Active/Day 4 PLC + PLC
PLC + PLC Group Pip - Active/Day 0 PLC + PLC PLC + PLC Group Plc -
Active/Day 0 PLC + PLC PLC + PLC Group Placebo PLC + PLC PLC + PLC
Informed Consent NECT* x x x x x x x x x x Vital Signs/Weight x x x
x x x x x x x LAB x x x x ECG x x x x Phys Exam x x x x Alc/Drugs
Screen x x x x CGI-S x x x x x x x x x x ****Q-LES-Q x x x x x x x
x x *Neuronal E-Clinical Trial = Vesalius Expert Development for
this Trial which includes the bottom-up measurement of: In- and
exclusioncriteria Functional status evaluation Medical history
(Pre-)treatment signs & symptoms DSM-IV rules for diagnosis
& efficacy Rating Scales: HDRS-28, MADRS, HAMA Medical resource
utulisation Pre-trial & Concomittant medication Drug
administration (Serious) Adverse events Admission to the acute and
extension phase of treatment Right flow of the trial **Entering
Acute Phase: only NON-placebo responders as defined by the DSM-IV
criteria of efficacy ***Entering Extension Phase: only remittors as
defined by the DSM-IV criteria of efficacy ****Q-LES-Q: Quality of
Life, Enjoyment and Satisfaction Questionnaire
TABLE-US-00004 TABLE 4 DAY TREATMENT GROUP minus D 7 D 0 =>D 4
Placebo (PLC) PLC + PLC 2 .times. (PLC + PLC) 2 .times. (PLC + PC)
PIP - Active/Day 4 PLC + PLC 2 .times. (PLC + PIP (4 mg))/d 2
.times. (CIT (10 mg) + PIP (4 mg))/d PIP - Active/Day 0 PLC + PLC 2
.times. (CIT (10 mg) + PIP (4 mg))/d 2 .times. (CIT (10 mg) + PIP
(4 mg))/d PLC - Active/Day 0 PLC + PLC 2 .times. (CIT (10 mg) +
PLC)/d 2 .times. (CIT (10 mg) + PLC)/d
TABLE-US-00005 TABLE 5 *SEE GLOSSARY HEREUNDER MEDICAMENT 92 91 90
85 60 62 61 82 51 3 4 5 6 7 8 9 COMBO's 5-HT2A/D4*-Antagonist + CNS
Compound MONO MAO-A* & 5-HT2A/D4* MAO-B* 5-HTA1* 5-HT1B*
5-HT2B* 5-HT2C* 5HT3* 5HT6* MEDICAL Antag- reuptake 5-HTA1* antag-
antag- antag- antag- antag- antag- INDICATION onist SSRI* SNRI*
SNDRI* SDRI* NARI* NDRI* NaSSA* RIMA* inhibitor agonist onist onist
onist onist onist onist DISORDER X X X X X X X X X X X X X X X X X
WITH AN UNDERLYING EMOTION DYSREGU- LATION NON-COGNI- TIVE MENTAL
DISORDERS (excl. Pain Disorder) mood X X X X X X X X X X X X X
disorders anxiety X X X X X X X X X X X X X X disorders psychotic
disorders eating X X X X X X X X X X X X disorders premenstrual X X
X X X X X X X X X X syndrome somatoform X X X X X X X X X X X X
disorders (excluding Pain Disorder) factitious X X X X X X X X X X
X X disorders dissociative X X X X X X X X X X X X disorders sexual
and X X X X X X X X gender identity disorders sleep X X X X X X X X
X X disorders adjustment X X X X X X X X X X X X X X disorders
impulse control X X X X X X X X X X X X disorders pervasive X
development disorders attention- X X X X X X X deficit disorders
disruptive X behaviour disorders substance- X X X X X X X X X X X
related disorders personality X X X X X X X X X X X X X X disorders
psychological X factors affecting medical conditions malingering X
antisocial X X X X X X X X X X X X X X behaviour bereavement X X X
X X X X X X X X X X X occupational X X X X X X X X X X X X X X
problem identity X problem phase of X life problem academic X
problem problems X X X X X X X X X X X X X X related to abuse or
neglect PAIN X X X X X X X X X X X DISORDER COGNITIVE DISORDERS
delirium X X X Alzheimer X X X X Disease substance- X X X X induced
persisting dementia vascular X X X X dementia dementia due to X X X
X HIV disease dementia due to X X X X head trauma dementia due to X
X X X Parkinson Disease dementia due to X X X X Huntington Disease
dementia due to X X X X Pick Disease dementia due to X X X X
Creutzfeldt- Jacob Disease amnestic X X X X X disorders due to a
general medical condition substance- X X X X X induced persisting
amnestic disorder mild cognitive X X X X X impairment disorder
other cognitive X X X X X disorders PARKINSON DISEASE MEDICAMENT 2
1 44 93 69 95 76 55 56 41 26 40 54 19 14 COMBO's
5-HT2A/D4*-Antagonist + CNS compound MONO 5-HT1* Sub- MCH*- beta-3-
5-HT2A/D4* auto- 5-HT* Increase brain stance P NK2* tachykinin
receptor GR* CRF-1* GPCR* MC4* adreno- alpha 2 MEDICAL Antag-
receptor reuptake concentrations Antag- Antag- antag- antag- MT*
antag- antag- modu- antag- ceptor antag- INDICATION onist agonist
enhancer of 5-HT* onist onist onist peptide onist agonist onist
onist lator onists agonist onists DISORDER X X X X X X X X X X X X
X X X X WITH AN UNDERLYING EMOTION DYSREGU- LATION NON-COGNI- TIVE
MENTAL DISORDERS (excl. Pain Disorder) mood X X X X X X X X X X X X
X X X disorders anxiety X X X X X X X X X X X X X X X X disorders
psychotic X disorders eating X X X X X X X X X X X X X X X X
disorders premenstrual X X X X X X X X X X X X X X X X syndrome
somatoform X X X X X X X X X X X X X X X X disorders (excluding
Pain Disorder) factitious X X X X X X X X X X X X X X X X disorders
dissociative X X X X X X X X X X X X X X X X disorders sexual and X
X X X X X X X X X X X X X X X gender identity disorders sleep X X X
X X X X X X X X X X X X X disorders adjustment X X X X X X X X X X
X X X X X X disorders impulse control X X X X X X X X X X X X X X X
X disorders pervasive X X development disorders attention- X
deficit disorders disruptive X X behaviour disorders substance- X X
X X X X X X X X X X X X X X related disorders personality X X X X X
X X X X X X X X X X X disorders psychological X factors affecting
medical conditions malingering X antisocial X X X behaviour
bereavement X X X X X X X X X X X X X X X X occupational X X X X X
X X X X X X X X X X X problem identity X problem phase of X life
problem academic X problem problems X X X X X X X X X X X X X X X X
related to abuse or neglect PAIN X X X X X X X X X X X X X X X
DISORDER COGNITIVE DISORDERS delirium Alzheimer X Disease
substance- X induced persisting dementia vascular X dementia
dementia due to X HIV disease dementia due to X head trauma
dementia due to X Parkinson Disease dementia due to X Huntington
Disease dementia due to X Pick Disease
dementia due to X Creutzfeldt- Jacob Disease amnestic X X disorders
due to a general medical condition substance- X X induced
persisting amnestic disorder mild cognitive X X impairment disorder
other cognitive X X disorders PARKINSON DISEASE MEDICAMENT 13 86 97
12 71 75 98 83 78 88 39 57 67 35 COMBO's 5-HT2A/D4*-Antagonist +
CNS compound MONO X Voltage-gated Glutamate nicotinic 5-HT2A/D4*
alpha 1 Second V1B* Adrenergic NMDA* calcium channel SCT-11*
Prodrug sigma receptor acetylcholine GABA-A* MEDICAL Antag- antag-
messenger antag- transmitter antag- PDE4* alpha(2)delta subunit
modu- of receptor antag- mGluR* receptor modu- INDICATION onist
onists beta agonist onist releaser onist inhibitor modulator lation
uridine agonist onist agonist antagonist lator DISORDER X X X X X X
X X X X X X X X X WITH AN UNDERLYING EMOTION DYSREGU- LATION
NON-COGNI- TIVE MENTAL DISORDERS (excl. Pain Disorder) mood X X X X
X X X X X X disorders anxiety X X X X X X X X X X X X X X X
disorders psychotic disorders eating X X X X X X X X X X X X
disorders premenstrual X X X X X X X X X X X X syndrome somatoform
X X X X X X X X X X X X X X X disorders (excluding Pain Disorder)
factitious X X X X X X X X X X X X X X X disorders dissociative X X
X X X X X X X X X X X X X disorders sexual and X X X X X X X X X X
X X gender identity disorders sleep X X X X X X X X X disorders
adjustment X X X X X X X X X X X X X X X disorders impulse control
X X X X X X X X X X X X X X X disorders pervasive X development
disorders attention- X X deficit disorders disruptive X behaviour
disorders substance- X X X X X X related disorders personality X X
X X X X X X X X X X X X X disorders psychological X factors
affecting medical conditions malingering X antisocial X behaviour
bereavement X X X X X X X X X X X X X X X occupational X X X X X X
X X X X X X X X X problem identity X problem phase of X life
problem academic X problem problems X X X X X X X X X X X X X X X
related to abuse or neglect PAIN X X X X X X X X X X X X X DISORDER
COGNITIVE DISORDERS delirium Alzheimer X X Disease substance- X X
induced persisting dementia vascular X X dementia dementia due to X
X HIV disease dementia due to X X head trauma dementia due to X X
Parkinson Disease dementia due to X X Huntington Disease dementia
due to X X Pick Disease dementia due to X X Creutzfeldt- Jacob
Disease amnestic X X X disorders due to a general medical condition
substance- X X X induced persisting amnestic disorder mild
cognitive X X X impairment disorder other cognitive X X X disorders
PARKINSON DISEASE MEDICAMENT 36 99 74 77 89 94 87 84 28 29 70 65 21
COMBO's 5-HT2A/D4*-Antagonist + CNS compound MONO Phospholipase
sigma neurotensin 5-HT2A/D4* GABA-B* A2 inhibtor receptor Secretin
D2*- D3*- NK3* receptor CB1* MEDICAL Antag- antag- opoid with
caspase antag- pancreatic antag- antag- antag- antag- antag-
INDICATION onist onist vomeropherin agonist inhibitor activity
onist sulfonamide hormone SDA* onist onist onist onist onist
DISORDER X X X X X X X X X X X X X X WITH AN UNDERLYING EMOTION
DYSREGU- LATION NON-COGNI- TIVE MENTAL DISORDERS (excl. Pain
Disorder) mood X X X X X X X X disorders anxiety X X X X X X X X X
X X disorders psychotic X X X X X X X X X X X disorders eating X X
X X X X disorders premenstrual X X X X X X syndrome somatoform X X
X X X X X X X X X X X X disorders (excluding Pain Disorder)
factitious X X X X X X X X X X X X X X disorders dissociative X X X
X X X X X X X X X X X disorders sexual and X X X X X X gender
identity disorders sleep X X X X X X X X X X X X X X disorders
adjustment X X X X X X X X X X X X X X disorders impulse control X
X X X X X X X X X X X X X disorders pervasive X X X X X X X X X X X
development disorders attention- X deficit disorders disruptive X X
X X X X X X X X X behaviour disorders substance- X X X X X X X X X
X X X related disorders personality X X X X X X X X X X X X X X
disorders psychological X X X X X X X X X factors affecting medical
conditions malingering X X X X X X X X X antisocial X X X X X X X X
X behaviour bereavement X X X X X X X X X X X X X X occupational X
X X X X X X X X X X X X X problem identity X X X X X X X X X
problem phase of X life problem academic X problem problems X X X X
X X X X X X X X X X related to abuse or neglect PAIN X X X X X X X
X X X DISORDER COGNITIVE DISORDERS delirium X X X X X X X X X X
Alzheimer Disease substance-
induced persisting dementia vascular dementia dementia due to HIV
disease dementia due to head trauma dementia due to Parkinson
Disease dementia due to Huntington Disease dementia due to X Pick
Disease dementia due to X Creutzfeldt- Jacob Disease amnestic X
disorders due to a general medical condition substance- X induced
persisting amnestic disorder mild cognitive impairment disorder
other cognitive disorders PARKINSON X DISEASE MEDICAMENT 15 34 18
79 81 16 73 27 38 50 43 10 23 66 58 COMBO's 5-HT2A/D4*-Antagonist +
CNS compound MONO gluco- acetyl- 5-HT2A/D4* AMPA* androgen prosta-
opioid D1* corticoid MAO* Hormonal cholin- choline mimics the
MEDICAL Antag- receptor GABA-A* receptor glandin Psycho- amphet-
receptor receptor synthesis reuptake Sub- estrase uptake effects of
INDICATION onist mediator agonist modulator E1 stimulant amine
inhibitor agonist inhibitor inhibitor stance inhibitor enhancer
NGF* NGF* DISORDER X X X X X X X X X X X X X X X X WITH AN
UNDERLYING EMOTION DYSREGU- LATION NON-COGNI- TIVE MENTAL DISORDERS
(excl. Pain Disorder) mood X disorders anxiety X X disorders
psychotic X disorders eating X X disorders premenstrual X X X
syndrome somatoform X X disorders (excluding Pain Disorder)
factitious X X disorders dissociative X X disorders sexual and X X
X X gender identity disorders sleep X X X X disorders adjustment X
X disorders impulse control X X disorders pervasive X X development
disorders attention- X X X X deficit disorders disruptive X X
behaviour disorders substance- X X X X X X X related disorders
personality X X disorders psychological X X factors affecting
medical conditions malingering X X antisocial X X behaviour
bereavement X X occupational X X problem identity X X problem phase
of X life problem academic X problem problems X X related to abuse
or neglect PAIN X DISORDER COGNITIVE DISORDERS delirium X Alzheimer
X X X X X Disease substance- X X X X X induced persisting dementia
vascular X X X X X dementia dementia due to X X X X X HIV disease
dementia due to X X X X X head trauma dementia due to X X X X X
Parkinson Disease dementia due to X X X X X Huntington Disease
dementia due to X X X X X Pick Disease dementia due to X X X X X
Creutzfeldt- Jacob Disease amnestic X X X X X X disorders due to a
general medical condition substance- X X X X X X induced persisting
amnestic disorder mild cognitive X X X X X X impairment disorder
other cognitive X X X X X X disorders PARKINSON X X X X DISEASE
MEDICAMENT 59 17 80 45 68 33 32 42 20 48 31 100 52 30 COMBO's
5-HT2A/D4*-Antagonist + CNS compound MONO Muscannic protect
5-HT2A/D4* receptor amyloid dopaminergic increasing nicotinic H3*
Calcium DA* MEDICAL Antag- partial aggregation and cholinergic
insulin receptor GABA* ERK* Antag- Channel Dopamine Dopamine
MAO-B*- uptake INDICATION onist agonist inhibitor neurons
sensitivity agonists agonist activation onist Modulator Levodopa
agonist releaser inhibitor inhibitor DISORDER X X X X X X X X X X X
X X X X WITH AN UNDERLYING EMOTION DYSREGU- LATION NON-COGNI- TIVE
MENTAL DISORDERS (excl. Pain Disorder) mood X X X disorders anxiety
X X X X disorders psychotic disorders eating X X X X disorders
premenstrual X X X X syndrome somatoform X X X X disorders
(excluding Pain Disorder) factitious X X X X disorders dissociative
X X X X disorders sexual and X gender identity disorders sleep X
disorders adjustment X X X X disorders impulse control X X X X
disorders pervasive X development disorders attention- X X X X
deficit disorders disruptive X behaviour disorders substance- X X X
X X related disorders personality X X X X disorders psychological X
factors affecting medical conditions malingering X antisocial X
behaviour bereavement X occupational X problem identity X
problem
phase of X life problem academic X problem problems X X X X related
to abuse or neglect PAIN X X X DISORDER COGNITIVE DISORDERS
delirium Alzheimer X X X X X X X X X Disease substance- X X X X X X
X X X induced persisting dementia vascular X X X X X X X X X
dementia dementia due to X X X X X X X X X HIV disease dementia due
to X X X X X X X X X head trauma dementia due to X X X X X X X X X
Parkinson Disease dementia due to X X X X X X X X X Huntington
Disease dementia due to X X X X X X X X X Pick Disease dementia due
to X X X X X X X X X Creutzfeldt- Jacob Disease amnestic X X X X X
X X X X X disorders due to a general medical condition substance- X
X X X X X X X X X induced persisting amnestic disorder mild
cognitive X X X X X X X X X X impairment disorder other cognitive X
X X X X X X X X X disorders PARKINSON X X X X X X X DISEASE
MEDICAMENT 49 63 64 37 46 11 24 25 72 47 22 96 53 COMBO's
5-HT2A/D4*-Antagonist + CNS compound Glial-cell inhibitor of
adenosine COX*- interleukin-1 MAO-B* 5-HT2A 5-HT2A MONO Lipid-
neuro- Line Derived the mixed A2a inhibiting beta cathepsin re-
Antagonist + Antag- 5-HT2A/D4* DNA immuno- neuro- Neuro- lineage
receptor COX2* nitric (nitric converting K uptake D4-Antag- onist +
MEDICAL Antag- Com- philin modu- trophic kinase antag- inhib- oxide
oxide) enzyme inhib- un- inhibi- onist + CNS D4-Antag- INDICATION
onist plex ligands lator Factor family onist itor donators NSAID*
inhibitor itor known tion Compound onist DISORDER X X X X X X X X X
X X X X X WITH AN UNDERLYING EMOTION DYSREGU- LATION NON-COGNI-
TIVE MENTAL DISORDERS (excl. Pain Disorder) mood X disorders
anxiety X X disorders psychotic X disorders eating X X disorders
premenstrual X X syndrome somatoform X X disorders (excluding Pain
Disorder) factitious X X disorders dissociative X X disorders
sexual and X X gender identity disorders sleep X X disorders
adjustment X X disorders impulse control X X disorders pervasive X
X development disorders attention- X X deficit disorders disruptive
X X behaviour disorders substance- X X related disorders
personality X X disorders psychological X X factors affecting
medical conditions malingering X X antisocial X X behaviour
bereavement X X occupational X X problem identity X X problem phase
of X X life problem academic X X problem problems X X related to
abuse or neglect PAIN X X X X X X DISORDER COGNITIVE DISORDERS
delirium X Alzheimer X X Disease substance- X induced persisting
dementia vascular X dementia dementia due to X HIV disease dementia
due to X head trauma dementia due to X Parkinson Disease dementia
due to X Huntington Disease dementia due to X Pick Disease dementia
due to X Creutzfeldt- Jacob Disease amnestic X X disorders due to a
general medical condition substance- X X induced persisting
amnestic disorder mild cognitive X X impairment disorder other
cognitive X X disorders PARKINSON X X X X X X X X DISEASE GLOSSARY
5-HT = serotonin 5-HT1 = serotonin 1 receptor 5-HT1A = serotonin 1A
receptor 5-HT1B = serotonin 1B receptor 5-HT2A/D4 = serotonin 2A en
dopamine D4 receptor 5-HT2B = serotonin 2B receptor 5-HT2C =
serotonin 2C receptor 5HT3 = serotonin 3 receptor 5HT6 = serotonin
6 receptor AMPA = alpha-amino-3-hydroxy-5-methyl-4-isoxazole
propionate CB1 = cannabioid receptor 1 CINODs = COX-inhibiting
nitric oxide donators COX = cyclooxigenase COX-2 = cyclooxigenase 2
CRF-1 = Corticotropin-Releasing Factor Receptor 1 D1 = Dopamine 1
D2 = Dopamine 2 D2 = Dopamine 3 DA = Dopamine ERK = extracellular
signal-related kinase GABA = gamma-aminobutyric acid GABA-A =
gamma-aminobutyric acid A receptor GABA-B = gamma-aminobutyric acid
B receptor GPCR = G-Protein-Coupled Receptor GR = glucocorticoid
receptor H3 = histamine H3 receptor MAO = mono-amine oxydase MAO-A
= mono-amine oxydase A MAO-B = mono-amine oxydase B MC4 =
melanocortin-4 receptor MCH = Melanin concentrating hormone MgluR =
metabotropic glutamate receptor MT = melatonin receptor NARI =
selective nor-adrenaline re-uptake inhibitor NaSSA =
noradrenergic/specific serotonergic antidepressant NDRI = selective
nor-adrenaline and dopamine re-uptake inhibitor NGF = Nerve Growth
Factor NGF = nerve growth factor NK1 = neurokinin 1 receptor NK2 =
neurokinin 2 receptor NK3 = neurokinin 3 receptor NMDA =
N-Methyl-D-aspartate NSAID = Non-steroidal anti-inflammatory drugs
PDE4 = phosphodiesterase-4 RIMA = reversible inhibitor of
mono-amine oxydase A SCT-11 = G protein-coupled receptor SDA =
Serotonin/Dopamine Antagonist SDRI = selective serotonin and
dopamine reuptake inhibitor SNDRI = selective serotonin,
nor-adrenaline and dopamine reuptake inhibitor SNRI = selective
serotonin and nor-adrenaline reuptake inhibitor SSRI = selective
serotonin reuptake inhibitor V1B = vasopressin 1B receptor
TABLE-US-00006 TABLE 6 nr. PH. PHARMACOLOGICAL MAIN DOSE PROF.
PROFILE INDICATIONS COMPOUND RANGE COMPANY PHARMAC. GROUP (see
overview hereunder) Monoaminergic 1 5-HT reuptake enhancer
Depression/Anxiety Tianeptine 25 to 50 mg daily Servier Transmitter
Systems Monoaminergic 2 5-HT1 autoreceptor agonist.
Depression/Anxiety SUNEPITRON unknown Pfizer Transmitter Systems
Monoaminergic 3 5HT1A agonist Anxiety MN-305 MediciNova Transmitter
Systems 5-HT1A agonist Depression/Anxiety Buspirone Bristol-Myers
Squibb 5-HT1A agonist Depression bupropion (controlled-release 150
mg to 450 mg GlaxoSmithKline formulation, once-day 5-HT1A agonist
Depression gepirone 20 mg to 60 mg Organon daily 5-HT1A agonist
Alzheimer's Disease xaliproden 1 to 2 mg daily Sanofi-Synthelabo
5-HT1A agonist Depression/Anxiety Flesinoxan unknown Solvay 5-HT1A
agonist Anxiety lesopitron Esteve 5-HT1A agonist Depression VPI-013
(also known Vela. Otsuka as OPC-14523) 5-HT1A agonist
Depression/Anxiety metanospirone ? 5-HT1A agonist
Depression/Anxiety EMD 68843 EMD Pharmaceuticals 5-HT1A agonist
Depression/Anxiety alnespirone Servier 5-HT1A agonist
Depression/Anxiety tandospirone Sumitomo 5-HT1A agonist
Depression/Anxiety zalospirone Weyth 5-HT1A agonist Parkinson's
Disease sarizotan unknown EMD Pharmaceuticals 5-HT1A agonist ADHD
PRX-00023 Predix 5-HT1A agonist Anxiety PRX-00023 Predix
Monoaminergic 4 5-HT1A antagonist Depression robalzotan unknown
AstraZeneca Transmitter Systems tartrate hydrate 5-HT1A antagonist
Depression NAD299 AstraZeneca Monoaminergic 5 5-HT1B antagonist
Depression/Anxiety AR-A2 AstraZeneca Transmitter Systems 5-HT1B
antagonist Depression/Anxiety elzasonan unknown Pfizer 5-HT1B
antagonist Depression/Anxiety A2D1134 AstraZeneca Monoaminergic 6
5-HT2B antagonist Depression/Anxiety Agomelatine 25 to 50 mg daily
Servier Transmitter Systems Monoaminergic 7 5-HT2C antagonist
Depression/Anxiety Agomelatine 25 to 50 mg daily Servier
Transmitter Systems 5-HT2C antagonist Depression/Anxiety SB 243213
GlaxoSmithKline Monoaminergic 8 5-HT3 antagonist Cocaine Dependence
ondansetron 8 to 32 mg daily National Institute Transmitter Systems
on Drug Abuse Monoaminergic 9 5-HT6 antagonist Alzheimer's Disease
SB-271046 GlaxoSmithKline Transmitter Systems 5-HT6 antagonist
Alzheimer's Disease 271046 GlaxoSmithKline 5-HT6 antagonist
Alzheimer's Disease 742457 GlaxoSmithKline Excitatory Amino 10
acetylcholinesterase inhibitor Alzheimer's Disease dichlorvos Bayer
Acid System acetylcholinesterase inhibitor Alzheimer's Disease
metritonate Bayer acetylcholinesterase inhibitor Alzheimer's
Disease physostigmine Lundbeck/Forest Laboratories
acetylcholinesterase inhibitor Alzheimer's Disease rivastigmine
Novartis Pharmaceuticals acetylcholinesterase inhibitor Alzheimer's
Disease lacrine Parke Davis acetylcholinesterase inhibitor
Alzheimer's Disease donezepil Pfizer acetylcholinesterase inhibitor
Alzheimer's Disease galantamine (extended 6 to 24 mg daily Johnson
& Johnson release formulation) Pharmaceutical
acetylcholinesterase inhibitor Alzheimer's Disease phenserine
tartrate 20 to 30 mg daily Axonyx acetylcholinesterase inhibitor
Alzheimer's Disease huperzine A Interneuron acetylcholinesterase
inhibitor Alzheimer's Disease rivastigmine tartrate 3 to 12 mg
daily Novartis Pharmaceuticals acetylcholinesterase inhibitor
Alzheimer's Disease anseculin hydrochloride Schwabe Adenosine
Transmitter 11 adenosine A2a receptor antagonist Parkinson's
Disease KW-6002 40 to 80 mg daily Kyowa Pharmaceutical System
Monoaminergic 12 Adrenergic transmitter releaser Depression
Piporazole 30 to 60 mg daily Sarget Transmitter Systems
Monoaminergic 13 alpha 1 adrenoreceptor antagonist
Depression/Anxiety Flesinoxan unknown Solvay Transmitter Systems
alpha 1 adrenoreceptor antagonist Parkinson's Disease SDZ NVI 085
unknown Sandoz Monoaminergic 14 alpha 2 adrenoreceptor antagonist.
Depression Mirtazapine Organon Transmitter Systems alpha 2
adrenoreceptor antagonist. Depression Idazoxan 20 mg daily Reckitt
and Colman alpha 2 adrenoreceptor antagonist. Schizophrenia
Idazoxan 20 mg daily Reckitt and Colman alpha 2 adrenoreceptor
antagonist. Depression/Anxiety SUNEPITRON unknown Pfizer alpha 2
adrenoreceptor antagonist Depression fluparoxan GlaxoSmithKline
alpha 2 adrenoreceptor antagonist. Depression/Anxiety (R)-A 75200
Abbott alpha 2 adrenoreceptor antagonist. Depression/Anxiety A
75200 Abbott alpha 2 adrenoreceptor antagonist Insomnia Mirtazepine
Organon alpha 2 adrenoreceptor antagonist. Depression UK-14304 ?
Excitatory Amino 15 AMPA receptor mediator Alzheimer's Disease
ampakine CX-516 Cortex Pharmaceuticals/ Acid System Organon AMPA
receptor mediator Alzheimer's Disease ampakine CX-717 unknown
Cortex Pharmaceuticals/ Organon AMPA receptor mediator
Schizophrenia ampakine ORG unknown Organon 24448/CX-619 AMPA
receptor mediator Depression Ampakine CX-691 unknown Cortex
Pharmaceuticals/ Organon Excitatory Amino 16 amphetamine ADHD
methylphenidate Noven Pharmaceuticals Acid System transdermal
system Pathogenic Mechanisms of 17 amyloid aggregation-inhibitor
Alzheimer's Disease Alzhemed 200 to 300 mg Neurochem Dementia of
the daily Alzheimer Type amyloid aggregation-inhibitor Alzheimer's
Disease APAN Praecis Pharmaceutical Endocrine System 18 androgen
receptor modulator Female Sexual Dysfunction LGD2226 Ligand
Pharmaceuticals Monoaminergic 19 beta 3 adrenoreceptor agonist
Depression/Anxiety SR 58611 unknown Sanofi-Synthelabo Transmitter
Systems Other/Unknown 20 Calcium Channel Modulator Alzheimer's
Disease MEM 1003 Memory Pharmaceuticals Calcium Channel Modulator
Parkinson's Disease safinamide Newron Pharmaceuticals Monoaminergic
21 cannabioid receptor antagonist Schizophrenia SR 141716 unknown
Sanofi-Synthelabo Transmitter Systems Enzymatic System 22 cathepsin
K inhibitor Pain 462795 GlaxoSmithKline Excitatory Amino 23 choline
uptake enhancer Alzheimer's Disease MKC-231 20 to 160 mg daily
Mitsubishi Pharma Acid System Enzymatic System 24 COX-2 inhibitor
Pain celecoxib Pfizer COX-2 inhibitor Pain rofecoxib Pfizer COX-2
inhibitor Pain valdecoxib Pfizer COX-2 inhibitor Pain etoricoxib 20
to 120 mg daily Merck COX-2 inhibitor Pain COX 189 100 to 800 mg
Novartis daily Pharmaceuticals COX-2 inhibitor Pain parecoxib 20 to
80 mg daily Pfizer COX-2 inhibitor Pain ABT-963 Abbott Enzymatic
System 25 COX-inhibiting nitric Pain AZD3582 375 mg daily
AstraZeneca oxide donators (CINODs) COX-inhibiting nitric Pain
AZD4717 AstraZeneca oxide donators (CINODs) Endocrine System 26
CRF1 antagonist Depression AAG 561 unknown Novartis Pharmaceuticals
CRF1 antagonist Depression/Anxiety R121919 5 to 8O mg daily Johnson
& Johnson Pharmaceutical CRF1 antagonist Depression/Anxiety
elzasonan unknown Pfizer CRF1 antagonist Depression 723620
GlaxoSmithKline CRF1 antagonist Depression/Anxiety NBI-34041
Neurocrine Biosciences CRF1 antagonist Depression/Anxiety
CP-154-526 Pfizer CRF1 antagonist Depression/Anxiety CP-448, 187
Pfizer Monoaminergic 27 D1 receotor agonist Cocaine Dependence
DAS-431 unknown Drug Abuse Sciences Transmitter Systems
Monoaminergic 28 D2 receptor antagonist Schizophrenia amisulpride
off patent Transmitter Systems D2 receptor antagonist Schizophrenia
bifeprunox unknown Solvay Monoaminergic 29 D3 antagonist Cocaine
Dependence BSF-201640 ? Transmitter Systems D3 antagonist Cocaine
Dependence PD 58491 ? D3 antagonist Parkinson's Disease BSF-201640
? D3 antagonist Parkinson's Disease PD 58491 ? D3 antagonist
schizophrenia BSF-201640 ? D3 antagonist schizophrenia PD 58491 ?
Monoaminergic 30 DA uptake inhibitor Cocaine Dependence GBR 12909
National Institute Transmitter Systems on Drug Abuse DA uptake
inhibitor Parkinson's Disease safinamide Newron Pharmaceuticals
Monoaminergic 31 dopamine agonist Parkinson's Disease sumanirole 4
to 16 mg daily Pfizer Transmitter Systems dopamine agonist
Parkinson's Disease, rotigotine CDS (Once-a-Day 4 5 to 13 5 mg
Schwarz Pharma Early and Advanced Transdermal Patch) daily dopamine
agonist Parkinson's Disease ropinirole HCL (controlled- 0 75 to 24
mg GlaxoSmithKline Restless Leg release formulation) daily dopamine
agonist Cocaine Dependence cabergoline Abbott dopamine agonist
Parkinson's Disease sarizotan EMD Pharmaceuticals dopamine agonist
Parkinson's Disease pramipexole Pfizer dopamine agonist Parkinson's
Disease DAB452 Weyth dopamine agonist Parkinson's Disease, SLV 308
Solvay Comorbid dopamine agonist Depression/Anxiety S32504 Servier
dopamine agonist Parkinson's Disease S32504 Servier dopamine
agonist Parkinson's Disease bromocriptine Novartis Pharmaceuticals
dopamine agonist Parkinson's Disease alaptide VU-Res Inst. Pharm
Biochem (CZ) dopamine agonist Parkinson's Disease cabergoline 1 to
4 mg daily Pharmacia dopamine agonist Parkinson's Disease lisuride
0.6 to 5 mg daily Shering dopamine agonist Parkinson's Disease
pergolide 2 to 3 mg daily Lilly Enzymatic System 32 ERK activation
Alzheimer's Disease CPI-1189 50 to 100 mg daily Centaur
Pharmaceuticals Inhibitory Amino 33 GABA agonist Alzheimer's
Disease Nefiracetam unknown DaiiChi Seiyaku, Acid System JPN
Nattermann, BRD Inhibitory Amino 34 GABA-A agonist Insomnia
Gaboxadol 5 to 20 mg daily Lundbeck Acid System Inhibitory Amino 35
GABA-A modulator Insomnia eszopiclone 2 to 3 mg daily Sepracor Acid
System GABA-A modulator Insomnia Zolpidem MR sustained- 10 to 20 mg
daily Sanofi-Synthelabo release version GABA-A modulator Insomnia
indiplon 10 to 20 mg daily DOV/Neurocone GABA-A modulator Anxiety
Pagoclone 30 mg daily Indevus GABA-A modulator Insomnia Zaleplon
extended-release 10 mg daily King Pharmaceuticals GABA-A modulator
Anxiety SEP174559 Sepracor GABA-A modulator Anxiety, muscular SL 65
1498 Sanofi-Synthelabo contractions GABA-A modulator Insomnia
CP-730,330 (NGD 96-3) Neurogen GABA-A modulator Insomnia NGD 96-3
Neurogen GABA-A modulator Anxiety Ocinaplon 10 to 60 mg daily DOV
Inhibitory Amino 36 GABA-B antagonist Depression/Anxiety AVE 7398
unknown Aventis Acid System Neurotrophic System 37 Glial-cell Line
Derived Parkinson's Disease GDNF 15 mg daily Amgen Neurotrophic
Factor Endocrine System 38 glucocorticoid synthesis Cocaine
Dependence metyrapone National Institute inhibitor on Drug Abuse
Excitatory Amino 39 Glutamate receptor Anxiety LY354740 Eli Lilly
Acid System antagonist
Other/Unknown 40 GPCR modulator Depression/Anxiety R1204 Roche
Endocrine System 41 GR antagonist depression (psychotic)
Mifepristone 500 to 1200 mg Corcept daily GR antagonist Depression
ORG 34517/34850 unknown Organon Monoaminergic 42 H3 Antagonist
Alzheimer's Disease ABT-239 Abbott Transmitter Systems H3
Antagonist Alzheimer's Disease ABT-834 Abbott Endocrine System 43
Hormonal Substance Premenstrual Syndrome drospirenone 3 mg/ethinyl
see formula Berlex Laboratories estradiol 0 020 mg tablets Hormonal
Substance Female Sexual Dysfunction female testosterone patch
Procter & Gamble Pharmaceuticals Hormonal Substance
Premenstrual Syndrome synthetic conjugated 0 3 mg daily Barr
Laboratories estrogen A Hormonal Substance Female Sexual
Dysfunction testosterone gel BioSante Pharmaceuticals Hormonal
Substance Female Sexual Dysfunction testosterone gel Cellegy
Pharmaceuticals Hormonal Substance Female Sexual Dysfunction
methyltestosterone Noven Pharmaceuticals Hormonal Substance Female
Sexual Dysfunction estrogens/methyltestosterone Solvay Hormonal
Substance Female Sexual Dysfunction testosterone transdermal spray
VIVUS Monoaminergic 44 Increase brain Depression/Anxiety KW 6055 ?
Transmitter Systems concentrations of 5-HT Increase brain
Depression/Anxiety PMD 145 ? concentrations of 5-HT Increase brain
Depression/Anxiety SP 186 ? concentrations of 5-HT Increase brain
Depression/Anxiety Triptotosine ? concentrations of 5-HT Endocrine
System 45 increasing insulin Alzheimer's Disease rosiglitazone
maleate GlaxoSmithKline sensitivity Enzymatic System 46 inibitor of
the mixed Parkinson's Disease CEP-1347 unknown Cephalon lineage
kinase family Enzymatic System 47 interleukin-1 beta Pain
pralnacasan Aventis converting enzyme inhibitor Monoaminergic 48
levodopa/decarboxylase inhibitor Parkinson's Disease
levadopa/carbidopa 250 to 600/25 Merck Transmitter Systems to 150
mg daily 48 levodopa/decarboxylase inhibitor Parkinson's Disease
levadopa/benserazide 100 to 600/25 Roche to 150 mg daily 48
levodopa/decarboxylase inhibitor Parkinson's Disease
etilevodopa/carbidopa unknown TEVA Pharmaceuticals USA 48
levodopa/decarboxylase inhibitor Parkinson's Disease
etilevodopa/benserazide unknown TEVA Pharmaceuticals USA
Other/Unknown 49 Lipid-DNA Complex Parkinson's Disease GR213487B
Valentis Monoaminergic 50 MAO reuptake inhibitor Cocaine Dependence
NS 2359 National Institute Transmitter Systems on Drug Abuse
Monoaminergic MAO reuptake inhibitor ADHD NS 2359 NeuroSearch
Transmitter Systems Monoaminergic 51 MAO-A & MAO-B reuptake
inhibitor ADHD SPD473 unknown Shire Pharmaceutical Transmitter
Systems Development Monoaminergic 52 MAO-B inhibitor Depression
EmSam (transdermal Somerset Transmitter Systems selegiline) MAO-B
inhibitor Parkinson's Disease selegiline 5 to 10 mg daily Amarin
Pharmaceuticals MAO-B inhibitor Parkinson's Disease rasagiline
(TVP-1012) 1 to 2 mg daily TEVA Pharmaceuticals USA/Lundbeck
Monoaminergic 53 MAO-B re-uptake inhibition Parkinson's Disease
safinamide Newron Pharmaceuticals Transmitter Systems Peptidergic
54 MC4 antagonists Depression/Anxiety MCL0129 Taisho Transmitter
System Peptidergic 55 MCH receptor antagonist Depression SNAP-7941
Synaptic Transmitter System Endocrine System 56 melatonin receptor
agonist Insomnia Ramelteon unknown Takeda melatonin receptor
agonist Depression/Anxiety Agomelatine 25 to 50 mg daily Servier
Excitatory Amino 57 MgluR agonist Anxiety PRE703 Prescient Acid
System Neurotrophic System 58 mimics the effects of NGF Alzheimer's
Disease Xaliproden 1 to 2 mg daily Sanofi-Synthelabo Excitatory
Amino 59 Muscarinic receptor Alzheimer (JP)/Sjogren Sevimeline
unknown DaiiChi Seiyaku Acid System partial agonist (US)
Monoaminergic 60 NARI Depression/Anxiety reboxetine Pfizer
Transmitter Systems NARI ADHD atomoxetine hydrochloride 40 to 100
mg daily Eli Lilly NARI Depression reboxetine 6 to 12 mg daily
Pfizer Monoaminergic 61 NaSSA Insomnia ORG 4420 unknown Organon
Transmitter Systems Monoaminergic 62 NDRI Depression (bipolar
disorder) GW353162 20 to 60 mg daily GlaxoSmithKline Transmitter
Systems Neuroimmunophilin 63 neuroimmunophilin ligands Parkinson's
Disease GPI 1485 200 to 1000 mg Guilford System daily
Pharmaceuticals Adenosine 64 neuromodulator Parkinson's Disease
adenosine Schering-Plough Transmitter System Peptidergic 65
neurotensin receptor antagonist Schizophrenia SR 48592 9O to 300 mg
daily Sanofi-Synthelabo Transmitter System Neurotrophic System 66
NGF (nerve growth factor) Alzheimer's Disease nerve growth factor
Ceregene (NGF) gene therapy Excitatory Amino 67 nicotinic
acetylcholine Anxiety SEP174559 unknown Sepracor Acid System
receptor antagonist Excitatory Amino 68 nicotinic receptor agonists
Alzheimer's Disease ABT-089 4 to 40 mg daily Abbott Acid System
Peptidergic 69 NK2 antagonist Depression/Anxiety saredutant 100 mg
daily Sanofi-Synthelabo Transmitter System Peptidergic 70 NK3
antagonist Schizophrenia osanetant Sanofi-Synthelabo Transmitter
System NK3 antagonist Schizophrenia/IBS/ talnetant 5 mg daily
GlaxoSmithKline Overactive bladder Excitatory Amino 71 NMDA
antagonist Anxiety SEP174559 Sepracor Acid System NMDA antagonist
Alzheimer's Disease memantine 20 mg daily Lundbeck/Forest
Laboratories NMDA antagonist Depression memantine 20 mg daily
Lundbeck/Forest Laboratories NMDA antagonist Pain memantine 20 mg
daily Lundbeck/Forest Laboratories NMDA antagonist Depression
Delucemine NPS Enzymatic System 72 NSAID Pain meloxicam
Boehringer-Ingelheim Pharmaceutical NSAID Pain piroxicam off patent
NSAID Alzheimer's Disease Flurizan (pure R-enanborner unknown
Myriad Genetics form of flurbiprofen) NSAID Pain MX-1094 Medinox
Excitatory Amino 73 opoid antagonist Alcohol/Drug Dependence
naltrexone depot 192 to 384 mg Drug Abuse Sciences Acid System
opoid antagonist Opiate/Alcohol Dependence depot naltrexone Biotek
microcapsules Excitatory Amino 74 opoid agonist Anxiety Siramesine
unknown Lundbeck/Forest Acid System opoid agonist Cocaine
Dependence cyclazocine National Institute on Drug Abuse opoid
agonist Schizophrenia E-5842 Esteve Enzymatic System 75 PDE4
inhibitor Depression ND1251 Neuro3d PDE4 inhibitor Alzheimer's
disease MEM 1917 (R1497) Roche/Memory Pharm PDE4 inhibitor
Depression MEM 1917 (R1497) Roche/Memory Pharm Peptidergic 76
peptide Depression INN 00835 18 to 160 mg daily Innapharma
Transmitter System peptide Autism secretin 0 2 to 0 4 Repligen
mg/kg daily peptide Female Sexual Dysfunction PT-141 Palatin
Technologies peptide Alzheimer's Disease beta-sheet breaker peptide
Serono Enzymatic System 77 Phospholipase A2 inhibitor Depression
LAX-101c unknown Laxdale with caspase inhibitor activity
Phospholipase A2 inhibitor Depression (bipolar disorder) LAX-101b
Laxdale with caspase inhibitor activity Phospholipase A2 inhibitor
Schizophrenia LAX-101a Laxdale with caspase inhibitor activity
Nucleosides 78 Prodrug of uridine depression (bipolar disorder)
RG2133 (triacetyluridine) unknown Repligen Endocrine System 79
prostaglandin E 1 Female Sexual Dysfunction alprostadil gel 50 to
300 VIVUS microgram/ application Prostaglandin E1 Female Sexual
Dysfunction alprostadil cream NexMed Neurotrophic System 80 protect
dopaminergic and Alzheimer's Disease SR 57667 unknown
Sanofi-Synthelabo cholinergic neurons Excitatory Amino 81
Psychostimulant ADHD modafinil 200 to 600 mg Cephalon Acid System
daily Psychostimulant ADHD SPD 503 unknown Shire Pharmaceutical
Development Psychostimulant Hypersomnia r-modafinil Cephalon
Psychosomulant Cocaine Dependence modafinil National Institute on
Drug Abuse Monoaminergic 82 RIMA Depression/Anxiety moclobemide
Roche Transmitter Systems RIMA Depression/Anxiety toloxatone
Sanofi-Synthelabo RIMA Depression/Anxiety Befloxatone 10 mg daily
Sanofi-Synthelabo RIMA Depression caroxazone F 16654 Farmitalia
RIMA Depression/Anxiety cimoxatone MD RIMA Depression/Anxiety RS
8359 Sankyo Other/Unknown 83 SCT-11 modulation Depression SNEC-2
Synaptic Monoaminergic 84 SDA Schizophrenia quetiapine AstraZeneca
Transmitter Systems SDA Schizophrenia aripiprazole Bristol-Myers
Squibb SDA Schizophrenia risperidone Johnson & Johnson
Pharmaceutical SDA Schizophrenia zotepine Knoll/BASF SDA
Schizophrenia olanzapine Lilly SDA Schizophrenia clozapine Novartis
Pharmaceuticals SDA Schizophrenia ziprasidone Pfizer SDA Depression
(Bipolar olanzapine Eli Lilly Maintainence) SDA Schizophrenia
perospirone unknown Sumitomo SDA Schizophrenia blonanserin unknown
Almirall Prodesfarma SDA Alzheimer's Disease olanzapine Eli Lilly
SDA Alzheimer's Disease aripiprazole Bristol-Myers Squibb SDA
Schizophrenia quetiapine fumarate AstraZeneca (granules) SDA
Schizophrenia quetiapine fumarate AstraZeneca (sustained release)
SDA Schizophrenia paliperidone 3 to 15 mg daily Johnson &
Johnson Pharmaceutical SDA Schizophrenia sertindole 12 to 24 mg
daily Lundbeck SDA Schizophrenia doperidone Novartis
Pharmaceuticals SDA Schizophrenia asenapine 10 mg daily Organon SDA
Schizophrenia SL 91 0177 unknown Sanofi-Synthelabo SDA
Schizophrenia bifeprunox unknown Solvay SDA Schiznphienia
ocaperidone Neuro3d SDA Schizophrenia SM-1349G Sumitomo SDA
Schizophrenia LU 31-131 Lundbeck SDA Schizophrenia BSF-190555 ? SDA
Schizophrenia S-18327 Servier Monoaminergic 85 SDRI
Depression/Anxiety Bazinapeine Sanofi-Synthelabo Transmitter
Systems Monoaminergic 86 Second messenger beta agonist Depression
rolipram 1 5 to 3 mg daily Shering Transmitter Systems Second
messenger beta agonist Depression SR 57227 Sanofi-Synthelabo Second
messenger beta agonist Depression eplivanserin Sanofi-Synthelabo
Second messenger beta agonist Insomnia eplivanserin
Sanofi-Synthelabo Endocrine System 87 Secretin pancreatic hormone
Axiety RG1068 unknown Repligen Secretin pancreatic hormone
Schizophrenia RG1068 unknown Repligen Excitatory Amino 88 sigma
receptor agonist Depression VPI-013 (also known unknown Vela.
Otsuka Acid System as OPC-14523) sigma receptor agonist ADHD
PRX-00023 Predix sigma receptor agonist Anxiety PRX-00023 Predix
Excitatory Amino 89 sigma receptor antagonist Depression/Anxiety
EMD 68843 20 mg daily EMD Pharmaceuticals Acid System Sigma
receptor antagonist Schizophrenia SR 31742 unknown
Sanofi-Synthelabo Monoaminergic 90 SNDRI Alzheimer's Disease NS
2330 unknown Boehringer-Ingelheim
Transmitter Systems Pharmaceuticals SNDRI Depression/Anxiety DOV
216,303 unknown DOV SNDRI Alzheimer's disease DOV 21,947 DOV SNDRI
Depression DOV 21,947 DOV SNDRI Depression McN 5652 McNeil
Monoaminergic 91 SNRI Depression milnacipran 50 to 200 mg daily
Pierre Fabre Transmitter Systems SNRI Depression/Anxiety nelazodone
Mead Johnson SNRI Depression/Anxiety amoxapine Weyth SNRI
Depression/Anxiety venlafaxine 75 to 300 mg daily Wyeth SNRI
Depression/Anxiety duloxetine 40 to 60 mg daily Eli Lilly SNRI ADHD
tomoxetine 1 9 mg/kg/day Lilly SNRI Depression/Anxiety
desvenlafaxine unknown Wyeth SNRI Depression talsupram Lundbeck
SNRI Dppression talopram Lundbeck/Weyth SNRI Depression tandamine
Wyeth SNRI Depression LY 113 821 Lilly Monoaminergic 92 SSRI
Depression/Anxiety paroxetine GlaxoSmithKline Transmitter Systems
SSRI Depression/Anxiety escitalopram 10 to 20 mg daily
Lundbeck/Forest Laboratories SSRI Depression/Anxiety citalopram 10
to 40 mg daily off patent SSRI Depression/Anxiety fluoxetine off
patent SSRI Depression/Anxiety fluvoxamine off patent SSRI
Depression/Anxiety sertraline Pfizer SSRI Anxiety (OCD/Soc Phobia)
fluvoxamine 100 to 300 mg Solvay controlled release daily SSRI
Depression/Anxiety litoxetine unknown Sanofi-Synthelabo SSRI
Depression/Anxiety femoxetine Ferrosan SSRI Depression/Anxiety
ifoxetine Novartis Pharmaceuticals SSRI Depression VPI 013 (also
Vela. Otsuka known as OPC-14523) SSRI Depression/Anxiety EMD 68843
EMD Pharmaceuticals SSRI Depression/Anxiety cericlamine Jouveinal
SSRI Depression Lu 35-138 Lundbeck SSRI Depression/OCD/Pain LY 214
281 Lilly SSRI Depression LU AA 21-004 Lundbeck SSRI
Depression/Anxiety cyanodothepine ? SSRI Depression/Anxiety
ademethionine/s- Sampl-Gibipharma adenosylmethionine SSRI
Depression/Anxiety YM 992 Yamanouchi Peptidergic 93 Substance P
receptor (NK1) antagonist Depression/Anxiety aprepitant 40 to 160
mg Merck Transmitter System daily Substance P receptor (NK1)
antagonist Depression/Anxiety TAK-637 Takeda/Abbott Substance P
receptor (NK1) antagonist Depression/Anxiety GW597599
GlaxoSmithKline Substance P receptor (NK1) antagonist
Depression/Anxiety vestipitant GlaxoSmithKline Substance P receptor
(NK1) antagonist Depression/Anxiety CP-122,721 Pfizer Substance P
receptor (NK1) antagonist Depression/Anxiety R673 Roche Substance P
receptor (NK1) antagonist Depression/Anxiety GW679769
GlaxoSmithKline Substance P receptor (NK1) antagonist
Depression/Anxiety GW823296 GlaxoSmithKline Substance P receptor
(NK1) antagonist Depression/Anxiety 679769 GlaxoSmithKline
Substance P receptor (NK1) antagonist Depression/Anxiety 823296
GlaxoSmithKline Other/Unknown 94 sulfonamide Mania zonisamide 100
to 600 mg Elan Pharmaceuticals daily Peptidergic 95 tachykinin
antagonists Depression/Anxiety SR 48960 unknown Sanofi-Synthelabo
Transmitter System Other/Unknown 96 unknown Alzheimer`s Disease DP
543 unknown Bristol Myers Squibb unknown Depression R228060
(YKP-10A) unknown Johnson & Johnson Parmaceutical unknown
Parkinson`s Disease palanpanel unknown IVAX unknown Premenstrual
Syndrome ORG 39479/PH80 unknown Organon unknown Depression ORG
34167 Organon unknown Dppression CJ-017,493 Pfzier Endocrine System
97 V1B antagonist Depression/Anxiety SSR149415 Sanofi-Synthelabo
Inhibitory Amino 98 modulator Depression/Anxiety Pregabalin 50 to
600 mg Pfizer Acid System daily modulator Pain Pregabalin 50 to 600
mg Pfizer daily modulator Insomnia PD-200,390 Pfizer Other/Unknown
99 vomeropherin Anxiety Acute PH94B Pherin Pharmaceuticals
Monoaminergic 100 dopamine release stimulation Parkinson`s disease
amantadine 100 to 300 mg Transmitter Systems daily dopamine release
stimulation Depression amantadine 100 to 300 mg daily Neurotrophic
System 66 NGF (nerve growth factor) Alzheimer`s Disease xaliproden
unknown Sanofi PHARMACOLOGICAL GROUPS: COMPOUNDS WORKING ON THE
Amino Acid Transmitter System Monoaminergic 1 Transmitter System
Excitatory Amino 2 Acid System Inhibitory Amino 3 Acid System
Peptidergic 4 Transmitter System Adenosine 5 Transmitter System
Endocrine System 6 Enzymatic System 7 Nerve Cell Function System
Neurotrophic System 9 Neuroimmunophilin 10 System Pathogenic
Mechanisms 11 of Dementia of the Alzheimer Type
EXAMPLES
Example 1
Measuring pKi Values of Test Compounds
[0682] In Table 1, the pKi values of test compounds are given for
each of the dopamine receptors, 5HT receptors, adrenergic receptors
and the histamine1 receptor. The affinity of test compounds for the
respective receptors has been performed according to conventional
procedures known in the art.
[0683] An indication "0" means that no affinity has been measured
between the test compound and the receptor.
[0684] The columns displaying the pKi values for the D4 and the
5-HT2A receptor are filled with dark grey. pKi values between 8 and
9 and higher than 9 are represented by light grey boxes.
Example 2
Foregoing Pipamperon-Citalopram Treatment in Major Depressive
Disorder: a Placebo and Active Controlled Period Finding Clinical
Trial
[0685] Table 2 represents the set-up of a clinical trial comprising
for treatment groups:
[0686] Group Plc--Active/Day 0 represents the group receiving 10 mg
citalopram, twice a day, starting the first day (Day 0) of active
treatment in the clinical trial. This administration regime is also
indicated as the mono therapy.
[0687] Group Pip--Active/Day 0 represents the group receiving a
combination of 4 mg pipamperon and 10 mg citalopram, twice a day,
starting the first day (Day 0) of active treatment in the clinical
trial. This administration regime is also indicated as the
non-foregoing combo therapy.
[0688] Group Pip--Active/Day 4 represents the group receiving 4 mg
pipamperon, twice a day, starting the first day (Day 0) of active
treatment in the clinical trial, followed by a combination of 4 mg
pipamperon and 10 mg citalopram, twice a day, starting the fifth
(Day 4) day of active treatment in the clinical trial. This
administration regime is also indicated as the foregoing therapy
with combination therapy starting after 4 days of active
treatment.
[0689] Group Pip--Active/Day 7 represents the group receiving 4 mg
pipamperon, twice a day, starting the first day (Day 0) of active
treatment in the clinical trial, followed by a combination of 4 mg
pipamperon and 10 mg citalopram, twice a day, starting the eight
(Day 7) day of active treatment in the clinical trial. This
administration regime is also indicated as the foregoing therapy
with combination therapy starting after 7 days of active
treatment.
[0690] All subjects also undergo a placebo (PLC) run-in therapy,
administered during a period of about 7 days before the active
treatment starts.
[0691] During daily (D), weekly (W) or monthly (M) visits, several
parameters are measured.
[0692] Under NECT is to be understood: Neuronal E-clinical
Trial=Vesalius Expert development for this trial which includes the
bottom-up measurement of: [0693] In- and exclusion-criteria [0694]
Functional status evaluation [0695] Medical history [0696]
(Pre-)treatment signs & symptoms [0697] DSM-IV rules for
diagnosis & efficacy [0698] HDRS-28 (Hamilton Depression Rating
Scale-28 items) [0699] Medical resource utilisation [0700]
Pre-trial & Concomittant medication [0701] Drug administration
[0702] (Serious) Adverse events [0703] Admission to the acute and
extension phase of treatment [0704] Right flow of the trial
Example 3
Combo Pipamperon-Citalopram: Therapeutic Use in Major
Depression
Purpose
[0705] Pipamperon
(1'-[3-(p-Fluorobenzoyl)propyl]-[1,4'-bipiperidine]-4'-carboxamide),
the active ingredient of Dipiperon (Janssen-Cilag B.V),
administered to patients in a dose ranging between 8 and 12 mg is
claimed via its specific pharmacological properties to be a booster
of the antidepressant effect of the selective serotonin re-uptake
inhibitor citalopram. Preferably, pipamperon is administered daily
at least 4-5 days before administering said antidepressant. The
mechanism of boosting of pipamperon has to deal with (i) the
selective affinity for the dopamine-4 (D4) receptor with a pKi
value equal to or higher than 8 towards the D4 receptor and less
than 8 towards other dopamine receptors, and (ii) the selective
affinity for the 5-HT2A receptor with a pKi value equal to or
higher than 8 towards the 5-HT2A receptor and less than 8 towards
other 5HT receptors. This semi-naturalistic open label study
investigated the efficacy and tolerability of the combo
pipamperon-citalopramin the treatment of patients with major
depression.
Details
[0706] Design: Semi-naturalistic i.e. inclusion of every `natural`
patient in an outpatient practice but without concomitant use of
mood enhancing drugs, open label [0707] Control: No [0708] Phase:
Phase IIa--preliminary Proof of Concept [0709] Location:
Belgium--Research Centre ANIMA, Alken [0710] End Points: Assessment
scale scores, Hamilton Depression Rating Scale 17 items, Reduction,
Response, Remission [0711] Medication: Exclusion of mood
stabilisers, antipsychotics (typical and atypical) and other
antidepressants
Subjects
TABLE-US-00007 [0712] Type No. Sex Age Patients 23 10 male & 13
female 23-80 (mean 47) years
[0713] Characteristics: patients had a major depressive disorder
according to DSM-IV criteria, with or without a chronic course and
a treatment refractory state towards another SSRI then
citalopram.
Treatments
[0714] PIP-CIT.sup.1 Add-on: Citalopram from Day Minus
60-20-Pipamperon from Day 0
TABLE-US-00008 Treatment Drug Dose Route Frequency Duration
Pipamperon.sup.1 + Pip.: 8-12 mg/day - PO bid 8 weeks
Citalopram.sup.1 Cit.: 20-40 mg/day .sup.1Pipamperon (Pip) and
citalopram (Cit) dosage was adjusted according to clinical
response.
[0715] PIP-CIT.sup.1 Fore-Going 1-5: Pipamperon from Day 0-Cital
from Day 1-5
TABLE-US-00009 Treatment Drug Dose Route Frequency Duration
Pipamperon.sup.1 + Pip.: 8-12 mg/day - PO bid 8 weeks
Citalopram.sup.1 Cit.: 20-40 mg/day .sup.1Pipamperon (Pip) and
citalopram (Cit) dosage was adjusted according to clinical
response.
[0716] PIP-CIT.sup.1 Fore-Going 6-8: Pipamperon from Day
0-Citalopram from Day 6-8
TABLE-US-00010 Treatment Drug Dose Route Frequency Duration
Pipamperon.sup.1 + Pip.: 8-12 mg/day - PO bid 8 weeks
Citalopram.sup.1 Cit.: 20-40 mg/day .sup.1Pipamperon (Pip) and
citalopram (Cit) dosage was adjusted according to clinical
response.
Results
TABLE-US-00011 [0717] PIP-CIT add-on PIP-CIT foregoing After 20-60
DAYS 1-5 DAYS 6-8 DAYS (mean 33) (n = 5 ) (mean 4) (n = 15) (mean
7) (n = 3 ) Mean Used Medication Pipamperone 9 mg/day 10 mg/day 11
mg/day Citalopram 30 mg/day 26 mg/day 30 mg/day Depression scale
scores HDRS 17-item total score baseline 29 23 28 endpoint (week 8)
4 5 11 diminishment at week 8 -25 (+8/-9) -18 (+8/-8) -17 (+17/-17)
% reduction at week 8 86 (+14/-12) 80 (+20/-30) 61 (+39/-61)
response.sup.1 at week 8 5 (100%) 15 (100%) 2 (67%) remission.sup.2
at week 8 4 (80%) 10 (67%) 1 (33%) .sup.1Response = .gtoreq.50%
reduction in HDRS 17-item score; .sup.2Remission = HDRS 17-item
score <8
[0718] Notably, the results obtained are highly significant since
the variability in every group is distributed evenly around the
mean.
Add-on PIP-CIT
[0719] FIG. 1 schematically depicts the "add-on" treatment with
pipamperon 8-12 (mean 9) mg (bid) after treatment with citalopram
10-20 (mean 30) mg (bid) during 20-60 (mean 33) days (PIPCIT
ADD-ON) with HDRS-17. Totalscore is 29 at baseline in MDD in
comparison with the standard efficacy of antidepressants in
clinical trials according to Khan et al. (2000), in "Symptom
Reduction and Suicide Risk in Patients Treated With Placebo in
Antidepressant Clinical Trials" (Arch. of General Psychiatry, Vol.
57, April 2000).
[0720] FIG. 2 schematically depicts the HDRS-17 change from
baseline in the combo pipamperon as "add-on" to citalopram vs. SNRI
(duloxetine) in Major Depression. Treatment with pipamperon 8-12
(mean 9 mg/day) during 20-60 (mean 33) days after treatment with
SSRI (n=5). The SNRI (duloxetine) treatment was 40-120 mg/day
(n=152) according to Goldstein et al., (Clin. Psychiatry, in
press).
[0721] FIG. 3 schematically depicts the remission rates (HDRS-17
<=7) with the combo pipamperon as "add-on" to citalopram vs SNRI
(venlafaxine) vs SSRIs vs placebo in Major Depression. Treatment
with pipamperon 8-12 (mean 9 mg/day) during 20-60 (mean 33) days
after treatment with SSRI (n=5). Treatment with the SNRI
venlafaxine is according to a meta-analysis of Thase et al. (Br. J.
Psychiatry (2001) 178:234-241). Treatment with SSRIs is according
to a meta-analysis of Thase et al. (Br. J. Psychiatry (2001)
178:234-241). Treatment with placebo is according to a
meta-analysis of Thase et al. (Br. J. Psychiatry (2001)
178:234-241).
Fore-Going 1-5 PIP-CIT
[0722] FIG. 4 schematically depicts the "fore-going" treatment
during 1-5 (mean 4) days with pipamperon 8-12 (mean 10) mg (bid),
followed with the combination treatment of pipamperon and
citalopram 20-50 (mean 26) mg/day (bid) (PIPCIT FG 1-5) in MDD
(HDRS-17 at BL=23) in comparison with the standard efficacy of
antidepressants in clinical trials according to Khan et al. (2000),
in "Symptom Reduction and Suicide Risk in Patients Treated With
Placebo in Antidepressant Clinical Trials" (Arch. of General
Psychiatry, Vol. 57, April 2000).
[0723] FIG. 5 schematically depicts the HDRS-17 change from
baseline in the combo pipamperon-citalopram treatment with a
"fore-going" treatment of 4 days with pipamperon (10 mg/day) vs
SNRI (duloxetine) in Major Depression. Treatment with the combo
pipamperon-citalopram with pipamperon 8-12 (mean 10 mg/day) (bid)
1-5 (mean 4) days before treatment with SSRI (n=15). The SNRI
(duloxetine) treatment was 40-120 mg/day (n=152) according to
Goldstein et al., (Clin. Psychiatry, in press).
[0724] FIG. 6 schematically depicts the remission rates (HDRS-17
<=7) with the combo pipamperon with a "fore-going" treatment of
4 days with pipamperon (10 mg/day) vs SNRI (venlafaxine) in Major
Depression. Treatment with the combo pipamperon-citalopram was with
pipamperon 8-12 (mean 10 mg/day) during 1-5 (mean 4) days before
treatment with the SSRI (n=5). Treatment with the SNRI venlafaxine
is according to a meta-analysis of Thase et al. (Br. J. Psychiatry
(2001) 178:234-241). Treatment with SSRIs is according to a
meta-analysis of Thase et al. (Br. J. Psychiatry (2001)
178:234-241). Treatment with placebo is according to a
meta-analysis of Thase et al. (Br. J. Psychiatry (2001)
178:234-241).
Fore-Going 6-8 PIP-CIT
[0725] FIG. 7 schematically depicts the "fore-going" treatment
during 6-8 (mean 7) days with pipamperon 8-12 (mean 11) mg/day
(bid), followed with the combination treatment of pipamperon and
citalopram 20-40 (mean 30) mg/day (bid) (PIPCIT FG 6-8) in MDD
(HDRS-17 at BL=28) in comparison with the standard efficacy of
antidepressants in clinical trials according to Khan et al. (2000),
in "Symptom Reduction and Suicide Risk in Patients Treated With
Placebo in Antidepressant Clinical Trials" (Arch. of General
Psychiatry, Vol. 57, April 2000).
[0726] FIG. 8 schematically depicts the HDRS-17 change from
baseline in the combo pipamperon-citalopram treatment with a
"fore-going" treatment of 7 days with pipamperon (11 mg/day) vs
SNRI (duloxetine) in Major Depression. Treatment with the combo
pipamperon-citalopram with pipamperon 8-12 (mean 11 mg/day) (bid)
6-8 (mean 7) days before treatment with SSRI (n=3). The SNRI
(duloxetine) treatment was 40-120 mg/day (n=152) according to
Goldstein et al., (Clin. Psychiatry, in press).
Comparison "Add-on" Vs "Fore-Going"
[0727] FIG. 9 schematically depicts a comparison between
"fore-going" and "add-on" treatments with pipamperon (8-12 mg/day;
bid) and citalopram (20-40 mg/day; bid) in MDD in comparison with
the standard efficacy of antidepressants in clinical trials
according to Khan et al. (2000), in "Symptom Reduction and Suicide
Risk in Patients Treated With Placebo in Antidepressant Clinical
Trials" (Arch. of General Psychiatry, Vol. 57, April 2000).
[0728] FIG. 10 schematically depicts a comparison between
"fore-going" and "add-on" treatments. In particular, the HDRS-17
change from baseline between "fore-going" and "add-on" treatment
with pipamperon (8-12 mg/day; bid) and citalopram (20-40 mg/day;
bid) in comparison with the SNRI duloxetine in Major Depression is
depicted. Treatment with the combo pipamperon as "add-on" to
citalopram, with pipamperon 8-12 mg/day (mean 9 mg/day) 20-60 (mean
33) days after treatment with the SSRI (n=5). Treatment with the
combo pipamperon-citalopram, with pipamperon 8-12 mg/day (mean 11
mg/day; bid) 6-8 days (mean 7 days) before treatment with the SSRI
(n=15). Treatment with the combo pipamperon-citalopram, with
pipamperon 8-12 mg/day (mean 10 mg/day; bid) 1-5 days (mean 4 days)
before treatment with the SSRI (n=15). The SNRI (duloxetine)
treatment was 40-120 mg/day (n=152) according to Goldstein et al.,
(Clin. Psychiatry, in press).
[0729] FIG. 11 schematically depicts the remission rates (HDRS-17
<=7) in a comparison between "fore-going" and "add-on" treatment
with pipamperon (8-12 mg/day; bid) and citalopram (20-40 mg/day;
bid) in comparison with the SNRI venlafaxine in Major Depression.
Treatment with the combo pipamperon-citalopram was with pipamperon
8-12 (mean 10 mg/day) during 1-5 (mean 4) days before treatment
with the SSRI (n=15). Treatment with the SNRI venlafaxine is
according to a meta-analysis of Thase et al. (Br. J. Psychiatry
(2001) 178:234-241). Treatment with pipamperon as "add-on" to
citalopram, with pipamperon 8-12 (mean 9 mg/day) during 20-60 (mean
33) days after treatment with SSRI (n=5).
[0730] The intention-to-treat/last-observation-carried-forward
analysis showed a high therapeutic efficacy according HDRS 17-item
in all the treatment groups. This was especially true for the
`add-on` group probably caused by the longer treatment with an
active antidepressant (+33 days). The huge therapeutic effect
observed in the `PIP-CIT 1-5` group present for at a mean dosage of
pipamperon of 10 mg per day and administered the first four days of
treatment without an active antidepressant, indicates the boosting
effect of pipamperon on the SSRI citalopram at an extremely and
thus unconventional low dose. Only 1 patient discontinued treatment
due to a lost of follow-up.
Adverse Events
TABLE-US-00012 [0731] PIP-CIT add-on PIP-CIT After 20-60 foregoing
6-8 DAYS DAYS (mean 33) 1-5 DAYS (mean (mean 7) Side effects
(patients) (n = 5 ) 4) (n = 15) (n = 3) Discontinued treatment 0 0
0 due to adverse events By system: body as a whole 0 0 0 central
and peripheral 1 (20%) 4 (26.6%) 0 nervous system gastrointestinal
1 (20%) 5 (33%) 2 (66.6%) musculoskeletal 1 (20%) 3 (20%) 0
psychiatric 0 0 0 respiratory 0 1 (6.6%) 0 skin and appendages 1
(20%) 2 (13.3%) 1 (33.3%) vascular 0 1 (6.6%) 0 urinary 0 1 (6.6%)
0
[0732] Laboratory parameters, ECG, bodyweight and vital signs were
not measured since this was a naturalistic study.
Assessment
Outcome
[0733] Efficacy: the 4-day fore-going combo pipamperon 8-12
mg/d-citalopram 20-40 mg/day is comparable to the add-on combo
pipamperon-citalopram.
[0734] Efficacy: the 4-day fore-going combo pipamperon 8-12
mg/d-citalopram 20-40 mg/day is larger than the 7-day fore-going
combo pipamperon 8-12 mg/d-citalopram 20-40 mg/day.
[0735] Efficacy: the combo pipamperon 8-12 mg/d-citalopram 20-40
mg/day is larger than the in the art known antidepressants
SSRIs.
Tolerability
[0736] Tolerability: the 4-day fore-going treatment is comparable
to the 7-day fore-going combo is comparable to add-on combo
pipamperon-citalopram.
[0737] Tolerability: no discontinued treatment due to adverse
events.
Study Messages
[0738] The boosting effect of pipamperon at an extremely
unconventional low dose on a SSRI is indicated since the efficacy
of the `add-on` and `4-day fore-going` combo `pipamperon 8-12
mg/d-citalopram 20-40 mg/day` is in this study as twice higher as
known in the art in the treatment of patients with major
depression.
[0739] The combo pipamperon-citalopram is generally well tolerated
in patients with depression i.e. at least no specific added adverse
events were occurring by adding pipamperon at the doses used in the
study.
Example 4
Combo Pipamperon-Citalopram: Therapeutic Use in
Obsessive-Compulsive Disorder (OCD)
Purpose
[0740] Pipamperon
(1'-[3-(p-Fluorobenzoyl)propyl]-[1,4'-bipiperidine]-4'-carboxamide),
the active ingredient of Dipiperon (Janssen-Cilag B.V),
administered to a patient in a dose ranging between 8 and 12 mg is
claimed via its specific pharmacological properties to be a booster
of the effect of the selective serotonin re-uptake inhibitor
citalopram towards OCD. Preferably, pipamperon is administered
daily at least 4-5 days before administering said antidepressant.
The mechanism of boosting of pipamperon has to deal with (i) the
selective affinity for the dopamine-4 (D4) receptor with a pKi
value equal to or higher than 8 towards the D4 receptor and less
than 8 towards other Dopamine receptors, and (ii) the selective
affinity for the 5-HT2A receptor with a pKi value equal to or
higher than 8 towards the 5-HT2A receptor and less than 8 towards
other 5HT receptors. This semi-naturalistic open label study
investigated the efficacy and tolerability of the combo
pipamperon-citalopram in the treatment of patients with OCD.
Details
[0741] Design: Semi-naturalistic i.e. inclusion of every `natural`
patient in an outpatient practice but without concomitant use of
mood enhancing drugs, open label [0742] Control: No [0743] Phase:
Phase IIa--preliminary Proof of Concept [0744] Location:
Belgium--Research Centre ANIMA, Alken [0745] End Points: Assessment
scale scores, Yale-Brown Obsessive-Compulsive Scale, Reduction,
Remission [0746] Medication: Exclusion of mood stabilisers,
antipsychotics (typical and atypical) and other antidepressants
Subjects
TABLE-US-00013 [0747] Type No. Sex Age Patients 7 1 male & 7
female 20-63 (mean 33) years
[0748] Characteristics: patients had an obsessive-compulsive
disorder according to DSM-IV criteria, with or without a chronic
course and a treatment refractory state towards another SSRI then
citalopram.
Treatments
[0749] PIP-CIT.sup.1 Add-on: Citalopram from Day Minus
730-60-Pipamperon from Day 0
TABLE-US-00014 Treatment Drug Dose Route Frequency Duration
Pipamperone.sup.1 + Pip.: 8-16 mg/day - PO bid 12 weeks
Citalopram.sup.1 Cit.: 30-80 mg/day .sup.1Pipamperone (Pip) and
Citalopram (Cit) dosage was adjusted according to clinical
response.
PIP-CIT.sup.1 Fore-Going 4-6: Pipamperon from Day 0-Citalopram from
Day 4-6
TABLE-US-00015 Treatment Drug Dose Route Frequency Duration
Pipamperone.sup.1 + Pip.: 8-16 mg/day - PO bid 12 weeks
Citalopram.sup.1 Cit.: 30-80 mg/day .sup.1Pipamperone (Pip) and
Citalopram (Cit) dosage was adjusted according to clinical
response.
Results
TABLE-US-00016 [0750] Y-BOCS score Baseline Total 31 Obsessions 18
Compulsions 13 Endpoint (week 12) Total 15 diminishment -16
(+16/-11) % reduction 53 Obsessions total 8 diminishment -10
(+9/-7) % reduction 57 Compulsions total 7 diminishment -6 (+7/-6)
% reduction 45 % Remission YBOCS score .ltoreq.8 29 BOCS score
.ltoreq.16 57 PIP-CIT add-on after 730-60 DAYS (mean 241) (n = 6)
with mean Cit. 54 mg/d and Pip. 11 mg/d PIP-CIT foregoing 4-6 DAYS
(mean 5) (n = 2) with mean Cit. 60 mg/d and Pip. 10 mg/d
[0751] Notably, the results obtained are highly significant since
the variability in every group is distributed evenly around the
mean.
[0752] FIG. 12 schematically depicts the Y-BOCS total score:
"fore-going" and "add-on" treatment with pipamperon (8-15 mg/day;
bid) and citalopram (30-80 mg/day; bid) in comparison with the SSRI
fluvoxamine in OCD. Treatment with the combo pipamperon-citalopram
(n=7). Treatment with fluvoxamine (controlled release) mean 271
mg/day (n=253) is according to Hollander et al. (2003).
[0753] FIG. 13 schematically depicts the Y-BOCS obsession score:
"fore-going" and "add-on" treatment with pipamperon (8-15 mg/day;
bid) and citalopram (30-80 mg/day; bid) in comparison with the SSRI
fluvoxamine in OCD. Treatment with the combo pipamperon-citalopram
(n=7). Treatment with fluvoxamine (controlled release) mean 271
mg/day (n=253) is according to Hollander et al. (2003).
[0754] FIG. 14 schematically depicts the Y-BOCS compulsion score:
"fore-going" and "add-on" treatment with pipamperon (8-16 mg/day;
bid) and citalopram (30-80 mg/day; bid) in comparison with the SSRI
fluvoxamine in OCD. Treatment with the combo pipamperon-citalopram
(n=7). Treatment with fluvoxamine (controlled release) mean 271
mg/day (n=253) is according to Hollander et al. (2003).
[0755] The intention-to-treat/last-observation-carried-forward
analysis showed a high therapeutic efficacy according Y-BOCS total
score, obsession and compulsion scores. This indicates the boosting
effect of pipamperon on the SSRI citalopram at an extremely and
thus unconventional low dose. No patient discontinued
treatment.
Assessment
[0756] Efficacy: the combo pipamperone 8-16 mg/d-citalopram 30-80
mg/day>the in the art known compounds effective towards OCD
(Hollander E, Koran L M, Goodman W K, Greist J H, Ninah P T, et al.
A double-blind, placebo-controlled study of the efficacy and safety
of controlled-release fluvoxamine in patients with
obsessive-compulsive disorder. Journal of Clinical Psychiatry 64:
640-647, June 2003 Mount Sinai School of Medicine, New York, N.Y.,
USA; Solvay Pharmaceuticals Inc., Marietta, Ga., USA).
Study Messages
[0757] The boosting effect of pipamperon at an extremely
unconventional low dose on a SSRI is indicated since the efficacy
of the `add-on` and `fore-going` combo `pipamperon 8-15
mg/d-citalopram 30-80 mg/day` is in this study as twice higher as
known in the art in the treatment of patients with
obsessive-compulsive disorder.
Example 5
Combo Pipamperon-Citalopram: Therapeutic Use in Panic Disorder
Purpose
[0758] Preliminary examination of a "fore-going" and "add-on"
treatment with pipamperon and citalopram in comparison with the
SSRI in Panic Disorder.
Results
[0759] The results are indicated in FIG. 15. FIG. 15 schematically
depicts the CGI-severity score: "fore-going" and "add-on" treatment
with pipamperon (8 mg/day; bid) and citalopram (20-40 mg/day; bid)
in comparison with the SSRI in Panic Disorder. Treatment with the
combo pipamperon-citalopram (n=3). Treatment with paroxetine is
according to the Journal of Clinical Psychiatry (2004) 65: 405-413.
Treatment with Sertraline is according to the Journal of Clinical
Psychiatry (2004) 65: 405-413.
Conclusion
[0760] Notably, although a small test group has been used (n=3),
the distribution around the mean is good. It will further be
apparent from FIG. 15 that the effect of the combo treatment of
pipamperon and citalopram is twice as high as the standard
treatments with paroxetine or sertraline.
Example 6
POC Process for Mayor Depressive Disorder
[0761] Concept: Combo of the High Selective 5-HT2A/D4 Antagonist
Pipamperon with: [0762] a compound active towards the Amino Acid
Transmitter, Peptidergic Transmitter, Adenosine Transmitter,
Endocrine and/or Enzymatic System; [0763] a fore-going admission
during 4 days of pipamperon; [0764] a dose of pipamperon of 12
mg/day Objectives: Demonstrating that this Combo Therapy has:
[0765] the potency of being a treatment standard for depression by
having an added value of reducing the total score of the Hamilton
Depression Rating Scale-17 items (HDRS-17) after 8 weeks of therapy
with a least 20% more than reached with the conventional known
antidepressants, i.e. 60% versus 40%. This stands for an added
medium demission of 5 points on the total score of the HDRS-17 and
by this will be very highly significant since the mean difference
in all recent clinical trials between placebo and active treatment
is 2.5; [0766] a more sustained therapeutic effect than the
conventional mono therapy by preventing significant more relapses
during 48 weeks following the acute treatment; and/or [0767] a
complete neutral safety profile, e.g. there are no more adverse
events in the combo therapy then in mono admission of the in the
combo used antidepressant compound. Process: the Following
Different Steps were Implemented to Reach Out for these Objectives
(See Also Tables 3 and 4): [0768] (1) an naturalistic open label
study (n=>20) on a depressive population with a normal
variability of medical and psychiatric history, course of
depression, earlier and concomitant therapy admitting the golden
standard antidepressant citalopram 20-40 mg/day and a dose of 8-12
mg/day of pipamperon in a foregoing, simultaneous or add-on use.
[0769] (2) a 16 weeks placebo controlled randomised four armed
study of each 36 patients with a mayor depressive disorder
admitting: [0770] from day 0: placebo or pipamperon (PIP) 10 mg/day
or an active antidepressant compound or the combination of the last
two; [0771] from day 4: placebo or pipamperon 10 mg/day combined
with an active antidepressant compound or an active antidepressant
compound without pipamperon. By including rigorous control groups
(placebo and active comparator; see Tables 3 and 4) this clinical
trial is evaluated as a proof of concept of the added value of the
combo and the foregoing treatment method since the
inclusion/exclusion of: [0772] a negative trial, i.e. no
significant difference between the placebo and active treatment
with the comparator; [0773] a failed trial, i.e. no significant
difference between the active and the studied treatment i.e. the
combo. [0774] (3) an active controlled randomised relapse
prevention study following the POC trial during another 36 weeks
with three arms of each 36 patients which is formed by: [0775]
continuation of the active mono therapy; [0776] randomising the
patients with a combo therapy in a group with an active mono
therapy and with a continuation of the combo treatment.
* * * * *
References