U.S. patent application number 15/572409 was filed with the patent office on 2019-03-07 for treatment of debilitating fatigue.
The applicant listed for this patent is A. CARLSSON RESEARCH AB. Invention is credited to Arvid Carlsson, Carl-Gerhard Gottfries.
Application Number | 20190070156 15/572409 |
Document ID | / |
Family ID | 56014983 |
Filed Date | 2019-03-07 |
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United States Patent
Application |
20190070156 |
Kind Code |
A2 |
Carlsson; Arvid ; et
al. |
March 7, 2019 |
Treatment of Debilitating Fatigue
Abstract
The present disclosure relates to a dopamine stabilizing agent
and an anti-depressive agent for use in the treatment of disorders
characterized by debilitating fatigue, such as myalgic
encephalomyelitis (ME)/Chronic fatigue syndrome (CFS), fibromyalgia
(FM) and depression, as well as of combinations thereof. Related
treatment methods, pharmaceutical compositions and combination kits
are also disclosed.
Inventors: |
Carlsson; Arvid; (Goteborg,
SE) ; Gottfries; Carl-Gerhard; (Goteborg,
SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
A. CARLSSON RESEARCH AB |
Goteborg |
|
SE |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20180169081 A1 |
June 21, 2018 |
|
|
Family ID: |
56014983 |
Appl. No.: |
15/572409 |
Filed: |
May 11, 2016 |
PCT Filed: |
May 11, 2016 |
PCT NO: |
PCT/EP2016/060562 PCKC 00 |
371 Date: |
November 7, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/137 20130101;
A61P 25/00 20180101; A61K 2300/00 20130101; A61K 31/445 20130101;
A61K 45/06 20130101; A61K 31/445 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/445 20060101
A61K031/445; A61K 45/06 20060101 A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
May 13, 2015 |
SE |
1550618-1 |
Claims
1. A method of treating a subject for a disorder characterized by
debilitating fatigue, comprising: administering a dopamine
stabilizing agent and an anti-depressive agent to the subject,
wherein the dopamine stabilizing agent is selected from the group
consisting of iv) a compound of formula I ##STR00010## wherein:
R.sup.1 and R.sup.2 are independently selected from the group
consisting of H, provided that not more than one of R.sup.1 and
R.sup.2 is H, CONH.sub.2, OH, CN, CH.sub.2CN, OSO.sub.2CH.sub.3,
OSO.sub.2CF.sub.3, SSO.sub.2CF.sub.3, COR, SO.sub.xCH.sub.3,
SO.sub.xCF.sub.3, O(CH.sub.2).sub.xCF.sub.3, where x is 0-2,
OSO.sub.2N(R).sub.2, CH.dbd.NOR, COCOOR, CO--COON(R).sub.2,
C.sub.3-8 cycloalkyl, NRSO.sub.2CF.sub.3, phenyl at position 2, 3
or 4, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, N-pyrrolinyl,
triazolyl and tetrazolyl of pyridinyl; R.sup.3 is independently
selected from the group consisting of H, CF.sub.3,
CH.sub.2CF.sub.3, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.4-C.sub.9 cycloalkyl-methyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, 3,3,3-trifluoropropyl,
4,4,4-trifluorobutyl and CH.sub.2SCH.sub.3, R.sup.4 and R are
independently selected from the group consisting of H,
CF.sub.3CH.sub.2CF.sub.3, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.4-C.sub.9 cycloalkyl-methyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, 3,3,3-trifluoropropyl,
4,4,4-trifluorobutyl and --(CH.sub.2)m-R.sup.5 where m is 1-8;
R.sup.5 is independently selected from the group consisting of
phenyl, phenyl substituted with CN, CF.sub.3, CH.sub.2CF.sub.3,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.9
cycloalkyl-methyl, C.sub.2-C.sub.8 alkenyl or C.sub.2-C.sub.8
alkynyl substituent , 2-thiophenyl, 3-thiophenyl,
--NR.sup.6CONR.sup.6R.sup.7 and --CONR.sup.6R.sup.7; and R.sup.6
and R.sup.7 are independently selected from the group consisting of
H, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.4-C.sub.9 cycloalkyl-methyl, C.sub.2-C.sub.8 alkenyl and
C.sub.2-C.sub.8 alkynyl; v) a compound of formula II ##STR00011##
wherein: R.sub.1 is independently selected from the group
consisting of OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3, SOR.sub.3,
SO.sub.2R.sub.3, COCH.sub.3 and COCH.sub.2CH.sub.3, wherein R.sub.3
is as defined below; R.sub.2 is independently selected from the
group consisting of C.sub.2-C.sub.4 branched or unbranched alkyls,
terminal allyl, CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2CH.sub.2F, CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl
and 4,4,4-trifluorobutyl, R.sub.3 is independently selected from
the group consisting of C.sub.1-C.sub.3 alkyls, CF.sub.3, and
N(CH.sub.3).sub.2; and vi) a compound of formula III ##STR00012##
wherein: X is independently selected from the group consisting of
N, CH and C, provided that X may only be C when the compound
comprises a double bond at the dotted line; R.sub.1 independently
is selected from the group consisting of OSO.sub.2CF.sub.3,
OSO.sub.2CH.sub.3, SOR.sub.5, SO.sub.2R.sub.5, COR.sub.5, CN,
NO.sub.2, CONHR.sub.5, CF.sub.3, 3-thiophene, 2-thiophene,
3-furane, 2-furane, F, Cl, Br, and I, wherein R.sub.5 is as defined
below; R.sub.2 is independently selected from the group consisting
of C.sub.1-C.sub.4 alkyls, allyls, CH.sub.2SCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2F,
CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and
--(CH.sub.2)--R.sub.6, wherein R.sub.6 is as defined below; R.sub.3
and R.sub.4 are independently selected from the group consisting of
H and C.sub.1-C.sub.4 alkyls, provided that both R.sub.3 and
R.sub.4 cannot be H at the same time; R.sub.5 is independently
selected from the group consisting of C.sub.1-C.sub.3 alkyls,
CF.sub.3 and N(R.sub.2).sub.2, wherein R.sub.2 is as defined above;
and R.sub.6 is independently selected from the group consisting of
C.sub.3-C.sub.6 cycloalkyls, 2-tetrahydrofurane and
3-tetra-hydrofurane; and pharmaceutically acceptable salts of any
one of the compounds of formula I, II or III.
2. The method of claim 1, wherein in formula I R.sup.1 is
independently selected from the group consisting of CN,
OSO.sub.2CF.sub.3 and SO.sub.2CH.sub.3; R.sup.2 is H; R.sup.3 is
C.sub.1-8 alkyl, such as n-propyl; and R.sup.4 is H.
3. The method of claim 1, wherein said dopamine stabilizing agent
is (3S)-3-[3-(methylsulfonyephenyl]-1-propylpiperidine or a
pharmaceutically acceptable salt thereof, such as
(3S)-3-[3-(methylsulfonyephenyl]-1-propylpiperidine
hydrochloride.
4. The method of claim 1, wherein said anti-depressive agent is
selected from the group consisting of selective serotonin reuptake
inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors
(SNRIs), serotonin modulators and stimulators (SMSs), serotonin
reuptake inhibitors (SARIS), norephinephrine reuptake inhibitors
(NRIs), tricyclic antidepressants (TCAs), monoamine oxidase
inhibitors (MAOIs), tetracyclic antidepressants (TeCAs),
noradrenergic and specific serotonergic antidepressant (NaSSAs),
buprenorphine, low-dose antipsychotics and St John's wort, such as
the group consisting of selective serotonin reuptake inhibitors
(SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI) and
tricyclic antidepressants (TCAs), such as the group consisting of
selective serotonin reuptake inhibitors (SSRI) and
serotonin-norepinephrine reuptake inhibitors (SNRI).
5. The method of claim 1, wherein said use involves concomitant or
simultaneous administration of said dopamine stabilizing agent and
said anti-depressive agent.
6. The method of claim 1, wherein said disorder is selected from
the group consisting of myalgic encephalomyelitis/chronic fatigue
syndrome, fibromyalgia, mental fatigue, post stroke fatigue,
Huntington's disease, Parkinson's disease, multiple sclerosis,
narcolepsy, post cancer fatigue, fatigue associated with cancer
with or without cytostatic treatment, depression and combinations
thereof.
7. The method of claim 1, wherein said disorder is a fatigue
disorder or pain disorder characterized by at least one of the
conditions selected from fibromyalgia, mental fatigue, myalgic
encephalomyelitis/chronic fatigue syndrome and depression.
8. The method of claim 1, wherein said dopamine stabilizing agent
is administered in a dose of approximately 0.1-45 mg, such as 0.1-5
mg or such as approximately 1-45 mg, such as approximately 1-30 mg,
such as approximately 5-30 mg, such as approximately 10-30 mg, such
as 15 mg or 30 mg.
9. The method of claim 1, wherein said dopamine stabilizing agent
is administered once, twice or three times a day, such as once or
twice a day.
10. The method of claim 1, wherein, upon administration, the
therapeutically effective blood plasma concentration of said
dopamine stabilizing agent is approximately 0.1-0.7 .mu.M, such as
approximately 0.3-0.7 .mu.M.
11. A pharmaceutical composition comprising a dopamine stabilizing
agent as defined in claim 1 and an anti-depressive agent.
12. A kit comprising a dopamine stabilizing agent as defined in
claim 1 and an anti-depressive agent.
13. A method of treating a subject for a disorder characterized by
debilitating fatigue, comprising administering the pharmaceutical
composition of claim 11 to the patient.
14. A method of treating a subject for a disorder characterized by
debilitating fatigue, comprising administering the dopamine
stabilizing agent and the anti-depressive agent of the kit of claim
12 to the patient.
Description
FIELD OF THE INVENTION
[0001] The present disclosure relates to a combination of a
dopamine stabilizing agent and an anti-depressive agent for use in
the treatment of disorders characterized by debilitating fatigue,
such as myalgic encephalomyelitis (ME)/Chronic fatigue syndrome
(CFS), fibromyalgia (FM) and depression, as well as of combinations
thereof. Related treatment methods, pharmaceutical compositions and
combination kits are also disclosed.
BACKGROUND
[0002] Myalgic encephalomyelitis (ME), also known as Chronic
fatigue syndrome (CFS), refers to a group of debilitating medical
conditions characterized by persistent fatigue and other specific
symptoms that last for a minimum of six months in adults (and 3
months in children or adolescents). This disease is also referred
to as systemic exertion intolerance disease (SEID), post-viral
fatigue syndrome (PVFS) and chronic fatigue immune dysfunction
syndrome (CFIDS).
[0003] ME/CFS is characterized by persistent and debilitating
fatigue, diffuse musculoskeletal pain, sleep disturbances,
neuropsychiatric symptoms and cognitive impairment which cannot be
explained by an underlying medical condition. The symptoms of
ME/CFS are not caused by ongoing exertion and are not relieved by
rest.
[0004] ME/CFS is a symptom-based diagnosis or clinical diagnosis
without distinguishing physical examination or routine laboratory
findings. Infectious, immunological, neuroendocrine, sleep and
psychiatric mechanisms have been investigated; however, a unifying
etiology for ME/CFS has not yet emerged. The majority of ME/CFS
cases start suddenly and they are usually accompanied by a
"flu-like illness", while a significant proportion of cases begin
within several months of severe adverse stress (Afari N et al
(2003), Am J Psychiatr 160 (2): 221-36). Often, there are courses
of remission and relapse of symptoms which make the illness
difficult to manage. Persons who feel better for a period may
overextend their activities, and the result can be a worsening of
their symptoms with a relapse of the illness.
[0005] ME/CFS often occurs together with other diseases such as
fibromyalgia (FM), multiple chemical sensitivities, irritable bowel
syndrome and temporomandibular joint disorder. In particular,
co-morbidity with fibromyalgia has been studied (Afari N et al,
supra). Fibromyalgia is a nonarticular rheumatic syndrome
characterized by myalgia and multiple points of focal muscle
tenderness to palpation (trigger points). Patients with FM often
experience muscle pain aggravated by inactivity or exposure to
cold. This condition is often associated with general symptoms,
such as sleep disturbances, fatigue, stiffness, headaches and
occasionally depression.
[0006] Despite the contrasting definitions of the two disorders,
20-70% of patients with fibromyalgia also meet the criteria for
chronic fatigue syndrome, and conversely, 35-70% of those with
chronic fatigue syndrome-like illnesses have concurrent
fibromyalgia (Afari N et al, supra).
[0007] ME/CFS is a common disorder. Estimates of the prevalence of
ME/CFS range from 0.07% to 2.8% in the general adult population and
is lower in children and adolescents (Afari N et al, supra). The
prevalence of the related fibromyalgia (FM) is 2-4%. This means
that in Sweden at least 40 000 patients suffer from ME/CFS and 270
000 from FM (for review see Zachrisson O (2002); Fatigue
Syndrome-aspects on biology, treatment and symptom evaluation
[dissertation]. ISBN 91-628-5386-4. Gothenburg University).
[0008] Many patients suffering from ME/CFS experience significant
functional impairment. Nearly all patients with ME/CFS notice a
decrease in social relationships in addition to other unwanted
consequences of illness; about one-third are unable to work or
study, and another one-third can only work part-time (Afari N et
al, supra). Many patients suffering from ME/CFS also experience
depression symptoms and are diagnosed with clinical depression, and
likewise, patients who suffer from depression often experience
symptoms of debilitating fatigue.
[0009] Currently, patients suffering from ME/CFS are treated by
cognitive behavioral therapy (CBT) or graded exercise therapy
(GET), which have shown moderate effectiveness in multiple
randomized controlled trials, however many patients do not make
recovery (Rimes K A et al (2005), Occupational Medicine 55(1):
32-39;Chambers D et al (2006). Journal of the Royal Society of
Medicine 99(10): 506-20). At present, medication plays a minor role
in disease management (Van Houdenhove B et al (2010) Expert opinion
on pharmacotherapy 11(2): 215-23).
[0010] Additionally, many disorders, in addition to ME/CFS and FM,
are characterized by symptoms of debilitating fatigue. Such
disorders include mental fatigue, post stroke fatigue, Huntington's
disease, Parkinson's disease, multiple sclerosis, narcolepsy, post
cancer fatigue, fatigue associated with cancer with or without
cytostatic treatment, depression and combinations thereof.
[0011] Thus there is a large need for novel therapies and
treatments to alleviate fatigue symptoms, such as ME/CFS associated
fatigue symptoms and fatigue symptoms associated with other
clinical indications, and thus the provision thereof remains a
matter of substantial interest within the field.
SUMMARY OF THE INVENTION
[0012] It is an object of the present disclosure to provide to a
new and efficient treatment for patients who are suffering from
disorders characterized by persistent and debilitating fatigue.
[0013] It is an object of the present disclosure to provide a
medicament for use in the treatment of said patients.
[0014] It is another object of the present disclosure to provide a
method of treatment of a disorder characterized by debilitating
fatigue for patients in need thereof.
[0015] These and other objects which are evident to the skilled
person from the present disclosure are met by different aspects of
the invention as claimed in the appended claims and as generally
disclosed herein.
[0016] The present inventors have unexpectedly found that the
clinical outcome of treatment of disorders characterized by
debilitating fatigue is significantly improved by the combination
of a dopamine stabilizing agent and an anti-depressive agent.
[0017] Thus, in the first aspect of the disclosure, there is
provided a dopamine stabilizing agent and an anti-depressive agent
for use in the treatment of a disorder characterized by
debilitating fatigue, wherein said dopamine stabilizing agent is
selected from the group consisting of
[0018] i) a compound of formula I
##STR00001##
[0019] wherein:
[0020] R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, provided that not more than one of R.sup.1
and R.sup.2 is H, CONH.sub.2, OH, CN, CH.sub.2CN,
OSO.sub.2CH.sub.3, OSO.sub.2CF.sub.3, SSO.sub.2CF.sub.3, COR,
SO.sub.xCH.sub.3, SO.sub.xCF.sub.3, O(CH.sub.2).sub.xCF.sub.3,
where x is 0-2, OSO.sub.2N(R).sub.2, CH.dbd.NOR, COCOOR,
COCOON(R).sub.2, C.sub.3-8 cycloalkyl, NRSO.sub.2CF.sub.3, phenyl
at position 2, 3 or 4, thienyl, furyl, pyrrolyl, oxazolyl,
thiazolyl, N-pyrrolinyl, triazolyl and tetrazolyl of pyridinyl;
[0021] R.sup.3 is independently selected from the group consisting
of H, CF.sub.3, CH.sub.2CF.sub.3, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.9 cycloalkyl-methyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and
CH.sub.2SCH.sub.3,
[0022] R.sup.4 and R are independently selected from the group
consisting of H, CF.sub.3CH.sub.2CF.sub.3, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.9 cycloalkyl-methyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and
--(CH.sub.2)m-R.sup.5 where m is 1-8;
[0023] R.sup.5 is independently selected from the group consisting
of phenyl, phenyl substituted with CN, CF.sub.3, CH.sub.2CF.sub.3,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.9
cycloalkyl-methyl, C.sub.2-C.sub.8 alkenyl or C.sub.2-C.sub.8
alkynyl substituent, 2-thiophenyl, 3-thiophenyl,
--NR.sup.6CONR.sup.6R.sup.7 and --CONR.sup.6R.sup.7; and
[0024] R.sup.6 and R.sup.7 are independently selected from the
group consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.4-C.sub.9 cycloalkyl-methyl,
C.sub.2-C.sub.8alkenyl and C.sub.2-C.sub.8 alkynyl;
[0025] ii) a compound of formula II
##STR00002##
[0026] wherein:
[0027] R.sub.1 is independently selected from the group consisting
of OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3, SOR.sub.3,
SO.sub.2R.sub.3, COCH.sub.3 and COCH.sub.2CH.sub.3, wherein R.sub.3
is as defined below;
[0028] R.sub.2 is independently selected from the group consisting
of C.sub.2-C.sub.4 branched or unbranched alkyls, terminal allyl,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2F,
CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl and
4,4,4-trifluorobutyl,
[0029] R.sub.3 is independently selected from the group consisting
of C.sub.1-C.sub.3 alkyls, CF.sub.3, and N(CH.sub.3).sub.2;
[0030] and
[0031] iii) a compound of formula III
##STR00003##
[0032] wherein:
[0033] X is independently selected from the group consisting of N,
CH and C, provided that X may only be C when the compound comprises
a double bond at the dotted line;
[0034] R.sub.1 is independently selected from the group consisting
of OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3, SOR.sub.5,
SO.sub.2R.sub.5, COR.sub.5, CN, NO.sub.2, CONHR.sub.5, CF.sub.3,
3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br, and I,
wherein R.sub.5 is as defined below;
[0035] R.sub.2 is independently selected from the group consisting
of C.sub.1-C.sub.4 alkyls, allyls, CH.sub.2SCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2F,
CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and
--(CH.sub.2)--R.sub.6, wherein R.sub.6 is as defined below;
[0036] R.sub.3 and R.sub.4 are independently selected from the
group consisting of H and C.sub.1-C.sub.4 alkyls, provided that
both R.sub.3 and R.sub.4 cannot be H at the same time;
[0037] R.sub.5 is independently selected from the group consisting
of C.sub.1-C.sub.3 alkyls, CF.sub.3 and N(R.sub.2).sub.2, wherein
R.sub.2 is as defined above; and
[0038] R.sub.6 is independently selected from the group consisting
of C.sub.3-C.sub.6 cycloalkyls, 2-tetrahydrofurane and
3-tetra-hydrofurane;
[0039] and pharmaceutically acceptable salts of any one of the
compounds of formula I, II or III.
[0040] Thus, said dopamine stabilizing agent may be any one of the
compounds with formula I, II or III as defined above or a
pharmaceutically acceptable salt of any one of the compounds with
formula I, II or III.
[0041] In one embodiment of the present disclosure, said dopamine
stabilizing agent is selected from the group consisting of
compounds with formula I or formula II; the group consisting of
compounds with formula II or formula III; or the group consisting
of compounds with formula I or formula III. In another embodiment,
said dopamine stabilizing agent is selected from the group
consisting of compounds with formula I. In one embodiment, said
dopamine stabilizing agent is selected from the group consisting of
compounds with formula II. In one embodiment, said dopamine
stabilizing agent is selected from the group consisting of
compounds with formula III.
[0042] Dopamine stabilizing substances of formula I and
pharmaceutically acceptable salts thereof have been described in
U.S. Pat. No. 5,462,947. U.S. Pat. No. 5,462,947 discloses the
compounds belonging to this group and also gives the definitions
for the different terms used--see in particular column 4, line
54--column 6, line 25. U.S. Pat. No. 5,462,947 also discloses how
these compounds may be obtained--see in particular column 7, lines
26-28 and the Examples.
[0043] According to one embodiment, said dopamine stabilizing agent
of formula I for use in the treatment as described herein is in the
form of a pure enantiomer or a pharmaceutically acceptable salt
thereof, such as a pure S-enantiomer or a pharmaceutically
acceptable salt thereof.
[0044] According to one embodiment, there is provided a dopamine
stabilizing agent of formula I for use in the treatment as
described herein, wherein R.sup.1 is CN, OSO.sub.2CF.sub.3, or
SO.sub.2CH.sub.3 or a pharmaceutically acceptable salt thereof. In
one embodiment, R.sup.1 is CN. In one embodiment, R.sup.1 is
SO.sub.2CH.sub.3. It may then be preferable that R.sup.2 is H and
R.sup.3 is C.sub.1-8 alkyl, and further that R.sup.3 is n-propyl,
and moreover that R.sup.4 is H. In one embodiment, R.sup.1 is
independently selected from the group consisting of CN,
OSO.sub.2CF.sub.3 and SO.sub.2CH.sub.3; R.sup.2 is H; R.sup.3 is
C.sub.1-8 alkyl, such as n-propyl; and R.sup.4 is H.
[0045] According to one embodiment, there is provided a dopamine
stabilizing agent of formula I for use in the treatment as
described herein wherein R.sup.1 is 3-OH, R.sup.2 is H, R.sup.3 is
n-propyl and R.sup.4 is C.sub.2-8 alkyl or a pharmaceutically
acceptable salt thereof.
[0046] According to one embodiment, said dopamine stabilizing agent
of formula I for use in the treatment as described herein is
(3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine.
[0047] Dopamine stabilizing substances of formula II and
pharmaceutically acceptable salts thereof, have been described in
U.S. Pat. No. 6,903,120.
[0048] According to one embodiment of the present aspect, there is
provided a dopamine stabilizing agent of formula II for use in the
treatment as described herein wherein R.sub.1 is selected from the
group consisting of OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3,
SO.sub.2CH.sub.3, SO.sub.2CF.sub.3, COCH.sub.3, and
SO.sub.2N(CH.sub.3).sub.2 or a pharmaceutically acceptable salt
thereof. It may then be preferable that R.sub.1 is selected from
the group consisting of SO.sub.2CF.sub.3, SO.sub.2CH.sub.3, and
COCH.sub.3.
[0049] According to one embodiment, there is provided a dopamine
stabilizing agent of formula II for use in the treatment as
described herein wherein R.sub.2 is selected from the group
consisting of n-propyl and ethyl or a pharmaceutically acceptable
salt thereof.
[0050] According to one embodiment the compound of formula II is
4-(3-methanesulfonylphenyl)-1-propyl-piperidine.
[0051] Dopamine stabilizing substances of formula III and
pharmaceutically acceptable salts thereof, have been described in
WO 01/46145.
[0052] According to one embodiment of the first aspect, there is
provided a dopamine stabilizing agent of formula III for use in the
treatment as described herein, wherein X is CH or C or a
pharmaceutically acceptable salt thereof. It may be preferable that
X is CH.
[0053] According to one embodiment, there is provided a dopamine
stabilizing agent of formula III for use in the treatment as
described herein wherein R.sub.1 is selected from the group
consisting of OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3,
SO.sub.2CH.sub.3, SO.sub.2CF.sub.3, COCH.sub.3, CF.sub.3, CN,
CON(CH.sub.3).sub.2, and SO.sub.2N(CH.sub.3).sub.2 or a
pharmaceutically acceptable salt thereof. When X is CH it may be
preferable that R.sub.1 is selected from the group consisting of
SO.sub.2CF.sub.3, SO.sub.2CH.sub.3, COCH.sub.3, CF.sub.3, and
CN.
[0054] According to one embodiment, there is provided a dopamine
stabilizing agent of formula III for use in the treatment as
described herein wherein R.sub.2 is selected from the group
consisting of n-propyl and ethyl or a pharmaceutically acceptable
salt thereof. According to one embodiment, there is provided a
dopamine stabilizing agent of formula III for use in the treatment
as described herein, wherein X is CH, R.sub.1 is SO.sub.2CH.sub.3,
and R.sub.2 is n-propyl or a pharmaceutically acceptable salt
thereof.
[0055] According to one embodiment the compound of formula III is
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine.
[0056] As stated above, the dopamine stabilizing agent may be a
pharmaceutically acceptable salt of a compound of formula I, II or
III. The term "pharmaceutically acceptable salt(s)", as used
herein, means those salts of compounds of the disclosure that are
safe and effective for oral, subcutaneously, intramuscularly or
intravenously administration in mammals and that possess the
desired biological activity. Pharmaceutically acceptable salts
include salts of acidic or basic groups present in compounds of the
invention. Pharmaceutically acceptable acid addition salts include,
but are not limited to, hydrochloride, hydrobromide and
hydroiodide.
[0057] Thus, in one embodiment, there is provided a dopamine
stabilizing agent of formula I, II or II for use in the treatment
as described herein, wherein said pharmaceutically acceptable salt
is hydrochloride, hydrobromide or hydroiodide, such as
hydrochloride. In one embodiment, said pharmaceutically acceptable
salt is a hydrochloride of a compound of formula I, II or II, such
as of a compound of formula I. In one embodiment, said
pharmaceutically acceptable salt is
(3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride.
In one embodiment, said pharmaceutically acceptable salt is
4-(3-methanesulfonylphenyl)-1-propyl-piperidine hydrochloride. In
one embodiment, said pharmaceutically acceptable salt is
4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine hydrochloride.
[0058] As used herein, the terms "antidepressants" and
"anti-depressive agents" refer to medicaments used for the
treatment of a major depressive disorder, which is a mental
disorder characterized by a pervasive and persistent low mood that
is accompanied by low self-esteem and by a loss of interest or
pleasure in normally enjoyable activities; and other similar
medical conditions. A non-limiting list of major types on
anti-depressive agents includes selective serotonin reuptake
inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors
(SNRIs), serotonin modulators and stimulators (SMSs), serotonin
reuptake inhibitors (SARIs), norepinephrine reuptake inhibitors
(NRIs), tricyclic antidepressants (TCAs), monoamine oxidase
inhibitors (MAOIs), tetracyclic antidepressants (TeCAs),
noradrenergic and specific serotonergic antidepressant (NaSSAs),
buprenorphine, low-dose antipsychotics and St John's wort.
[0059] One major class of anti-depressive agents are selective
serotonin reuptake inhibitors (SSRIs) which increase the
extracellular level of the neurotransmitter serotonin by inhibiting
its reuptake into the presynaptic cell and thus increase the level
of serotonin in the synaptic cleft available to bind to the
postsynaptic receptor. Non-limiting examples of SSRI include
citalopram, fluvoxamine, escitalopram, paroxetine, sertaline and
flouxetine. Another large class of anti-depressive agents are
serotonin-norepinephrine reuptake inhibitors (SNRIs) which are
potent inhibitors of the reuptake of serotonin and norepinephrine.
Non-limiting examples of SNRIs include venlafaxine, milnacipran,
duloxetine, levomilnacipran, desvenlafaxine and sibutramine. The
term serotonin modulators and stimulators (SMSs) refers to drugs
with a multimodal action specific to the serotonin neurotransmitter
system by simultaneously modulating one or more serotonin receptors
and inhibiting the reuptake of serotonin. Non-limiting examples of
SMSs include vortioxetine and vilazodone. Serotonin reuptake
inhibitors (SARIs) are drugs that act by antagonizing serotonin
receptors, such as 5-HT.sub.2A, and inhibiting the reuptake of
serotonin, norepinephrine and/or dopamine. The majority of the
currently marketed SARIs belong to the phenylpiperazine class of
compounds and non-limiting examples of SARIs include etoperidone,
lorpiprazole, lubazodone, mepiprazole, nefazodone and trazodone.
Also known are tricyclic anti-depressant (TCAs), which are chemical
compounds used primarily as antidepressants. Examples of TCA that
act to preferentially inhibit the reuptake of serotonin are
clomipramine and imipramine and examples of TCA that act to
preferentially inhibit the reuptake of norepinephrine include
desipramine, dibenzepin, lofepramine, nortriptyline and
protriptyline. TCA which are considered to be fairly balansed
serotonin-norepinephrine reuptake inhibitors include amitriptyline,
amitriptylinoxide, amoxapine, butriptyline, demexiptiline,
dimetacrine, dosulepin, doxepin, imipraminoxide, melitracen,
metapramine, nitroxazepine, noxiptiline, pipofezine, propizepine
and quinupramine. TCAs that act via other mechanisms beside
serotonin-norepinephrine reuptake inhibition include but are not
limited to amineptine, iprindole, opipramol, tianeptine and
trimipramine. Monoamine oxidase inhibitors (MAOIs) are chemicals
which inhibit the activity of the monoamine oxidase enzyme family
and are also used for the treatment of depression, typically for
the treatment of atypical depression where treatment with other
anti-depressant has failed. Non-limiting examples of MOAIs include
nonselective MAO-A/MAO-B Inhibitors, such as hydrazines (for
example isocarboxazid, nialamide, phenelzine and hydracarbazine)
and non-hydrazines (for example tranylcypromine); selective MAO-A
inhibitors, such as moclobemide, pirlindole and toloxatone; and
selective MAO-B Inhibitors, such as rasagiline and selegiline.
Additionally, other drugs with monoamine oxidase inhibiting
activity may be used for the treatment of depression, such as
linezolid which is an antibiotic drug with weak monoamine oxidase
inhibiting activity. Also known are tetracyclic antidepressants
(TeCAs) and a non-limiting list of TeCAs includes amoxapine,
loxapine, maprotiline, mazindol, and setiptiline. Noradrenergic and
specific serotonergic antidepressants (NaSSAs) act to block
.alpha..sub.2-adrenergic autoreceptors and heteroreceptors and
enhance adrenergic and serotonergic neurotransmission involved in
mood regulation, such as 5-HT.sub.1A-mediated transmission.
Non-limiting examples of NaSSAs include aptazapine, esmirtazapine,
setiptiline and S32212. Notably, many of these compounds are also
classified as tetracyclic antidepressants (TeCAs) based on their
chemical structures. Additionally, other agents, which may act as
anti-depressive agents may be useful for the purposes of the
present disclosure. Examples of potentially useful additional
agents include, but are not limited to, buprenorphine (a semi
synthetic opioid derivative of thebaine), low dose anti-phychotic
drugs and St John's wort (Hypericum perforatum), which is a
medicinal herb with antidepressant activity.
[0060] The skilled person will appreciate that the above lists of
anti-depressive agents are by no means limiting and other agents
may be equally useful for the purposes of the present disclosure.
Additionally, the skilled person will appreciate that combinations
of said anti-depressive agents may used.
[0061] Thus, in one embodiment, there is provided a dopamine
stabilizing agent and an anti-depressive agent for use in the
treatment of a disorder characterized by debilitating fatigue as
described herein, wherein said anti-depressive agent is selected
from the group consisting of selective serotonin reuptake
inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors
(SNRIs), serotonin modulators and stimulators (SMSs), serotonin
reuptake inhibitors (SARIs), norephinephrine reuptake inhibitors
(NRIs), tricyclic antidepressants (TCAs), monoamine oxidase
inhibitors (MAOIs), tetracyclic antidepressants (TeCAs),
noradrenergic and specific serotonergic antidepressant (NaSSAs),
buprenorphine, low-dose antipsychotics and St John's wort, such as
a group consisting of selective serotonin reuptake inhibitors
(SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs),
serotonin modulators and stimulators (SMSs), serotonin reuptake
inhibitors (SARIs), norephinephrine reuptake inhibitors (NRIs),
tricyclic antidepressants (TCAs), tetracyclic antidepressants
(TeCAs), noradrenergic and specific serotonergic antidepressant
(NaSSAs), buprenorphine, low-dose antipsychotics and St John's
wort. In one embodiment, said anti-depressive agent is selected
from the group consisting of selective serotonin reuptake
inhibitors (SSRI) , serotonin-norepinephrine reuptake inhibitors
(SNRI) and tricyclic antidepressants (TCAs), such as the group
consisting of selective serotonin reuptake inhibitors (SSRI) and
serotonin-norepinephrine reuptake inhibitors (SNRI) or combinations
thereof. In one embodiment, said selective serotonin reuptake
inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor
(SNRI) is selected from the group consisting of escitalopram,
citalopram, sertraline, fluoxetine, paroxetine, duloxetine,
amitriptyline, fluvoxamine, dapoxetine, indalpine, zemelidinem
venlafaxine, desvenlafaxine, milnacipran, levomilnacipran and
sibutramine or combinations thereof, such as the group consisting
of escitalopram, citalopram, sertraline, fluoxetine, paroxetine,
amitriptyline, fluvoxamine, dapoxetine, indalpine, zemelidinem
venlafaxine, desvenlafaxine, milnacipran, levomilnacipran and
sibutramine or combinations thereof. In another embodiment, said
selective serotonin reuptake inhibitors (SSRI),
serotonin-norepinephrine reuptake inhibitors (SNRI) or tricyclic
antidepressant (TCAs) is selected from the group consisting of
escitalopram, citalopram, sertraline, fluoxetine, paroxetine,
duloxetine, amitriptyline and venlafaxine or combinations thereof,
such as the group consisting of escitalopram, citalopram,
sertraline, fluoxetine, paroxetine, amitriptyline and venlafaxine
or combinations thereof.
[0062] As mentioned above, the present disclosure is based on the
unexpected finding that the clinical outcome of treatment of
disorders characterized by debilitating fatigue is significantly
improved by the combination of a dopamine stabilizing agent and an
anti-depressive agent in the patient. The skilled person will
appreciate that a patient may have a therapeutically effective
concentration in blood of a dopamine stabilizing agent as defined
above and of an anti-depressive agent, irrespective of in which
order said agents are administered relative to each other. In other
words, the skilled person will appreciate that the
co-administration of said agents may be simultaneous or
concomitant. As used herein, the term "co-administration" refers to
the administration of two or more drugs together, such as
administration of the dopamine stabilizing agent as defined herein
and an anti-depressive agent.
[0063] Thus, in one embodiment, there is provided a dopamine
stabilizing agent and an anti-depressive agent for use in treatment
as described herein, wherein said use involves concomitant or
simultaneous co-administration of said agents. Concomitant
administration may be co-administration, wherein said dopamine
stabilizing agent and said anti-depressive agent are administered
within a predefined time period (irrespective of which agent is
administered first). For example, the predefined time period may be
72 hours, 48 hours, 24 hours, 12 hours, 6 hours or 1 hour. Thus, in
one embodiment there is provided a dopamine stabilizing agent and
an anti-depressive agent for use as defined herein, wherein said
co-administration is concomitant administration within less than 72
hours, such as within less than 48 hours, such as within less than
24 hours, such as within less than 12 hours, such as within less
than 6 hours, such as within less than 1 hour. In another
embodiment, said administration is simultaneous. It will be
appreciated that the patient may be on ongoing treatment with an
anti-depressive agent at the time point of starting said
co-administration, such as treatment that has been ongoing for at
least 6 months, such as at least 3 months, such as at least 1
month, such as at least 2 weeks.
[0064] In one embodiment, there is provided a dopamine stabilizing
agent and an anti-depressive agent for use in the treatment as
described herein, wherein at least one or both agents is/are
administered orally, subcutaneously, intramuscularly or
intravenously, such as orally. The skilled person will appreciate
that one or both of said agents may be administered by any one of
said administration routes. For example, said dopamine stabilizing
agent may be administered subcutaneously while said anti-depressive
agent may be administered orally. Alternatively, both agents may be
administered by the same administration route. It will be
appreciated that non-invasive administration may generally be
preferable. Thus, in one embodiment, said dopamine stabilizing
agent and said at least one anti-depressive agent are administered
orally. In one embodiment, said administration is in a dose of
approximately 0.1-45 mg, such as approximately 0.1-5 mg, such as
approximately 0.1-2 or such as approximately 1-45 mg, such as
approximately 1-30 mg, such as approximately 5-30 mg, such as
approximately 10-30 mg, such as 15 mg or 30 mg.
[0065] In one embodiment, said administration is at a dose of
approximately 1-20 mg, such as approximately 5-20 mg, such as
approximately 10-20 mg, such as 15 mg and in another embodiment,
said dose is approximately 1-30 mg, such as approximately 15-30 mg,
such as approximately 20-30 mg, such as 30 mg.
[0066] In one embodiment, wherein said dopamine stabilizing agent
is administered orally said dose is approximately 1-45 mg, such as
approximately 1-30 mg, such as approximately 5-30 mg, such as
approximately 10-30 mg, such as 15 mg or 30 mg. When the
administration is subcutaneous or intramuscular, it may be suitable
that the administered dose corresponds to approximately half of the
oral dose. Thus, in one embodiment, wherein said dopamine
stabilizing agent is administered subcutaneously or
intramuscularly, the dose is approximately 1-30 mg, such as
approximately 1-20 mg, such as approximately 15 mg ,10 mg or 8
mg.
[0067] In another embodiment, wherein the dopamine stabilizing
agent is administered intravenously, the dose of said agent is
approximately 0.1-5 mg, such as approximately 0.1-2 mg.
[0068] In order to obtain high patient compliance, that is the
degree to which a patient correctly follows medical advice, it is
generally considered that the treatment regimes may not be complex
in order to for a patient to be able to easily follow them. For
example, it may be preferable that the administration of a drug is
once, twice or three times a day, such as twice or once a day.
Thus, in one embodiment, there is provided a dopamine stabilizing
agent and an anti-depressive agent for use as described herein,
wherein said dopamine stabilizing agent is administered once, twice
or three times a day, such as once or twice a day. To clarify, thus
the dopamine stabilizing agent may for example be administered
orally twice a day in a dose of 30 mg, resulting in a daily dose of
60 mg. For example, it may be preferred that said dopamine
stabilizing agent and an anti-depressive agent are concomitantly
administered once, twice or three times a day, such as once or
twice a day. It will be appreciated, that said dopamine stabilizing
agent and said anti-depressive agent may be administered a
different number of times a day. For example, said dopamine
stabilizing agent may be administered twice a day and said
anti-antidepressive agent may be administered once a day.
[0069] As disclosed in the Example section, superior patient
outcomes were observed in patients whose blood plasma concentration
of dopamine stabilizing agent was approximately 0.1-0.7 .mu.M. In
particular, superior outcomes were observed in patients whose blood
plasma concentration of dopamine stabilizing agent was
approximately 0.3-0.7 .mu.M. Thus, in one embodiment there is
provided a dopamine stabilizing agent and at least one
anti-depressive agent for use as described herein, wherein, upon
administration, the therapeutically effective blood plasma
concentration of said dopamine stabilizing agent is approximately
0.1-0.7 .mu.M, such as approximately 0.3-0.7 .mu.M.
[0070] As disclosed in the Example section of the present
disclosure, a dopamine stabilizing agent as defined herein and an
anti-depressive agent may be useful in the treatment of a disorder
characterized by debilitating fatigue, which disorder often
includes symptoms such as persistent and/or recurrent debilitating
fatigue, diffuse musculoskeletal pain, sleep disturbances and
subjective cognitive impairment. Non-limiting examples of such
disorders include myalgic encephalomyelitis (ME), also known as
chronic fatigue syndrome (CFS), which refers to a group of
debilitating medical conditions characterized by persistent and
debilitating fatigue, diffuse musculoskeletal pain, sleep
disturbances, neuropsychiatric symptoms and cognitive impairment
that last for a minimum of at least six months in adults. ME/CFS
often occurs together with other diseases such as fibromyalgia
(FM), multiple chemical sensitivities, irritable bowel syndrome and
temporomandibular joint disorder. Additionally, a number of other
disorders are also characterized by disabling fatigue. A
non-limiting list of such diseases includes FM, mental fatigue,
post stroke fatigue, Huntington's disease, Parkinson's disease,
multiple sclerosis, narcolepsy, post cancer fatigue, ADHD,
depression and combinations thereof. Additionally, fatigue may be
associated with cancer with or without cytostatic treatment. The
skilled person will appreciate that the disorder characterized by
disabling fatigue may be a fatigue disorder or a pain disorder.
[0071] Thus, in one embodiment, there is provided a dopamine
stabilizing agent and an anti-depressive agent as described herein
for use in the treatment of a disorder characterized by persistent
and debilitating fatigue, wherein said disorder is selected from
the group consisting of myalgic encephalomyelitis/chronic fatigue
syndrome, fibromyalgia, mental fatigue, post stroke fatigue,
Huntington's disease, Parkinson's disease, multiple sclerosis,
narcolepsy, post cancer fatigue, fatigue associated with cancer
with or without cytostatic treatment, depression and combinations
thereof.
[0072] In one embodiment, said fatigue disorder is characterized by
at least one of the conditions selected from fibromyalgia, mental
fatigue, myalgic encephalomyelitis/chronic fatigue syndrome and
depression. In another embodiment, said disorder is a pain disorder
characterized by at least one of the conditions selected from of
fibromyalgia, mental fatigue myalgic encephalomyelitis/chronic
fatigue syndrome- and depression. In one embodiment, said disorder
is ME/CFS. In one embodiment, said disorder is mental fatigue. In
one embodiment, said disorder is depression and in another
embodiment, said disorder is fibromyalgia. In one embodiment, said
disorder is a combination of two or more above mentioned disorders,
such as a combination selected from the group of: a combination of
myalgic encephalomyelitis/chronic fatigue syndrome and
fibromyalgia; a combination of myalgic encephalomyelitis/chronic
fatigue syndrome and mental fatigue; a combination of myalgic
encephalomyelitis/chronic fatigue syndrome and depression; a
combination of mental fatigue and depression; a combination of
fibromyalgia and depression; and a combination of mental fatigue
and fibromyalgia. In one embodiment, said combination is selected
from: a combination of myalgic encephalomyelitis/chronic fatigue
syndrome, mental fatigue and fibromyalgia; a combination of myalgic
encephalomyelitis/chronic fatigue syndrome, mental fatigue and
depression; a combination of myalgic encephalomyelitis/chronic
fatigue syndrome, depression and fibromyalgia; a combination of
depression, mental fatigue and fibromyalgia.
[0073] The skilled person will appreciate that the embodiments
discussed above in relation to the first aspect of the present
disclosure, are equally relevant and applicable to the second,
third, fourth, fifth, sixth, seventh and eighth aspect disclosed
herein. This particularly applies to embodiments relating to the
identity of the dopamine stabilizing agent, the identity of the
anti-depressive agent, as well as, where applicable, the mode and
route of administration as well as amounts of agents administered.
For the sake of brevity these will not be repeated here or will
only be briefly mentioned.
[0074] In a second aspect of the present disclosure, there is
provided a pharmaceutical composition comprising a dopamine
stabilizing agent as described herein and an anti-depressive
agent.
[0075] In one embodiment, said pharmaceutical composition further
comprises at least one pharmaceutically acceptable excipient or
carrier. Non-limiting examples of excipients includes diluents,
disinteragrants, binders, lubricants, glidants and agents that
modify release of the active agent, such as polymers. The skilled
person is aware of suitable excipients and carriers.
[0076] In another embodiment, said pharmaceutical composition
further comprises at least one additional active agent. In one
embodiment, said additional agent is an anti-fatigue agent, such as
a stimulant, for example a caffeine-based stimulant or a central
nervous system stimulating agent, such as methylphenidate and
various amphetamine derivatives.
[0077] In one embodiment, there is provided a pharmaceutical
composition as described herein comprising an amount of dopamine
stabilizing agent of approximately 0.1-45 mg, such as 0.1-5 mg,
such as approximately 0.1-2 or such as approximately 1-45 mg, such
as approximately 1-30 mg, such as approximately 5-30 mg, such as
approximately 10-30 mg, such as 15 mg or 30 mg. In one embodiment,
said amount is approximately 1-20 mg, such as approximately 5-20
mg, such as approximately 10-20 mg, such as 15 mg and in another
embodiment, said amount is approximately 1-30 mg, such as
approximately 15-30 mg, such as approximately 20-30 mg, such as 30
mg.
[0078] In one embodiment, said pharmaceutical composition is
formulated for oral, subcutaneous, intramuscular or intravenous
administration. As discussed above, it will be appreciated that
non-invasive administration may be generally preferable. In one
particular embodiment, said pharmaceutical composition is
formulated for oral administration.
[0079] In one embodiment, wherein said pharmaceutical is formulated
for oral administration, the pharmaceutical composition comprises
approximately 1-45 mg, such as approximately 1-30 mg, such as
approximately 5-30 mg, such as approximately 10-30 mg, such as 15
mg or 30 mg of dopamine stabilizing agent. When said pharmaceutical
is formulated for subcutaneous or intramuscular administration, it
may be suitable that the administered dose corresponds to
approximately half of the oral dose. Thus, in one embodiment
wherein said pharmaceutical is formulated for subcutaneously or
intramuscularly administration, the pharmaceutical composition
comprises approximately 1-30 mg, such as approximately 1-20 mg,
such as approximately 15 mg, 10 mg or 8 mg.
[0080] In another embodiment, wherein said pharmaceutical
composition is formulated for intravenous administration, the
pharmaceutical composition comprises approximately 0.1-5 mg, such
as approximately 0.1-2 mg dopamine stabilizing agent.
[0081] In one embodiment, there is provided a pharmaceutical
composition formulated as a pill, tablet, capsule, dragee, liquid,
gel capsule, syrup, slurry or suspension, such as a pill.
[0082] In one embodiment, there is provided a pharmaceutical
composition formulated for administration once, twice or three
times a day, such as once or twice a day.
[0083] In one embodiment, there is provided a pharmaceutical
composition for use as described herein, said composition being
formulated to provide, upon administration, a therapeutically
effective blood plasma concentration of said dopamine stabilizing
agent of approximately 0.1-0.7 .mu.M, such as approximately 0.3-0.7
.mu.M.
[0084] It is furthermore contemplated that the dopamine stabilizing
agent as defined herein and an anti-depressive agent are combined
into a combination kit. For example, a combination kit could
comprise a dosage form of said dopamine stabilizing agent as
described herein and a dosage form of an anti-depressive agent.
Additionally, said kit may comprise printed matter with information
and/or a suitable box container for storage of said agents.
[0085] The kit is envisioned to provide all components necessary
for the administration of the dopamine stabilizing agent and the
anti-depressive agent in a safe and convenient manner. For example,
if the dopamine stabilizing agent and the anti-depressive agent are
to be administered separately in tablet or pill form, it may be
suitable for the kit to comprise an indicator for indicating that a
corresponding number of tablets or pill of each types has been
administered. In the instance when at least one of said agents is
to be administered by injection, said kit may comprise an injection
device. Thus, kits for administration by injection, such as
subcutaneous, intramuscular or intravenous injection are also
contemplated. Such kits may comprise said dopamine stabilizing
agent and said anti-depressive agent in the same container, in form
of a solution or powder or the like. Also contemplated are kits
wherein said dopamine stabilizing agent and said at least one
anti-depressive agent are present in separate containers. Said kits
may furthermore comprise for example an injection device and/or
written information.
[0086] Thus, in third aspect of the present disclosure, there is
provided a combination kit comprising a dopamine agent as defined
herein and an anti-depressive agent. In one embodiment, said
anti-depressive agent is as defined herein.
[0087] In one embodiment of the present aspect, there is provided a
combination kit wherein said dopamine stabilizing agent and said
anti-depressive agent are formulated for concomitant or
simultaneous administration. Kits comprising oral dosage forms are
contemplated, for example kits wherein said dopamine stabilizing
agent and said anti-depressive agent are present in one pill,
tablet, capsule, dragee, liquid, gel capsule, syrup, slurry or
suspension (or other suitable form); and kits wherein said dopamine
stabilizing agent and said anti-depressive agent are present as
separate pills, tablets, capsules, dragees, liquids, gel capsules,
syrups, slurrys or suspensions (or other suitable forms).
[0088] In one embodiment, said combination kit is formulated to
comprise an amount of dopamine stabilizing agent of approximately
0.1-45 mg such as approximately 0.1-5 mg, such as approximately
0.1-2 mg or such as approximately 1-45 mg, such as approximately
1-30 mg, such as approximately 5-30 mg, such as approximately 10-30
mg, such as 15 mg or 30 mg.
[0089] In one embodiment, said amount is approximately 1-20 mg,
such as approximately 5-20 mg, such as approximately 10-20 mg, such
as 15 mg and in another embodiment, said amount is approximately
1-30 mg, such as approximately 15-30 mg, such as approximately
20-30 mg, such as 30 mg.
[0090] In one embodiment, said combination kit is formulated for
oral, subcutaneous, intramuscular or intravenous administration and
in another embodiment, said combination kit is formulated for oral
administration.
[0091] In one embodiment, said kit is formulated for oral
administration and comprises approximately 1-45 mg, such as
approximately 1-30 mg, such as approximately 5-30 mg, such as
approximately 10-30 mg, such as 15 mg or 30 mg dopamine stabilizing
agent. When said kit is formulated for subcutaneous or
intramuscular administration, it may be suitable that the
administered dose corresponds to approximately half of the oral
dose. Thus, in one embodiment wherein said kit is formulated for
subcutaneously or intramuscularly administration, the
pharmaceutical composition comprises approximately 1-30 mg, such as
approximately 1-20 mg, such as approximately 15 mg ,10 mg or 8 mg.
In another embodiment, said kit is formulated intravenous
administration and comprises approximately 0.1-5 mg, such as
approximately 0.1-2 mg dopamine stabilizing agent.
[0092] In one embodiment, said combination kit is formulated for
administration once, twice or three times a day, such as once or
twice a day.
[0093] In one embodiment, said combination kit is formulated such
that, upon administration, the therapeutically effective blood
plasma concentration of said dopamine stabilizing agent is
approximately 0.1-0.7 .mu.M, such as approximately 0.3-0.7
.mu.M.
[0094] As disclosed in the Example section of the present
disclosure, the dopamine stabilizing agent or pharmaceutical
composition comprising the same may be useful for the treatment of
a disorder characterized by debilitating fatigue in a subject on
treatment with at least one anti-depressive agent (AD). It will be
appreciated that the subject may have been on ongoing treatment
with an anti-depressive agent for at least 6 months, such as at
least 3 months, such as at least 1 month, such as at least 2
weeks.
[0095] Thus, in a fourth aspect of the present disclosure there is
provided a dopamine stabilizing agent as described herein for use
in the treatment of a disorder characterized by debilitating
fatigue in a subject on treatment with at least one anti-depressive
agent. It will be appreciated that said subject may be suffering
from a disorder characterized by debilitating fatigue as described
above and that the mode and route of administration of said
dopamine stabilizing agent and the amount administered may be as
described above. In one embodiment of this aspect, said subject is
on treatment with an anti-depressive agent as described above.
[0096] In an additional aspect of the present disclosure, there is
provided the use of a dopamine stabilizing agent as defined herein
and an anti-depressive agent, for the manufacture of a medicament
for the treatment a disorder characterized by persistent and
debilitating fatigue, such as a disorder disclosed herein. In one
embodiment, said anti-depressive agent is as defined herein.
[0097] In a related aspect, there is provided the use of a dopamine
stabilizing agent as defined herein, for the manufacture of a
medicament for the treatment a disorder characterized by
debilitating fatigue in a subject on treatment with an
anti-depressive agent, such as in a subject on treatment with an
anti-depressive agent as described herein. It will also be
appreciated that said disorder characterized by debilitating
fatigue may be any one of the disorders disclosed herein.
[0098] In the seventh aspect of the present disclosure, there is
provided a method for the treatment of a disorder characterized by
persistent and debilitating fatigue, wherein the method comprises
administering to a subject in need thereof a therapeutically
effective dose of a dopamine stabilizing agent, wherein said
subject is on treatment with an anti-depressive agent and wherein
said dopamine stabilizing agent is as defined above. In one
embodiment, said subject in on treatment with an anti-depressive
agent selected from the anti-depressive agents defined above.
[0099] In a related, eighth aspect of the present disclosure, there
is provided a method of treatment of a disorder characterized by
persistent and debilitating fatigue, the method comprising
co-administration, to a subject in need thereof, of a
therapeutically effective dose of a dopamine stabilizing agent as
defined above and a therapeutically effective dose of an
anti-depressive agent. In one embodiment, said anti-depressive
agent may be selected from the anti-depressive agents defined
above. It will be appreciated, that in the context of the eighth
aspect of the present disclosure, said co-administration may be
concomitant or simultaneous, such as concomitant administration
within less than 24 hours, such as within less than 12 hours, such
as within less than 6 hours, such as within less than 1 hour or
such as simultaneous co-administration.
[0100] In embodiments of the seventh and eight aspects of the
present disclosure, the disorder characterized by debilitating
fatigue may be as described above and the mode and route of
administration as well as amount administrated may be as described
above.
Measurements of Clinical Outcome
[0101] As described in the Example section to follow, the clinical
outcome of administration of a dopamine stabilizing agent and an
anti-depressive agent to a subject suffering from a disorder as
described herein or of administration of a dopamine stabilizing
agent as described herein to a subject on treatment with an
anti-depressive agent, may be evaluated by the following tests and
questionnaires. The skilled person is aware of the applicability of
these test for the evaluation of fatigue and depression related
symptoms.
[0102] As used herein, the term "Clinical Global Impression" (CGI)
refers to a rating scale commonly used to measure symptom severity,
treatment response and the efficacy of treatments in treatment
studies of patients with mental disorders (Guy W: Clinical Global
Impressions (CGI) Scale. Modified From: Rush J, et al.: Psychiatric
Measures, APA, Washington D.C., 2000).
[0103] As used herein "Clinical Global Impression of Change"
(CGI-C) (also known as Clinical Global Impression-Improvement
(CGI-I)) scale is a 7 point scale that requires the clinician to
assess how much the patient's illness has improved or worsened
relative to a baseline state at the beginning of the intervention.
The ratings are as follows: 1, very much improved; 2, much
improved; 3, minimally improved; 4, no change; 5, minimally worse;
6, much worse; or 7, very much worse.
[0104] As used herein, the term "MFS" refers to a the mental
fatigue self-assessment questionnaire (Johansson B et al (2010)
Brain Injury 2010;24:2-12).
[0105] Additionally, the clinical outcome of the treatment may be
evaluated using the FF-scale, The Beck/BDI scale, VAS pain scale
and by neuropsychological tests.
[0106] As used herein, the term "FF-scale" or "FF" refers to the
FibroFatigue scale also known as the fibromyalgia and chronic
fatigue syndrome rating scale described in by Zachrisson and
coworkers (Zachrisson O, et al, (2002) J Psychosom Res
Jun;52(6):501-9). The FibroFatigue scale is an observer's rating
scale with 12 items measuring pain, muscular tension, fatigue,
concentration difficulties, failing memory, irritability, sadness,
sleep disturbances, and autonomic disturbances and irritable bowel,
headache and subjective experience of infection.
[0107] As used herein, the terms "Beck/BDI scale" and "BD" refers
to the Beck Depression Inventory created by Aaron T. Beck (Beck A T
et al., (1961) Arch. Gen. Psychiatry 4(6): 561-71). It is a
21-question multiple-choice self-report inventory and one of the
most widely used instruments for measuring the severity of
depression. The BDI questionnaire is designed for individuals aged
13 and over, and is composed of items relating to symptoms of
depression such as hopelessness and irritability, cognitions such
as guilt or feelings of being punished, as well as physical
symptoms such as fatigue, weight loss, and lack of interest in
sex.
[0108] As used herein, the term "VAS pain scale" refers to the
visual analog scale for measuring a patient's pain intensity or
other features. The VAS scale is a psychometric response scale and
is often used in questionnaires. It is a measurement instrument for
subjective characteristics or attitudes that cannot be directly
measured. When responding to a VAS item, respondents specify their
level of agreement to a statement by indicating a position along a
continuous line between two end-points.
[0109] As used herein, the term "neuropsychological tests" refers
to tests designed to measure unobserved constructs, also known as
latent variables. Psychological tests are typically, but not
necessarily, a series of tasks or problems that the respondent has
to solve and measure a respondent's maximum performance. The
neuropsychological tests employed in this study are described in
Example 6.
Statistical Analysis
[0110] This study employs statistical evaluations of obtained data.
The skilled person is aware of and knows how to employ the tests
used herein. Any deviations from standard calculations procedures
are explained in the Example section of the disclosure. Briefly,
the statistics test employed herein are as follows:
[0111] The Mann-Whitney U test (also called the
Mann-Whitney-Wilcoxon (MWW), Wilcoxon rank-sum test (WRS), or
Wilcoxon-Mann-Whitney test) is a nonparametric test of the null
hypothesis that two populations are the same against an alternative
hypothesis, especially that a particular population tends to have
larger values than the other.
[0112] The 2-way interaction analysis (2-way analysis of variance
(ANOVA)) is a test that examines the influence of two different
categorical independent variables on one continuous dependent
variable. The two-way ANOVA not only aims at assessing the main
effect of each independent variable but also at assessing if there
is any interaction between them.
[0113] The 3-way interaction analysis (3-way analysis of variance
(ANOVA)) is a test that examines if there is a 2-way interaction
that varies across levels of a third variable.
[0114] Spearman's rank correlation coefficient is a nonparametric
measure of statistical dependence between two variables. It
assesses how well the relationship between two variables can be
described using a monotonic function. If there are no repeated data
values, a perfect Spearman correlation of +1 or -1 occurs when each
of the variables is a perfect monotone function of the other.
[0115] While the invention has been described with reference to
various exemplary aspects and embodiments, it will be understood by
those skilled in the art that various changes may be made and
equivalents may be substituted for elements thereof without
departing from the scope of the invention. Therefore, it is
intended that the invention not be limited to any particular
embodiment contemplated, but that the invention will include all
embodiments falling within the scope of the appended claims.
BRIEF DESCRIPTION OF THE FIGURES
[0116] FIG. 1 is an overview of the clinical phase II study. In
each of the columns Screening, Random and Check 1-4 it is indicated
if it was performed on site or not, when it was performed in
relation to the start of the study and what tests and analysis were
performed.
[0117] FIG. 2 is a summary of the demographic and baseline
characteristics of the patient cohort. The quantity or mean
(standard deviation (SD)) is shown.
[0118] FIGS. 3A, B and C show the CGI-C values in the placebo
treated patient population (empty circle) and the OSU6162 treated
patient population (filled circle) after 1 week of treatment, after
2 weeks of treatment and after 6 weeks, respectively. Each circle
represents one patient.
[0119] FIGS. 4A, B and C show the CGI-C values in the placebo
treated patient population (empty circle) and the OSU6162 treated
patient population (filled circle) not on treatment with an
anti-depressive agent (no AD) as well as the CGI-C values in the
placebo treated patient population (empty circle) and the OSU6162
treated patient population on treatment with (filled circle)
anti-depressive agent (AD). Values are shown after 1 week of
treatment, after 2 weeks of treatment and after 6 weeks,
respectively. Each circle represents one patient.
[0120] FIGS. 5A, B and C show the FF total score, MFS total score
and the BDI total score, respectively, as measured at the time
points of the study in the placebo treated patient group (circle)
and the OSU6162 treated patient group (triangle). The x-axis shows
the time points in weeks and the y-axis shows the total score.
[0121] FIGS. 6A, B and C show the FF total score, MFS total score
and the BDI total score, respectively, as measured at the time
points of the study in the placebo treated patient group not on AD
treatment (circle, solid line); the OSU6162 treated patient group
not on AD treatment (triangle, solid line); the placebo treated
patient group on AD treatment (circle, dashed line); and the
OSU6162 treated patient group on AD treatment (triangle, dashed
line). The x-axis shows the time points in weeks and the y-axis
shows the total score. Group means and SEM for OSU6162 and placebo
groups on AD treatment and not on AD treatment are shown.
[0122] FIG. 7 is a scatter plot, wherein each dot represents a
patient sample. The change in FF total score from week 0 is shown
on the y-axis and the plasma concentration of OSU6162 in .mu.M is
shown on the x-axis.
[0123] FIG. 8 is a scatter plot, wherein each dot represents a
patient sample. The change in MFS total score from week 0 is shown
on the y-axis and the plasma concentration of OSU6162 in .mu.M is
shown on the x-axis.
[0124] FIG. 9 is a scatter plot, wherein each dot represents a
patient sample. The change in BDI total score from week 0 is shown
on the y-axis and the plasma concentration of OSU6162 in .mu.M is
shown on the x-axis.
EXAMPLES
Summary
[0125] The following Examples disclose the outcome of a phase II
clinical study aiming at investigating the therapeutic effects of
the S enatiomer of
(3S)-3-[3-(methylsulfonyl)-phenyl]-1-propylpiperidine hydrochloride
(herein interchangeably referred to as OSU6162 and (--OSU6162) for
the treatment of ME/CFS as measured by mental fatigue
self-assessment (MFS) questionnaire and Clinical Global Impression
of Change (CGI-C) as well as some other additional parameters. The
study was performed as a double-blind placebo-controlled study,
wherein half of the patients were administered the active drug and
the other half were administered placebo. Importantly, the study
demonstrated significantly improved outcomes in a subgroup of
patient who were treated with an anti-depressive agent compared to
the corresponding sub-group being treated by OSU6162 without any
anti-depressive treatment.
Example 1
Description of the Clinical Phase II Study
[0126] The study was performed in accordance with the current
version of the declaration of Helsinki (52nd WMA General Assembly,
Edinburgh, Scotland, October 2000) and in compliance with the
requirements of the Medical Products Agency of Sweden. The trial
was conducted in agreement with the International Conference on
Harmonisation (ICH) guidelines on Good Clinical Practise (GCP). All
patients provided written informed consent to participate in the
study prior to being screened.
[0127] FIG. 1 shows an overview of the study performed. The
overview shows when, where and what data was collected from the
patients at each instance.
Example 2
Selection of the Study Population
Inclusion Criteria
[0128] The Fukuda criteria and the International Consensus Criteria
(ICC) for diagnosis of ME/CFS were applied as inclusion criteria in
this study.
[0129] The ICC for the diagnosis ME was presented in the Journal of
Internal Medicine (International Consensus Criteria, ICC,
Carruthers et al (2011) Volume 270, Issue 4 Pages 295-400) and are
an update of the previously used Fukuda (Fukuda et al (1994) Annals
of Internal Medicine; 121:953-959) and Canadian Criteria
(Carruthers et al (2003) Journal of Chronic Fatigue Syndrome
11(1):7-115).
Patient Population
[0130] Patients were recruited from the ambulatory service at the
Gottfries Clinic AB. 79 patient were screened and 17 did not meet
the inclusion criteria for various reason (significant pathological
lab finding and not permitted concomitant medication: 1 patient;
significant pathological lab findings: 4 patients; depression: 3
patients; high blood pressure: 3 patients; diagnostic criteria ME
not fulfilled: 1 patient; concomitant medications: 2 patients; post
commotio cerebri: 1 patient; pregnancy: 1 patient; cancelation by
patient due to night work: 1 patient; drop-out: 1 patient;
technical mistake with study drug by research nurse: 2 patients)
resulting in a group of 62 patients which were randomized.
Exclusion Criteria
[0131] Medication that is known/judged not to interfere with
OSU6162 was permitted. Medications which were not permitted were
anti-epileptics or antipsychotics.
[0132] Patients with active substance abuse, pregnant women, women
of childbearing age not on contraceptives and patients with
abnormal laboratory parameters (e.g. Hb, white blood cells count,
electrolytes, tests of liver and kidney functions, TSH, T4, B12,
folic acid) judged to be of clinical significance were not
accepted.
[0133] Unstable therapies were not allowed but stable therapies
were allowed. A stable therapy is defined as having started at
least 6 months before the study and continued to be unchanged
during the study period. Examples of such therapies are treatments
with anti-depressants. Other stable therapies with hypnotics and
anxiolytics were also allowed if they were given at doses
recommended by the manufacturers.
[0134] Furthermore, analgesics such as NSAIDs, e.g. acetyl
salicylic acid, paracetamol and duloxetine were permitted as well
as stable anti-hypertensive therapy. Acute or chronic medications
for other medical conditions were allowed based on clinical
judgment.
[0135] Occasional use of over-the-counter (OTC) medications was
allowed at the investigator's discretion.
[0136] All concomitant medications, whether OTC or prescription,
were noted.
Withdrawal of Patients from Therapy or Assessment
[0137] Patients were free to withdraw from the study at any time
without giving a reason. Patients were advised that a request to
withdraw from the study, at any time during the trial, would have
no negative consequences. The investigators could also withdraw
patients from the trial if they deemed it appropriate for safety or
ethical reasons or if they considered further participation in the
study detrimental to the well-being of the patient. Patients who
withdrew or were withdrawn underwent a final evaluation as soon as
possible.
[0138] Any adverse event (AE) or serious adverse event (SAE) were
reported and to the Ethics committee according to regulations.
[0139] To summarize, 62 patient were included in the study
population and 1 patient withdrew from the study (Table 1). One
patient in the OSU6162 treatment group, who lacked detectable
levels of plasma OSU6162 was not included in the analysis.
TABLE-US-00001 TABLE 1 Disposition of patients. Number of patients
is indicated. Group A are patients who received OSU6162 and group B
are patients who received the placebo control. Group A Group B
Total Enrolled 31 31 62 (received at least one tablet) Completed 31
30 61 (Withdrawn) (1*) *Patient withdrawn from study according to
patient wish due to urinary tract infection.
Example 3
Treatment with OSU6162
[0140] The study was performed as a double-blinded
placebo-controlled study, where half of the patients received the
active drug and the other half received placebo. Circular coated
tablets for oral use of 15 mg and matching placebos was used. The
tablets were administered by research nurses at the study site.
Description of Investigational Products
[0141] The investigated substance is the S enantiomer with the
chemical name (S)-3-[3-(methylsulfonyl) phenyl]-1-propylpiperidine
hydrochloride, referred herein to as OSU6162. The substance is a
white powder with a melting point of 177-182.degree. C. and water
solubility of >2000 mg/ml.
[0142] OSU6162 belongs to a group of compounds called dopaminergic
stabilizers which modulate dopaminergic transmission.
Method of Assigning Patients to Treatment Groups
[0143] Randomization of patients participating in the study was
done by an external agent. The randomization procedure was
performed in agreement with CONSORT (Consolidated Standards of
Reporting Trials) guidelines.
Doses for use in the Study
[0144] Tablets were delivered in sets of 20 packages of tablets
containing 10 with active substance and 10 with placebo. Procedures
were taken to guarantee blinding and the code was kept in a locked
drawer at the study site. All persons dealing with the patients
were blinded towards active drug or placebo.
[0145] The tablets were circular coated tablets for oral use
containing 15 mg OSU6162. Matching placebos were used. The start
dose was 15 mg OSU6162 twice daily (before breakfast and lunch)
during 1 week with dose increase up to 30 mg twice daily during the
following week.
[0146] The dosage was individually flexible which means that if a
patient experienced adverse events, the dose was reduced with 15 mg
OSU6162 (one tablet), thus continuing with 15 mg once daily taken
in the morning.
[0147] Total period for active drug treatment for each participant
was two weeks.
Treatment Compliance
[0148] All study treatment was administered by the study
investigator or designated member of staff. To ensure drug
accountability the investigator or designated deputy maintained
accurate records of the dates and amounts of drug received, to whom
it was dispensed and accounts of any supplies which were
accidentally or deliberately destroyed; these details were recorded
on a drug accountability form. All unused clinical supplies and the
drug accountability forms were returned to the sponsor at the end
of the study.
Efficacy and Safety Variables
[0149] Efficacy was measured according to ratings using the
self-assessment questionnaire for mental fatigue and related
symptoms (MFS) after neurological disorders and injuries (Johansson
et al, supra). Another primary endpoint was the result of the
rating by the Clinical Global Impression of Change (Guy, supra),
which rating was made by the doctor in charge of the patient. CGI-C
scores range from 1 (very much improved) through to 7 (very much
worse).
[0150] Additionaly, the clinical effect was evaluated using the
FF-scale, The Beck/BDI scale, VAS pain scale and with
neuropsychological tests.
[0151] Patient safety was measured by ECG and was subject to
clinical investigation of vital signs and laboratory tests.
[0152] FIG. 1 provides a summary of the assessment and analysis
done at each of the visits to the clinic.
Example 4
Outcome of Treatment with OSU6162 Alone or Concomitant with
Anti-Depressant Treatment
[0153] In this Example, outcome variables of the treatment with
OSU6162 alone or concomitant with anti-depressant treatment were
evaluated.
Overview of Patient Population
[0154] Data from 60 patients was analyzed, whereof 30 received the
placebo control and 30 received treatment with OSU6162. In each
group, 11 patients were on treatment with a stable dose of an
anti-depressive agent (AD). Table 2 summaries the antidepressant
agents taken by patients included in the study. FIG. 2 shows an
overview of the demographic distribution of the patient population,
as well as the base line characteristics of the patients at the
start of the study (week 0). No significant difference was observed
between the placebo and the OSU6162 group and no significant
difference was observed between the patients on anti-depressant
treatment and the patients not on antidepressant treatment. Thus,
it was concluded that the randomization was satisfactory.
TABLE-US-00002 TABLE 2 Summary of anti-depressive agents (AD) taken
by patients concomitantly with OSU6162. Anti-depressive Type of
anti-depressive Number of agent (AD) agent patients Escitalopram,
selective serotonin reuptake 8 Citalopram inhibitor Venlafaxine
serotonin-norepinephrine 4 reuptake inhibitor Sertaline selective
serotonin reuptake 3 inhibitor Flouxetine selective serotonin
reuptake 1 inhibitor Paroxetine selective serotonin reuptake 1
inhibitor Duloxetine serotonin-norepinephrine 10 reuptake inhibitor
Amitryptine tricyclic antidepressant 10
Clinical Global Impression of Change
[0155] Clinical Global Impression of Change (CGI-C) was evaluated
by the clinician for each patient.
[0156] After one week of treatment, 13 of 30 (43%) OSU6162-treated
patients exhibited improved CGI-C values and 11 of 30 (37%)
placebo-treated patients exhibited improved CGI-C values. After two
weeks, 17 of 30 (57%) OSU6162-treated patients exhibited improved
CGI-C values and 19 of 30 (63%) placebo-treated patients exhibited
improved CGI-C values. Thus, no significant difference in CGI-C was
observed the between treatment groups for the entire patient
population (FIG. 3).
[0157] Importantly, in the subgroup receiving concomitant
antidepressant treatment (for the treatment of depression), there
was a clear tendency after one week for a greater improvement among
patients treated with OSU6162 than among those treated with placebo
(Mann-Whitney U-test: p=0.0524) (FIG. 4).
2-Way Interaction Analysis
[0158] In order to investigate if the was any interaction between
two different, categorical independent variables on the treatment
outcome, 2-way ANOVA analysis was performed.
[0159] 2-way ANOVA analysis did not show any interactions between
treatment and time, i.e. the effect of OSU6162 vs. placebo did not
differ over time.
[0160] For MFS there was a borderline significant trend to an
overall group difference between OSU6162 and placebo treatment
(F.sub.1,60=3.997, p=0.050 (FIG. 4B). None of the other outcome
targets (FF (FIG. 4A), BDI (FIG. 4C) and neuropsychological tests)
showed any main effect of treatment.
[0161] Consistently, all outcome targets (FF, MFS, BDI, pain VAS
and neuropsychological tests) showed main effects of time, i.e.
regardless of treatment there were improvements in these scale
scores over time (p<0.0001). Compared to week 0, FF and MFS
scores were improved after both week 1 (week 0-1) and week 2 (week
0-2) but not at follow-up after 6 weeks. BDI score was
significantly improved after week 2 compared to week 0. Statistical
analysis was performed using IBM SPSS Statistics. Version 20
software and is presented below:
[0162] FF (week 0-1): t.sub.180=-2.914, p=0.004;
[0163] FF (week 0-2): t.sub.180=-4.446; p=0.00002;
[0164] MFS (week 0-1): t.sub.180=-2.961; p=0.003;
[0165] MFS (week 0-2): t.sub.180=-4.649; p<0.00001; and
[0166] BDI (week 0-2): t.sub.180=-2.300; p=0.023.
3-Way Interaction Analysis
[0167] To examine the effect of treatment and concomitant use of an
antidepressant, antidepressant was included as a fixed factor in
the analyses. This resulted in improved models and reduced level of
unexplained variance. The antidepressant factor included two
levels: 1) patients on stable antidepressant therapy to treat
depression (i.e. since at least 6 months before start of the trial)
and 2) patients who did not receive medication to treat depression.
Outcome targets FF, MFS and BDI were measured.
[0168] Similarly to the 2-way interaction analysis there were no
significant interactions between treatment and time, nor main
effect of treatments. However, the tendency to an overall
difference between OSU6162 and placebo treatment on MFS remained
(F.sub.1,60=3.578, p=0.063) and FF, MFS and BDI showed main effects
of time (p<0.0001; FIGS. 5A, B and E).
[0169] Importantly, it was unexpectedly observed that there were
statistically significant 3-way interactions between the effects of
treatment with OSU6162 and antidepressant over time
(week*treatm*antidepr) for FF (F.sub.3,180=6.785, p=0.0002) (dashed
line, empty triangle, FIG. 6A) and MFS (F.sub.3,180=2.755 p=0.044)
(dashed line, empty triangle, FIG. 6B). The significant
interactions were found between week 1 and inclusion for FF and
MFS. Statistical analysis was performed using IBM SPSS Statistics.
Version 20 software and is presented below:
[0170] FF (week 0-1) t.sub.180=-3.491, p=0.001;
[0171] MFS (week 0-1) t.sub.180=-2.254, p=0.025;
[0172] FF (week 0-2) t.sub.180=-1.709, p=0.089; and
[0173] MFS (week 0-2) t.sub.180=-1.914, p=0.057.
[0174] These significant 3-way interactions were followed by post
hoc t-test comparisons. Changes from week 0 were used to evaluate
the effect of OSU6162 treatment in patients on stable
antidepressant therapy and in patients who were not on treatment
for depression, respectively. Significant improvements after one
week of treatment were observed on the FF- and MFS-scales in the
OSU6162 treated patient group on antidepressant therapy compared to
placebo treated patient group on antidepressant therapy [FF
(F.sub.1,56=6.320; p=0.015); 95% confidence interval for the
difference: -7.23 (-13.1 to -1.48) and MFS (F1,.sub.56=5.915;
p=0.018); 95% Cl for the difference: -4.82 (-8.79 to -0.85);
Bonferroni correction for multiple comparisons was applied]. No
difference between OSU6162 treated and placebo treated patients on
any scale was observed in the groups of patients who were not on
antidepressant therapy.
[0175] In summary, the above analyses show that OSU6162 was, after
one week of treatment, more efficient than placebo in improving
symptoms according to the FF- and MFS-scales in patients on stable
antidepressant therapy.
Example 5
Measurements of OSU6162 Concentration in Blood Plasma
[0176] Next, the concentration of OSU6162 in blood plasma was
measured and analyzed for correlations with time and changes in FF,
MFS and BDI score.
Results of OSU6162 Plasma Concentration Measurements
[0177] Plasma concentrations of OSU6162 were measured in 30
patients who received placebo and in 31 patients who received
OSU6162. The blood sample was drawn in the morning after the tablet
was taken--the time of the tablet intake was noted and reported to
the clinic by the patient. The blood sample was taken at minimum 65
and at maximum 180 minutes after tablet intake. The mean time was
123 minutes and the standard deviation 33 minutes.
[0178] As expected, no concentration of OSU6162 was detected in
placebo-treated patients. In one patient who received OSU6162
treatment there was no detectable level of OSU6162, hence this
patient was omitted from the statistical analyses.
[0179] A correlation analysis (Spearman rank correlation) was made
between plasma concentration of OSU6162 and time elapsed in minutes
between intake of tablet and blood sampling. No significant
correlation was found.
[0180] Correlations Between OSU6162 Concentration in Plasma and
Change in FF, MFS and BDI Score
[0181] In order to analyze the relationship between the treatment
outcome and the concentration of OSU6162 in blood plasma, OSU6162
concentrations in patients measured after week 2 were plotted
against change in FF, MFS and BDI score (FIGS. 6, 7 and 8). It was
noted that there seems to be a therapeutic optimum around 0.3-0.7
.mu.M as concentrations above 0.7 .mu.M do not seem to lead to any
further improvement.
[0182] Correlation analyses (Spearman rank correlation) showed a
significant correlation between OSU6162 concentration and change in
FF, MFS and BDI score, respectively, within the concentration
interval 0.1-0.7 .mu.M. Statistical analysis was performed using
IBM SPSS Statistics. Version 20 software and is presented
below:
[0183] FF: Rs=0.418, p=0.038;
[0184] MFS: Rs=0.466, p=0.019; and
[0185] BDI: Rs=0.491 p=0.013.
Example 6
Neuropsychological Testing of Cognitive Functioning
[0186] Next, patients were evaluated using a neuropsychological
test. 61 patients were included in a neuropsychological
examination. All subjects were tested once in connection with the
randomization with the BNIS neuropsychological screening test.
20-30 minutes was required for this test. With the purpose of
measuring the cognitive effects of the OSU6162 treatment six more
tests were distributed at a first occasion before the initiation of
treatment and at a second occasion after the treatment was
completed. These tests required 20 minutes each. All tests were
performed by a neuropsychologist.
[0187] Below follows a description of the tests performed and the
results thereof:
Barrow Neurological Institute Screen for Higher Cerebral
Functions
[0188] Barrow Neurological Institute Screen for Higher Cerebral
Functions (BNIS) is a screening test constructed to quantitatively
and qualitatively reflect the outcome of a range of higher cerebral
functions. The three initial items are pre-screening items where
arousal level, basic communication skills and level of cooperation
are assessed (a maximum score of 9) to decide whether the status of
the patients allows further testing. At least two points in each
item are required. The BNIS contains the following domains: speech
and language (maximum score 15), orientation (maximum score 3),
attention/concentration (maximum score 3), visual and visual
spatial problem solving (maximum score 8), learning and memory
(maximum score 7), affect (maximum score 4) and awareness vs.
performance (maximum score 1). The test provides a total score=50
of overall cognitive functioning and subscale scores. A score less
than 47 indicates brain dysfunction. [0189] Results: Table 3 show
the results from the BNIS test for the OSU6162 treated patient
group and for the placebo treated patient group. No significant
difference was observed between the groups.
TABLE-US-00003 [0189] TABLE 3 Results from BNIS test. BNIS OSU6162
Placebo Mean 45.2 44.5 STDEV 3.5 2.6 Min 33 39 Max 50 48
Coding Test
[0190] The Coding test is a subtest from WAIS, Wechsler Adult
Intelligence Scale and measures the processing speed. The
performance reflects abilities such as visual-motor coordination,
motor and mental speed and working memory. It requires the subject
to copy, as quickly and correctly as possible, nine symbols, one by
one in 93 boxes, placed below each number. The symbol connected
with the numbers is available. The score is the number of symbols
registered within 90 seconds. [0191] Results: Table 4 shows the
results from the Coding test before and after treatment from
patients treated with OSU6162 and patients treated with placebo. No
significant differences were observed between the groups.
TABLE-US-00004 [0191] TABLE 4 Results from Coding test. OSU6162
OSU6162 Differ- Placebo Placebo Differ- CODING Before After ence
Before After ence MEAN 51.42 56.29 49.07 56.17 MEDIAN 51 56 50 58
STDEV 12.32 12.45 9.48 10.24 MIN 31 37 28 36 MAX 80 93 68 82
Increased 5 7 mean
Trail Making Test A
[0192] Trail making test A (TMT A) requires the subject to draw a
line as quickly as possible connecting a series of numbers. It is a
time-based measure of attention, where time and quality are noted
and requires motor effectiveness, visual scanning, speed and
flexibility. The test has a high sensitivity for brain dysfunction.
[0193] Results: Table 5 shows the results from the TMT A before and
after treatment from patients treated with OSU6162 and patients
treated with placebo. No significant differences were observed
between the groups.
TABLE-US-00005 [0193] TABLE 5 Results from TMT A. TMT A Before
After Difference OSU6162 MEAN 33.4 28.5 10 MEDIAN 32 29 STDEV 10.8
7.8 MIN 16 15 MAX 57 48 Placebo MEDEL 32.7 28 7 MEDIAN 32 26 STDAV
10.7 9.5 MIN 15 13 MAX 55 57
Trail Making Test B
[0194] Trail making test B (TMT B) demonstrates the effectiveness
of visual scanning and measures alternating attention. The subject
follows a mental track and the test requires the ability to handle
more than one stimulus at a time, as well as flexibility in
shifting between different activities. It has a high sensitivity
for brain dysfunction and is regarded to be related to prefrontal
functioning. [0195] Results: Table 6 shows the results from the TMT
B before and after treatment from patients treated with OSU6162 and
patients treated with placebo. No significant differences were
observed between the groups.
TABLE-US-00006 [0195] TABLE 6 Results from TMT B. TMT B Before
After Difference OSU6162 MEAN 71.7 61.2 10 MEDIAN 32 29 STDEV 20.8
21.8 MIN 44 31 MAX 134 145 Placebo MEDEL 73 63.4 14 MEDIAN 65.5
58.5 STDAV 29.4 23.6 MIN 34 26 MAX 167 155
Stroop Tests
[0196] The Stroop test (Victoria version) is a time-based test
sensitive to frontal lobe dysfunction. It measures executive
functioning and is validated and used internationally. Depression
and anxiety could influence the results. Speeds of processing and
conceptual abilities contribute to the performance. It also
reflects the ability of concentration. The test consists of three
cards each containing six rows of four items. [0197] Stroop I is on
the first card. In this subtest the subject must name as quickly as
possible the color of 24 dots printed in blue, green, red and
yellow. Each color is used six times and the four colors are
arranged in pseudo-random order within the array, each color
appears once in a row. [0198] Stroop 2 is on the second card. In
this subtest the dots are replaced by common words printed in
lower-case letters. The subject is required to name the colors in
which the stimuli are presented and to disregard their verbal
content. [0199] Stroop 3 is on the third card. In this subtest the
colored stimuli are the color names "blue, green, red and yellow"
printed in lower case letters so that the print color never
corresponds to the color name. [0200] Results: Table 7 shows the
results from the Stroop tests before and after treatment from
patients treated with OSU6162 and patients treated with placebo. No
significant differences were observed between the groups.
TABLE-US-00007 [0200] TABLE 7 Results from Stroop tests. OSU6162
Before After Difference Placebo Before After Difference Stroop 1
MEAN 13.97 12.77 1.2 MEAN 14.57 12.97 1.6 MEDIAN 14 12 MEDIAN 13.5
12 STDAV 3.02 2.51 STDAV 4.26 3.03 MIN 9 8 MIN 9 9 MAX 22 20 MAX 27
19 Stroop 2 MEAN 19.5 16.9 3.2 MEAN 19.7 16.6 3.2 MEDIAN 19 16
MEDIAN 26 21 STDAV 5.8 4.35 STDAV 6.62 3.8 MIN 10 9 MIN 13 12 MAX
39 29 MAX 43 27 Stroop 3 MEAN 26.8 23.48 4.9 MEAN 27.63 22.4 5.6
MEDIAN 24 23 MEDIAN 26 21 STDAV 8.85 8.6 STDAV 9.52 7.3 MIN 14 12
MIN 13 15 MAX 51 62 MAX 59 52
[0201] In summary, no significant difference between the placebo
treated and the OSU6162 treated groups was observed in the
psychoneurological tests employed, indicating that treatment with
OSU6162 does not affect the cognitive abilities of treated
patients.
ITEMIZED LIST OF EMBODIMENTS
[0202] 1. A dopamine stabilizing agent and an anti-depressive agent
for use in the treatment of a disorder characterized by
debilitating fatigue, wherein said dopamine stabilizing agent is
selected from the group consisting of [0203] i) a compound of
formula I
[0203] ##STR00004## [0204] wherein: [0205] R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, provided
that not more than one of R.sup.1 and R.sup.2 is H, CONH.sub.2, OH,
CN, CH.sub.2CN, OSO.sub.2CH.sub.3, OSO.sub.2CF.sub.3,
SSO.sub.2CF.sub.3, COR, SO.sub.xCH.sub.3, SO.sub.xCF.sub.3,
O(CH.sub.2).sub.xCF.sub.3, where x is 0-2, OSO.sub.2N(R).sub.2,
CH.dbd.NOR, COCOOR, CO--COON(R).sub.2, C.sub.3-8 cycloalkyl,
NRSO.sub.2CF.sub.3, phenyl at position 2, 3 or 4, thienyl, furyl,
pyrrolyl, oxazolyl, thiazolyl, N-pyrrolinyl, triazolyl and
tetrazolyl of pyridinyl; [0206] R.sup.3 is independently selected
from the group consisting of H, CF.sub.3, CH.sub.2CF.sub.3,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.9
cycloalkyl-methyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and
CH.sub.2SCH.sub.3, [0207] R.sup.4 and R are independently selected
from the group consisting of H, CF.sub.3CH.sub.2CF.sub.3,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.9
cycloalkyl-methyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and
--(CH.sub.2)m-R.sup.5 where m is 1-8; [0208] R.sup.5 is
independently selected from the group consisting of phenyl, phenyl
substituted with CN, CF.sub.3, CH.sub.2CF.sub.3, C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.9
cycloalkyl-methyl, C.sub.2-C.sub.8 alkenyl or C.sub.2-C.sub.8
alkynyl substituent, 2-thiophenyl, 3-thiophenyl,
--NR.sup.6CONR.sup.6R.sup.7 and --CONR.sup.6R.sup.7; and [0209]
R.sup.6 and R.sup.7 are independently selected from the group
consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.4-C.sub.9 cycloalkyl-methyl, C.sub.2-C.sub.8alkenyl and
C.sub.2-C.sub.8 alkynyl; [0210] ii) a compound of formula II
[0210] ##STR00005## [0211] wherein: [0212] R.sub.1 is independently
selected from the group consisting of OSO.sub.2CF.sub.3,
OSO.sub.2CH.sub.3, SOR.sub.3, SO.sub.2R.sub.3, COCH.sub.3 and
COCH.sub.2CH.sub.3, wherein R.sub.3 is as defined below; [0213]
R.sub.2 is independently selected from the group consisting of
C.sub.2-C.sub.4 branched or unbranched alkyls, terminal allyl,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2F,
CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl,
R.sub.3 is independently selected from the group consisting of
C.sub.1-C.sub.3 alkyls, CF.sub.3, and N(CH.sub.3).sub.2; [0214] and
[0215] iii) a compound of formula III
[0215] ##STR00006## [0216] wherein: [0217] X is independently
selected from the group consisting of N, CH and C, provided that X
may only be C when the compound comprises a double bond at the
dotted line; [0218] R.sub.1 independently is selected from the
group consisting of OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3,
SOR.sub.5, SO.sub.2R.sub.5, COR.sub.5, CN, NO.sub.2, CONHR.sub.5,
CF.sub.3, 3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br,
and I, wherein R.sub.5 is as defined below; [0219] R.sub.2 is
independently selected from the group consisting of C.sub.1-C.sub.4
alkyls, allyls, CH.sub.2SCH.sub.3, CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2CH.sub.2F, CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl,
4,4,4-trifluorobutyl and --(CH.sub.2)--R.sub.6, wherein R.sub.6 is
as defined below; [0220] R.sub.3 and R.sub.4 are independently
selected from the group consisting of H and C.sub.1-C.sub.4 alkyls,
provided that both R.sub.3 and R.sub.4 cannot be H at the same
time; [0221] R.sub.5 is independently selected from the group
consisting of C.sub.1-C.sub.3 alkyls, CF.sub.3 and
N(R.sub.2).sub.2, wherein R.sub.2 is as defined above; and R.sub.6
is independently selected from the group consisting of
C.sub.3-C.sub.6 cycloalkyls, 2-tetrahydrofurane and
3-tetra-hydrofurane; [0222] and pharmaceutically acceptable salts
of any one of the compounds of formula I, II or III.
[0223] 2. A dopamine stabilizing agent and an anti-depressive agent
for use according to item 1, wherein in formula I R.sup.1 is
independently selected from the group consisting of CN,
OSO.sub.2CF.sub.3 and SO.sub.2CH.sub.3, such as CN.
[0224] 3. A dopamine stabilizing agent and an anti-depressive agent
for use according to item 1 or 2, wherein in formula I R.sup.2 is
H.
[0225] 4. A dopamine stabilizing agent and an anti-depressive agent
for use according to any one of items 1-3, wherein in formula I
R.sup.3 is C.sub.1-.sub.8 alkyl.
[0226] 5. A dopamine stabilizing agent and an anti-depressive agent
for use according to any one of items 1-4, wherein in formula I
R.sup.3 is n-propyl.
[0227] 6. A dopamine stabilizing agent and an anti-depressive agent
for use according to any one of items 1-5, wherein in formula I
R.sup.4 is H.
[0228] 7. A dopamine stabilizing agent and an anti-depressive agent
for use according to any preceding item , wherein said dopamine
stabilizing agent is
(3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine or a
pharmaceutically acceptable salt thereof, such as
(3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine
hydrochloride.
[0229] 8. A dopamine stabilizing agent and an anti-depressive agent
for use according to any one of items 1-7, wherein said
anti-depressive agent is selected from the group consisting of
selective serotonin reuptake inhibitors (SSRIs),
serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin
modulators and stimulators (SMSs), serotonin reuptake inhibitors
(SARIs), norephinephrine reuptake inhibitors (NRIs), tricyclic
antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs),
tetracyclic antidepressants (TeCAs), noradrenergic and specific
serotonergic antidepressant (NaSSAs), buprenorphine, low-dose
antipsychotics and St John's wort, such as a group consisting of
selective serotonin reuptake inhibitors (SSRIs),
serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin
modulators and stimulators (SMSs), serotonin reuptake inhibitors
(SARIs), norephinephrine reuptake inhibitors (NRIs), tricyclic
antidepressants (TCAs), tetracyclic antidepressants (TeCAs),
noradrenergic and specific serotonergic antidepressant (NaSSAs),
buprenorphine, low-dose antipsychotics and St John's wort
[0230] 9. A dopamine stabilizing agent and an anti-depressive agent
for use according to item 8, wherein the anti-depressive agent is
selected from the group consisting of selective serotonin reuptake
inhibitors (SSRI) , serotonin-norepinephrine reuptake inhibitors
(SNRI) and tricyclic antidepressants (TCAs), such as the group
consisting of selective serotonin reuptake inhibitors (SSRI) and
serotonin-norepinephrine reuptake inhibitors (SNRI).
[0231] 10. A dopamine stabilizing agent and an anti-depressive
agent for use according to item 9, wherein said selective serotonin
reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake
inhibitor (SNRI) is selected from the group consisting of
escitalopram, citalopram, sertraline, fluoxetine, paroxetine,
duloxetine, amitriptyline, fluvoxamine, dapoxetine, indalpine,
zemelidinem venlafaxine, desvenlafaxine, milnacipran,
levomilnacipran and sibutramine or combinations thereof.
[0232] 11. A dopamine stabilizing agent and an anti-depressive
agent for use according to item 9, wherein said selective serotonin
reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake
inhibitors (SNRI) or tricyclic antidepressant (TCAs) is selected
from the group consisting of escitalopram, citalopram, sertraline,
fluoxetine, paroxetine, duloxetine, amitriptyline and venlafaxine
or combinations thereof.
[0233] 12. A dopamine stabilizing agent and an anti-depressive
agent for use according to any one of items 1-11, wherein said use
involves concomitant or simultaneous administration of said
dopamine stabilizing agent and said anti-depressive agent.
[0234] 13. A dopamine stabilizing agent and an anti-depressive
agent for use according to item 12, wherein said concomitant
administration is within less than 72 hours, such as within less
than 48 hours, such as within less than 24 hours, such as within
less than 12 hours, such as within less than 6 hours, such as
within less than 1 hour.
[0235] 14. A dopamine stabilizing agent and an anti-depressive
agent for use according to any preceding item, wherein at least one
or both of said dopamine stabilizing agent and said anti-depressive
agent is/are administered orally, subcutaneously, intramuscularly
or intravenously, such as orally.
[0236] 15. A dopamine stabilizing agent and an anti-depressive
agent for use according to any preceding item, wherein said
dopamine stabilizing agent is administered in a dose of
approximately 0.1-45 mg, such as 0.1-5 mg or such as approximately
1-45 mg, such as approximately 1-30 mg, such as approximately 5-30
mg, such as approximately 10-30 mg, such as 15 mg or 30 mg.
[0237] 16. A dopamine stabilizing agent and an anti-depressive
agent for use according to any preceding item, wherein said
dopamine stabilizing agent is administered once, twice or three
times a day, such as once or twice a day.
[0238] 17. A dopamine stabilizing agent and an anti-depressive
agent for use according to any preceding item, wherein, upon
administration, the therapeutically effective blood plasma
concentration of said dopamine stabilizing agent is approximately
0.1-0.7 .mu.M, such as approximately 0.3-0.7 .mu.M.
[0239] 18. A dopamine stabilizing agent and an anti-depressive
agent for use according to any preceding item, wherein said
disorder is selected from the group consisting of myalgic
encephalomyelitis/chronic fatigue syndrome, fibromyalgia, mental
fatigue, post stroke fatigue, Huntington's disease, Parkinson's
disease, multiple sclerosis, narcolepsy, post cancer fatigue,
fatigue associated with cancer with or without cytostatic
treatment, depression and combinations thereof.
[0240] 19. A dopamine stabilizing agent and an anti-depressive
agent for use according to any one of items 1-18, wherein said
disorder is a fatigue disorder characterized by at least one of the
conditions selected from fibromyalgia, mental fatigue, myalgic
encephalomyelitis/chronic fatigue syndrome and depression.
[0241] 20. A dopamine stabilizing agent and an anti-depressive
agent for use according to any one of items 1-18, wherein said
disorder is a pain disorder characterized by at least one of the
conditions selected from fibromyalgia, mental fatigue, myalgic
encephalomyelitis/chronic fatigue syndrome and depression.
[0242] 21. A dopamine stabilizing agent and an anti-depressive
agent for use according to item 18, wherein said disorder is
selected from the group consisting of myalgic
encephalomyelitis/chronic fatigue syndrome, mental fatigue,
fibromyalgia, depression and combinations thereof.
[0243] 22. A dopamine stabilizing agent and an anti-depressive
agent for use according to item 21, wherein said disorder is
myalgic encephalomyelitis/chronic fatigue syndrome.
[0244] 23. A dopamine stabilizing agent and an anti-depressive
agent for use according to item 21, wherein said disorder is mental
fatigue.
[0245] 24. A dopamine stabilizing agent and an anti-depressive
agent for use according to item 21, wherein said disorder is
depression
[0246] 25. A dopamine stabilizing agent and an anti-depressive
agent for use according to item 21, wherein said disorder is
fibromyalgia.
[0247] 26. A dopamine stabilizing agent and an anti-depressive
agent for use according to item 21, wherein said disorder is a
combination of selected from the group of a combination of myalgic
encephalomyelitis/chronic fatigue syndrome and fibromyalgia; a
combination of myalgic encephalomyelitis/chronic fatigue syndrome
and mental fatigue; a combination of myalgic
encephalomyelitis/chronic fatigue syndrome and depression; a
combination of mental fatigue and depression; a combination of
fibromyalgia and depression; and a combination of mental fatigue
and fibromyalgia
[0248] 27. A dopamine stabilizing agent and an anti-depressive
agent for use according to item 21, wherein said disorder is a
combination selected from a combination of myalgic
encephalomyelitis/chronic fatigue syndrome, mental fatigue and
fibromyalgia; a combination of myalgic encephalomyelitis/chronic
fatigue syndrome, mental fatigue and depression; a combination of
myalgic encephalomyelitis/chronic fatigue syndrome, depression and
fibromyalgia; a combination of depression, mental fatigue and
fibromyalgia.
[0249] 28. Pharmaceutical composition comprising a dopamine
stabilizing agent as defined in any one of items 1-7 and an
anti-depressive agent.
[0250] 29. Pharmaceutical composition according to item 28, wherein
said anti-depressive agent is as defined in any one of items
8-11.
[0251] 30. Pharmaceutical composition according to any one of items
28-29 wherein said composition is formulated for oral,
subcutaneous, intramuscular or intravenous administration, such as
for oral administration.
[0252] 31. Pharmaceutical composition according to any one of items
28-30, comprising an amount of dopamine stabilizing agent of
approximately 0.1-45 mg, such as 0.1-5 mg or such as approximately
1-45 mg, such as approximately 1-30 mg, such as approximately 5-30
mg, such as approximately 10-30 mg, such as 15 mg or 30 mg.
[0253] 32. Pharmaceutical composition according to any one of items
26-31, wherein said composition is formulated as a pill, tablet,
capsule, dragee, liquid, gel capsule, syrup, slurry or suspension,
such as a pill.
[0254] 33. Combination kit comprising a dopamine stabilizing agent
as defined in any one of items 1-7 and an anti-depressive
agent.
[0255] 34. Combination kit according to item 31, wherein said
anti-depressive agent is as defined in any one of items 8-11.
[0256] 35. Combination kit according to item 33 or 34, wherein said
dopamine stabilizing agent and said anti-depressive agent are
formulated for concomitant or simultaneous administration.
[0257] 36. Combination kit according to item 35, wherein said kit
is formulated for concomitant administration within less than 72
hours, such as less than 48 hours, such as less than 24 hours, such
as within less than 12 hours, such as within less than 6 hours,
such as within less than 1 hour.
[0258] 37. Combination kit according to item 35, wherein said kit
is formulated for simultaneous administration.
[0259] 38. Combination kit according to any one of items 33-37,
wherein said kit is formulated for is oral, subcutaneous,
intramuscular or intravenous administration, such as oral
administration.
[0260] 39. Combination kit according to any one of items 33-39,
wherein said combination kit is formulated such that the dose of
dopamine stabilizing agent of approximately 0.1-45 mg, such as
0.1-5 mg or such as approximately 1-45 mg, such as approximately
1-30 mg, such as approximately 5-30 mg, such as approximately 10-30
mg, such as 15 mg or 30 mg.
[0261] 40. Dopamine stabilizing agent for use in the treatment of a
disorder characterized by debilitating fatigue in a subject on
treatment with at least one anti-depressive agent, wherein said
dopamine stabilizing agent is as defined in any one of items
1-7.
[0262] 41. Dopamine stabilizing agent for use according to item 40,
wherein said disorder is as defined in any one of items 18-27.
[0263] 42. Dopamine stabilizing agent for use according to any one
of items 40-41, wherein said dopamine stabilizing agent is
administered orally, subcutaneously, intramuscularly or
intravenously, such as orally.
[0264] 43. Dopamine stabilizing agent for use according to any one
of items 38-40, wherein said dopamine stabilizing agent is
administered as defined by any one of items 10-14.
[0265] 44. Dopamine stabilizing agent for use according to any one
of items 38-41, wherein said subject is on treatment with an
anti-depressive agent as defined in any one of items 8-11.
[0266] 45. Use of a dopamine stabilizing agent as defined in any
one of items 1-7 and an anti-depressive agent, for the manufacture
of a medicament for the treatment a disorder characterized by
persistent and debilitating fatigue.
[0267] 46. Use of a dopamine stabilizing agent according to item
45, wherein said anti-depressive agent as defined in any one of
items 8-11, wherein said disorder is as defined in any one of items
18-27.
[0268] 47. Use of a dopamine stabilizing agent as defined in any
one of items 1-7, for the manufacture of a medicament for the
treatment a disorder characterized by debilitating fatigue in a
subject on treatment with at least one anti-depressive agent.
[0269] 48. Method for treatment of a disorder characterized by
debilitating fatigue, the method comprising administering to a
subject in need thereof a therapeutically effective dose of a
dopamine stabilizing agent, wherein said subject is on treatment
with an anti-depressive agent, wherein the dopamine stabilizing
agent is selected from the group consisting of [0270] (i) a
compound of formula I
[0270] ##STR00007## [0271] wherein: [0272] R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, provided
that not more than one of R.sup.1 and R.sup.2 is H, CONH.sub.2, OH,
CN, CH.sub.2CN, OSO.sub.2CH.sub.3, OSO.sub.2CF.sub.3,
SSO.sub.2CF.sub.3, COR, SO.sub.xCH.sub.3, SO.sub.xCF.sub.3,
O(CH.sub.2).sub.xCF.sub.3, where x is 0-2, OSO.sub.2N(R).sub.2,
CH.dbd.NOR, COCOOR, CO--COON(R).sub.2, C.sub.3-8 cycloalkyl,
NRSO.sub.2CF.sub.3, phenyl at position 2, 3 or 4, thienyl, furyl,
pyrrolyl, oxazolyl, thiazolyl, N-pyrrolinyl, triazolyl and
tetrazolyl of pyridinyl; [0273] R.sup.3 is independently selected
from the group consisting of H, CF.sub.3, CH.sub.2CF.sub.3,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.9
cycloalkyl-methyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and
CH.sub.2SCH.sub.3, [0274] R.sup.4 and R are independently selected
from the group consisting of H, CF.sub.3CH.sub.2CF.sub.3,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.9
cycloalkyl-methyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and
--(CH.sub.2)m-R.sup.5 where m is 1-8; [0275] R.sup.5 is
independently selected from the group consisting of phenyl, phenyl
substituted with CN, CF.sub.3, CH.sub.2CF.sub.3, C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.9
cycloalkyl-methyl, C.sub.2-C.sub.8 alkenyl or C.sub.2-C.sub.8
alkynyl substituent, 2-thiophenyl, 3-thiophenyl,
--NR.sup.6CONR.sup.6R.sup.7 and --CONR.sup.6R.sup.7; and [0276]
R.sup.6 and R.sup.7 are independently selected from the group
consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.4-C.sub.9 cycloalkyl-methyl, C.sub.2-C.sub.8alkenyl and
C.sub.2-C.sub.8 alkynyl; [0277] (ii) a compound of formula II
[0277] ##STR00008## [0278] wherein: [0279] R.sub.1 is independently
selected from the group consisting of OSO.sub.2CF.sub.3,
OSO.sub.2CH.sub.3, SOR.sub.3, SO.sub.2R.sub.3, COCH.sub.3 and
COCH.sub.2CH.sub.3, wherein R.sub.3 is as defined below; [0280]
R.sub.2 is independently selected from the group consisting of
C.sub.2-C.sub.4 branched or unbranched alkyls, terminal allyl,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2F,
CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl,
[0281] R.sub.3 independently is selected from the group consisting
of C.sub.1-C.sub.3 alkyls, CF.sub.3, and N(CH.sub.3).sub.2; [0282]
and [0283] (iii) a compound of formula III
[0283] ##STR00009## [0284] wherein: [0285] X is independently
selected from the group consisting of N, CH and C, provided that X
may only be C when the compound comprises a double bond at the
dotted line; [0286] R.sub.1 is independently selected from the
group consisting of OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3,
SOR.sub.5, SO.sub.2R.sub.5, COR.sub.5, CN, NO.sub.2, CONHR.sub.5,
CF.sub.3, 3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br,
and I, wherein R.sub.5 is as defined below; [0287] R.sub.2 is
independently selected from the group consisting of C.sub.1-C.sub.4
alkyls, allyls, CH.sub.2SCH.sub.3, CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2CH.sub.2F, CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl,
4,4,4-trifluorobutyl and --(CH.sub.2)--R.sub.6, wherein R.sub.6 is
as defined below; [0288] R.sub.3 and R.sub.4 are independently
selected from the group consisting of H and C.sub.1-C.sub.4 alkyls,
provided that both R.sub.3 and R.sub.4 cannot be H at the same
time; [0289] R.sub.5 is independently selected from the group
consisting of C.sub.1-C.sub.3 alkyls, CF.sub.3 and
N(R.sub.2).sub.2, wherein R.sub.2 is as defined above; and R.sub.6
is selected from the group consisting of C.sub.3-C.sub.6
cycloalkyls, 2-tetrahydrofurane and 3-tetra-hydrofurane; [0290] and
pharmaceutically acceptable salts of any one of the compounds of
formula I, II or III.
[0291] 49. Method of treatment of a disorder characterized by
debilitating fatigue according to item 48, wherein in formula I
R.sup.1 is independently selected from the group consisting of CN,
OSO.sub.2CF.sub.3 and SO.sub.2CH.sub.3, such as CN.
[0292] 50. Method of treatment of a disorder characterized by
debilitating fatigue according to item 48 or 49, wherein in formula
I R.sup.2 is H
[0293] 51. Method of treatment of a disorder characterized by
debilitating fatigue according to any one of items 48-50, wherein
in formula I R.sup.3 is C.sub.1-8 alkyl.
[0294] 52. Method of treatment of a disorder characterized by
debilitating fatigue according to any one of items 48-51, wherein
in formula I R.sup.3 is n-propyl.
[0295] 53. Method of treatment of a disorder characterized by
debilitating fatigue according to any one of items 48-52, wherein
in formula I R.sup.4 is H.
[0296] 54. Method of treatment of a disorder characterized by
debilitating fatigue according to any one of items 48-53, wherein
said dopamine stabilizing agent is
(3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine or a
pharmaceutically acceptable salt thereof, such as
(3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine
hydrochloride.
[0297] 55. Method of treatment of a disorder characterized by
debilitating fatigue, the method comprising co-administration, to a
subject in need thereof, of a therapeutically effective dose of a
dopamine stabilizing agent and a therapeutically effective dose of
an anti-depressive agent, wherein the dopamine stabilizing agent is
defined as in any of one items 48-54.
[0298] 56. Method of treatment according to any one of items 48-55,
wherein said disorder is selected from the group consisting of
myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia,
mental fatigue, post stroke fatigue, Huntington's disease,
Parkinson's disease, multiple sclerosis, narcolepsy, post cancer
fatigue, fatigue associated with cancer with or without cytostatic
treatment, depression and combinations thereof.
[0299] 57. Method of treatment according to any one of items 48-54,
wherein said disorder is at least one fatigue disorder or pain
disorder characterized by at least one of the conditions selected
from fibromyalgia, mental fatigue, myalgic
encephalomyelitis/chronic fatigue syndrome and depression.
[0300] 58. Method of treatment according to item 55, wherein said
disorder is at least one fatigue disorder or pain disorder
characterized by at least one of the conditions selected from
fibromyalgia, mental fatigue, depression and myalgic
encephalomyelitis/chronic fatigue syndrome.
[0301] 59. Method of treatment according to item 56, wherein the
disorders is selected from the group consisting of myalgic
encephalomyelitis/chronic fatigue syndrome; mental fatigue;
fibromyalgia; depression; a combination of myalgic
encephalomyelitis/chronic fatigue syndrome and fibromyalgia; a
combination of myalgic encephalomyelitis/chronic fatigue syndrome
and mental fatigue; a combination of myalgic
encephalomyelitis/chronic fatigue syndrome and depression; a
combination of mental fatigue and depression; a combination of
fibromyalgia and depression; and a combination of mental fatigue
and fibromyalgia; a combination of myalgic
encephalomyelitis/chronic fatigue syndrome, mental fatigue and
fibromyalgia; a combination of myalgic encephalomyelitis/chronic
fatigue syndrome, mental fatigue and depression; a combination of
myalgic encephalomyelitis/chronic fatigue syndrome, depression and
fibromyalgia; a combination of depression, mental fatigue and
fibromyalgia.
[0302] 60. Method of treatment according to item 59, wherein the
disorders is myalgic encephalomyelitis/chronic fatigue
syndrome.
[0303] 61. Method of treatment according to any one of items 48-60,
wherein said anti-depressive agent is selected from the group
consisting of the selective serotonin reuptake inhibitors (SSRIs),
serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin
modulators and stimulators (SMSs), serotonin reuptake inhibitors
(SARIs), norephinephrine reuptake inhibitors (NRIs), tricyclic
antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs),
tetracyclic antidepressants (TeCAs), noradrenergic and specific
serotonergic antidepressant (NaSSAs), buprenorphine, low-dose
antipsychotics and St John's wort, such as the group consisting of
selective serotonin reuptake inhibitors (SSRI) and
serotonin-norepinephrine reuptake inhibitors (SNRI).
[0304] 62. Method of treatment according to item 61, wherein said
selective serotonin reuptake inhibitor (SSRI),
serotonin-norepinephrine reuptake inhibitor (SNRI) or tricyclic
antidepressant (TCA) is selected from escitalopram, citalopram,
sertraline, fluoxetine, paroxetine, duloxetine, amitriptyline,
fluvoxamine, dapoxetine, indalpine, zemelidinem venlafaxine,
desvenlafaxine, milnacipran, levomilnacipran and sibutramine or
combinations thereof, such as the group consisting of escitalopram,
citalopram, sertraline, fluoxetine, paroxetine, duloxetine,
amitriptyline, venlafaxine or combinations thereof.
[0305] 63. Method of treatment according to any one of items 46-55,
wherein the co-administration is concomitant or simultaneous.
[0306] 64. Method of treatment according to item 63, wherein said
co-administration is concomitant administration within less than 72
hours, such as less than 48 hours, such as less than 24 hours, such
as within less than 12 hours, such as within less than 6 hours,
such as within less than 1 hour.
[0307] 65. Method of treatment according to item 63, wherein said
co-administration is simultaneous.
[0308] 66. Method of treatment according to any one of items 48-65,
wherein said dopamine stabilizing agent is administered orally,
subcutaneously, intramuscularly or intravenously, such as
orally.
[0309] 67. Method of treatment according to any one of items 55-66,
wherein said anti-depressive agent is administered orally,
subcutaneously, intramuscularly or intravenously, such as
orally.
[0310] 68. Method of treatment according to item 48-67, wherein
said dopamine stabilizing agent is administered in a dose of
approximately 0.1-45 mg, such as 0.1-5 mg or such as approximately
1-45 mg, such as approximately 1-30 mg, such as approximately 5-30
mg, such as approximately 10-30 mg, such as 15 mg or 30 mg.
[0311] 69. Method of treatment according to any one of items 48-68,
wherein said dopamine stabilizing agent is administered once, twice
or three times a day, such as once or twice a day.
[0312] 70. Method of treatment according to any one of items 48-69,
wherein, upon administration, the therapeutically effective blood
plasma concentration of said dopamine stabilizing agent is
approximately 0.1-0.7 .mu.M, such as approximately 0.3-0.7
.mu.M.
* * * * *