U.S. patent application number 12/051807 was filed with the patent office on 2009-02-26 for combinations of 5-ht2a inverse agonists and antagonists with antipsychotics.
This patent application is currently assigned to Acadia Pharmaceuticals, Inc.. Invention is credited to Daun Bahr, Mark Brann, David Furlano, Perry Peters, Daniel Van Kammen.
Application Number | 20090053329 12/051807 |
Document ID | / |
Family ID | 39744932 |
Filed Date | 2009-02-26 |
United States Patent
Application |
20090053329 |
Kind Code |
A1 |
Peters; Perry ; et
al. |
February 26, 2009 |
COMBINATIONS OF 5-HT2A INVERSE AGONISTS AND ANTAGONISTS WITH
ANTIPSYCHOTICS
Abstract
Combinations of 5-HT2A inverse agonists or antagonists such as
pimavanserin with antipsychotics such as risperidone are shown to
induce a rapid onset of antipsychotic action and increase the
number of responders when compared to therapy with the
antipsychotic alone. These effects can be achieved at a low dose of
the antipsychotic, thereby reducing the incidence of side effects.
The combinations are also effective at decreases the incidence of
weight gain and increased glucose or prolactin levels caused by the
antipsychotic.
Inventors: |
Peters; Perry; (San Diego,
CA) ; Furlano; David; (San Diego, CA) ; Bahr;
Daun; (San Diego, CA) ; Van Kammen; Daniel;
(San Diego, CA) ; Brann; Mark; (Rye, NH) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET, FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Assignee: |
Acadia Pharmaceuticals,
Inc.
San Diego
CA
|
Family ID: |
39744932 |
Appl. No.: |
12/051807 |
Filed: |
March 19, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60895735 |
Mar 19, 2007 |
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60908921 |
Mar 29, 2007 |
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61012771 |
Dec 10, 2007 |
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61026092 |
Feb 4, 2008 |
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Current U.S.
Class: |
424/722 ;
514/212.01; 514/222.2; 514/254.06; 514/259.41; 514/278;
514/329 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/554 20130101; A61P 7/02 20180101; A61K 31/5513 20130101;
A61K 31/519 20130101; A61K 31/5513 20130101; A61P 25/06 20180101;
A61P 43/00 20180101; A61K 31/519 20130101; A61P 9/00 20180101; A61P
9/10 20180101; A61P 25/24 20180101; A61P 25/18 20180101; A61K
31/496 20130101; A61K 49/0008 20130101; A61P 9/12 20180101; A61K
31/00 20130101; A61K 31/4468 20130101; A61K 31/451 20130101; A61K
33/00 20130101; A61P 25/22 20180101; A61K 31/4468 20130101; A61K
31/554 20130101; A61K 31/4515 20130101; A61K 31/435 20130101; A61P
25/20 20180101; G16C 20/50 20190201; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/454 20130101; A61K 2300/00 20130101;
A61K 31/4515 20130101; A61K 31/00 20130101 |
Class at
Publication: |
424/722 ;
514/329; 514/259.41; 514/278; 514/254.06; 514/222.2;
514/212.01 |
International
Class: |
A61K 33/00 20060101
A61K033/00; A61K 31/445 20060101 A61K031/445; A61K 31/519 20060101
A61K031/519; A61K 31/438 20060101 A61K031/438; A61P 25/18 20060101
A61P025/18; A61K 31/497 20060101 A61K031/497; A61K 31/54 20060101
A61K031/54; A61K 31/55 20060101 A61K031/55 |
Claims
1.-32. (canceled)
33. A method of inducing a rapid onset of an antidepressant effect,
comprising co-administering a 5-HT2A inverse agonist or antagonist
and an antipsychotic agent to a subject suffering from depression
such that there is a rapid onset of antidepressant effect.
34. The method of claim 33, wherein the 5-HT2A inverse agonist or
antagonist is the compound of formula (I): ##STR00010## or a
pharmaceutically acceptable salt thereof.
35.-40. (canceled)
41. A method of increasing patient compliance during antipsychotic
therapy, comprising co-administering a 5-HT2A inverse agonist or
antagonist with an antipsychotic agent, wherein the doses of
co-administration are such that patient compliance is increased as
compared to compliance when administering an efficacious dose of
the antipsychotic agent alone.
42. The method of claim 41, wherein the 5-HT2A inverse agonist or
antagonist is the compound of formula (I): ##STR00011## or a
pharmaceutically acceptable salt thereof.
43. The method of claim 41, wherein the antipsychotic agent is
risperidone.
44.-48. (canceled)
49. A method of reducing or preventing one or more side effects
associated with administration of an antipsychotic agent,
comprising co-administering a 5-HT2A inverse agonist or antagonist
with the antipsychotic agent to a subject at risk of or suffering
from said one or more side effects.
50. The method of claim 49, wherein the 5-HT2A inverse agonist or
antagonist is the compound of formula (I): ##STR00012## or a
pharmaceutically acceptable salt thereof.
51. The method of claim 50, wherein the antipsychotic agent is
risperidone.
52.-70. (canceled)
71. The method of claim 49, wherein the one or more side effects
are selected from the group consisting of stroke, tremors,
sedation, gastrointestinal problems, neurological problems,
increased risk of death, cerebrovascular events, movement disorder,
dystonia, akathisia, parkinsoniam movement disorder, tardive
dyskinesia, cognitive disorders, prolactinemia, catalepsy,
psychosis, neuroleptic malignant syndrome, heart problems,
pulmonary problems, diabetes, liver failure, suicidality, sedation,
orthostatic hypotension, choking, dizziness, tachycardia, blood
abnormalities, abnormal triglyceride levels, increased cholesterol
levels, dyslipidemia, hyperglycemia, syncope, seizures, dysphagia,
priapism, thrombotic thrombocytopenic purpura, disruption of body
temperature regulation, insomnia, agitation, anxiety, somnolence,
aggressive reaction, headache, constipation, nausea, dyspepsia,
vomiting, abdominal pain, saliva increase, toothache, rhinitis,
coughing, sinusitis, pharyngitis, dyspnea, back pain, chest pain,
fever, rash, dry skin, seborrhea, increased upper respiratory
infection, abnormal vision, arthralgia, hypoaesthesia, manic
reaction, concentration impairment, dry mouth, pain, fatigue, acne,
pruritus, myalgia, skeletal pain, hypertension, diarrhea,
confusion, asthenia, urinary incontinence, sleepiness, increased
duration of sleep, accommodation disturbance, palpitations,
erectile dysfunction, ejaculatory dysfunction, orgastic
dysfunction, lassitude, increased pigmentation, increased appetite,
automatism, increased dream activity, diminished sexual desire,
nervousness, depression, apathy, catatonic reaction, euphoria,
increased libido, amnesia, emotional liability, nightmares,
delirium, yawning, dysarthria, vertigo, stupor, paraesthesia,
aphasia, hypoesthesia, tongue paralysis, leg cramps, torticollis,
hypotonia, coma, migraine, hyperreflexia, choreoathetosis,
anorexia, flatulence, stomatitis, melena, hemorrhoids, gastritis,
fecal incontinence, erutation, gastroeophageal reflux,
gastroenteritis, esophagitis, tongue discoloration, choleithiasis,
tongue edema, diverticulitis, gingivitis, discolored feces,
gastrointestinal hemorrhage, hematemesis, edema, rigors, malaise,
pallor, enlarged abdomen, ascites, sarcoidosis, flushing,
hyperventilation, bronchospasm, pneumonia, tridor, asthma,
increased sputum, aspiration, photosensitivity, increased sweating,
acne, decreased sweating, alopecia, hyperkeratosis, skin
exfoliation, bullous eruption, skin ulceration, aggravated
psoriasis, furunculosis, verruca, dermatitis lichenoid,
hypertrichosis, genital pruritus, urticaria, ventricular
tachycardia, angina pectoris, premature atrial contractions, T wave
inversion, ventricular extrasystoles, ST depression, AV block,
myocarditis, abnormal accommodation, xerophthalmia, diplopia, eye
pain, blepharitis, photopsia, photophobia, abnormal lacrimation,
hyponatremia, creatine phosphokinase increase, thirst, weight
decrease, decreased serum iron, cachexia, dehydration, hypokalemia,
hypoproteinemia, hyperphosphatemia, hypertrigylceridemia,
hyperuricemia, hypoglycemia, polyuria, polydipsia, hemturia,
dysuria, urinary retention, cystitis, renal insufficiency,
arthrosis, synostosis, bursitis, arthritis, menorrhagia, dry
vagina, nonpeurperal lactation, amenorrhea, female breast pain,
leukorrhea, mastitis, dysmenorrhea, female perineal pain,
intermenstrual bleeding, vaginal hemorrhage, increased SGOT,
increased SGPT, cholestatic hepatitis, cholecystitis,
choleithiasis, hepatitis, hepatocellular damage, epistaxis,
superficial phlebitis, thromboplebitis, thrombocytopenia, tinnitus,
hyperacusis, decreased hearing, anemia, hypochromic anemia,
normocytic anemia, granulocytopenia, leukocytosis, lymphadenopathy,
leucopenia, Pelger-Huet anomaly, gynecomastia, male breast pain,
antiduretic hormone disorder, bitter taste, micturition
disturbances, oculogyric crisis, abnormal gait, involuntary muscle
contraction, and increased injury.
72. The method of claim 49, wherein the one or more side effects
are selected from the group consisting of weight gain, increased
serum glucose, hyperprolactinemia or a combination thereof.
73. The method of claim 49, wherein the side effect is weight
gain.
74. The method of claim 49, wherein the side effect is increased
serum glucose.
75. The method of claim 49, wherein the side effect is
hyperprolactinemia.
76. The method of claim 49, wherein the 5-HT2A inverse agonist or
antagonist is a compound selected from the group consisting of:
##STR00013##
77. The method of claim 1, wherein the 5-HT2A inverse agonist or
antagonist is selected from the group consisting of Adatanserin,
Altanserin, Benanserin, Blonanserin, Butanserin, Cinanserin,
Eplivanserin, Fananserin, Flibanserin, Glemanserin, Iferanserin,
Ketanserin, Lidanserin, Mianserin, Pelanserin, Pruvanserin,
Ritanserin, Seganserin, and Tropanserin.
78. The method of claim 50, wherein the antipsychotic agent is
haloperidol.
79. The method of claim 49, wherein the antipsychotic agent is
selected from the group consisting of a phenothiazine, a
phenylbutylpiperidine, a dibenzapine, a benzisoxidil, and a salt of
lithium.
80. The method of claim 51, wherein the dose of risperidone is less
than about 6 mg per day.
81. The method of claim 51, wherein the dose of the compound of
formula (I) is from about 20 mg per day, and the dose of
risperidone is about 2 mg per day.
82. The method of claim 78, wherein the dose of haloperidol is less
than about 3 mg per day.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/895,735, filed Mar. 19, 2007; 60/908,921, filed
Mar. 29, 2007; 61/012,771, filed Dec. 10, 2007; and 61/026,092,
filed Feb. 4, 2008, all of which are entitled "COMBINATIONS OF
N-(1-METHYLPIPERIDIN-4-YL)-N-(4-FLUOROPHENYLMETHYL)-N'-(4-(2-METHYLPROPYL-
OXY)PHENYLMETHYL) WITH ANTIPSYCHOTICS" and are incorporated herein
by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to the fields of chemistry and
medicine. More particularly, some embodiments of the invention
relate to co-administration of 5-HT2A receptor inverse agonists or
antagonists with antipsychotics.
[0004] 2. Description of the Related Art
[0005] Serotonin or 5-hydroxytryptamine (5-HT) plays a significant
role in the functioning of the mammalian body. In the central
nervous system, 5-HT is an important neurotransmitter and
neuromodulator that is implicated in such diverse behaviors and
responses as sleeping, eating, locomotion, perceiving pain,
learning and memory, sexual behavior, controlling body temperature
and blood pressure. In the spinal column, serotonin plays an
important role in the control systems of the afferent peripheral
nociceptors (Moulignier, Rev. Ne rol. 150:3-15, (1994)). Peripheral
functions in the cardiovascular, hematological and gastrointestinal
systems have also been ascribed to 5-HT. 5-HT has been found to
mediate a variety of contractile, secretory, and electrophysiologic
effects including vascular and nonvascular smooth muscle
contraction, and platelet aggregation. (Fuller, Biology of
Serotonergic Transmission, 1982; Boullin, Serotonin In Mental
Abnormalities 1:316 (1978); Barchas, et al., Serotonin and
Behavior, (1973)). The 5-HT2A receptor subtype (also referred to as
subclass) is widely yet discretely expressed in the human brain,
including many cortical, limbic, and forebrain regions postulated
to be involved in the modulation of higher cognitive and affective
functions. This receptor subtype is also expressed on mature
platelets where it mediates, in part, platelet aggregation, one of
the initial steps in the process of vascular thrombosis.
[0006] Given the broad distribution of serotonin within the body,
it is understandable that tremendous interest in drugs that affect
serotonergic systems exists (Gershon, et al., The Peripheral
Actions of 5-Hydroxytryptamine, 246 (1989); Saxena, et al., J.
Cardiovascular Pharmacol. 15: Supp. 7 (1990)). Serotonin receptors
are members of a large human gene family of membrane-spanning
proteins that function as transducers of intercellular
communication. They exist on the surface of various cell types,
including neurons and platelets, where, upon their activation by
either their endogenous ligand serotonin or exogenously
administered drugs, they change their conformational structure and
subsequently interact with downstream mediators of cellular
signaling. Many of these receptors, including the 5-HT2A subclass,
are G-protein coupled receptors (GPCRs) that signal by activating
guanine nucleotide binding proteins (G-proteins), resulting in the
generation, or inhibition of, second messenger molecules such as
cyclic AMP, inositol phosphates, and diacylglycerol. These second
messengers then modulate the function of a variety of intracellular
enzymes, including kinases and ion channels, which ultimately
affect cellular excitability and function.
[0007] At least 15 genetically distinct 5-HT receptor subtypes have
been identified and assigned to one of seven families (5-HT1-7).
Each subtype displays a unique distribution, preference for various
ligands, and functional correlate(s).
[0008] Serotonin may be an important component in various types of
pathological conditions such as certain psychiatric disorders
(depression, aggressiveness, panic attacks, obsessive compulsive
disorders, psychosis, schizophrenia, suicidal tendency), certain
neurodegenerative disorders (Alzheimer-type dementia, Parkinsonism,
Huntington's chorea), anorexia, bulimia, disorders associated with
alcoholism, cerebral vascular accidents, and migraine (Meltzer,
Neuropsychopharmacology, 21:106 S-115S (1999); Barnes & Sharp,
Neuropharmacology, 38:1083-1152 (1999); Glennon, Neurosci.
Biobehavioral Rev., 14:35 (1990)).
[0009] Given the broad distribution of serotonin within the body
and its role in a wide range of physiological and pathological
processes, it is understandable that there is tremendous interest
in drugs that affect serotonergic systems (Gershon, et al., The
Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); Saxena, et
al., J. Cardiovascular Pharmacol. 15: Supp. 7 (1990)).
[0010] The effects of serotonin are mediated by at least 15
genetically distinct 5-HT receptor subtypes have been identified
and assigned to one of seven families (5-HT1-7). Each subtype
displays a unique distribution, preference for various ligands, and
functional correlate(s). Serotonin receptors are members of a large
human gene family of membrane-spanning proteins that function as
transducers of intercellular communication. They exist on the
surface of various cell types, including neurons and platelets,
where, upon their activation by either their endogenous ligand
serotonin or exogenously administered drugs, they change their
conformational structure and subsequently interact with downstream
mediators of cellular signaling. Many of these receptors, including
the 5-HT2A subclass, are G-protein coupled receptors (GPCRs) that
signal by activating guanine nucleotide binding proteins
(G-proteins), resulting in the generation, or inhibition of, second
messenger molecules such as cyclic AMP, inositol phosphates, and
diacylglycerol. These second messengers then modulate the function
of a variety of intracellular enzymes, including kinases and ion
channels, which ultimately affect cellular excitability and
function.
[0011] The 5-HT2A receptor subtype (also referred to as subclass)
is widely yet discretely expressed in the human brain, including
many cortical, limbic, and forebrain regions postulated to be
involved in the modulation of higher cognitive and affective
functions. This receptor subtype is also expressed on mature
platelets where it mediates, in part, platelet aggregation, one of
the initial steps in the process of vascular thrombosis. Recent
evidence strongly implicates the 5-HT2 receptor subtype in the
etiology of such medical conditions as hypertension, thrombosis,
migraine, vasospasm, ischemia, depression, anxiety, psychosis,
schizophrenia, sleep disorders and appetite disorders.
[0012] Schizophrenia is a particularly devastating neuropsychiatric
disorder that affects approximately 1% of the human population. It
has been estimated that the total financial cost for the diagnosis,
treatment, and lost societal productivity of individuals affected
by this disease exceeds 2% of the gross national product (GNP) of
the United States. Current treatment primarily involves
pharmacotherapy with a class of drugs known as antipsychotics.
Antipsychotics are effective in ameliorating positive symptoms
(e.g., hallucinations and delusions), yet they frequently do not
improve negative symptoms (e.g., social and emotional withdrawal,
apathy, and poverty of speech).
[0013] Currently, nine major classes of antipsychotics are
prescribed to treat psychotic symptoms. Use of these compounds is
limited, however, by their side effect profiles. Nearly all of the
"typical" or older generation compounds have significant adverse
effects on human motor function. These "extrapyramidal" side
effects, so termed due to their effects on modulatory human motor
systems, can be both acute (e.g., dystonic reactions, a potentially
life threatening but rare neuroleptic malignant syndrome) and
chronic (e.g., akathisias, tremors, and tardive dyskinesia). Drug
development efforts have, therefore, focused on newer "atypical"
agents free of some of these adverse effects. However, atypical
agents also have the potential for serious side effects including
increased risk of stroke, abnormal shifts in sleep patterns,
extreme tiredness and weakness, metabolic disorders (including
hyperglycemia and diabetes), and weight gain. One of the most
common reasons for noncompliance and discontinued use of
antipsychotic medication is weight gain. Non-compliance can lead to
increased hospitalization and health care costs.
[0014] Antipsychotic drugs have been shown to interact with a large
number of central monoaminergic neurotransmitter receptors,
including dopaminergic, serotonergic, adrenergic, muscarinic, and
histaminergic receptors. It is likely that the therapeutic and
adverse effects of these drugs are mediated by distinct receptor
subtypes. The high degree of genetic and pharmacological homology
between these receptor subtypes has hampered the development of
subtype-selective compounds, as well as the determination of the
normal physiologic or pathophysiologic role of any particular
receptor subtype. Thus there is a need to develop drugs that are
selective for individual receptor classes and subclasses amongst
monoaminergic neurotransmitter receptors.
[0015] The prevailing theory for the mechanism of action of
antipsychotic drugs involves antagonism of dopamine D2 receptors.
Unfortunately, it is likely that antagonism of dopamine D2
receptors also mediates the extrapyramidal side effects as well as
some additional undesired effects of antipsychotic therapies such
as a worsening of depression symptoms, anhedonia and impairment of
cognitive processes. Antagonism of 5-HT2A receptors is an alternate
molecular mechanism for drugs with antipsychotic efficacy, possibly
through antagonism of heightened or exaggerated signal transduction
through serotonergic systems. 5-HT2A antagonists are therefore good
candidates for treating psychosis without extrapyramidal side
effects or other undesired effects associated with blockade of
dopamine D.sub.2 receptors.
[0016] Traditionally, GPCRS such as the 5-HT2A receptor have been
assumed to exist in a quiescent state unless activated by the
binding of an agonist (a drug that activates a receptor). It is now
appreciated that many, if not most, of the GPCR monoamine
receptors, including serotonin receptors, can exist in a partially
activated state in the absence of their endogenous agonists. This
increased basal activity (constitutive activity) can be inhibited
by compounds called inverse agonists. Both agonists and inverse
agonists possess intrinsic activity at a receptor, in that they
alone can activate or inactivate these molecules, respectively. In
contrast, classic or neutral antagonists compete against agonists
and inverse agonists for access to the receptor, but do not possess
the intrinsic ability to inhibit elevated basal or constitutive
receptor responses.
SUMMARY OF THE INVENTION
[0017] Some embodiments described herein include a method of
treating a condition amenable to treatment with an antipsychotic,
comprising administering a first amount of a 5-HT2A inverse agonist
or antagonist and administering a second amount of an antipsychotic
agent, wherein the first and second amounts are such that an
efficacious effect is achieved faster than when the antipsychotic
agent is administered alone at an efficacious dose. In some
embodiments, the second amount is less than a maximal dose of the
antipsychotic agent when it is administered alone. In some
embodiments, the second amount is less than an efficacious dose of
the antipsychotic agent when it is administered alone.
[0018] In some embodiments, the first and second amounts are such
that the severity or onset of one or more side effects due to the
antipsychotic agent are reduced as compared to administration of an
efficacious dose of the antipsychotic agent alone. In some
embodiments, the side effect is weight gain. In some embodiments,
the side effect is selected from the group consisting of an
extrapyramidal side effect, a histaminic side effect, an alpha
adrenergic side effect, and an anticholinergic side effect. In some
embodiments, the side effect is selected from the group consisting
of stroke, tremors, sedation, gastrointestinal problems,
neurological problems, increased risk of death, cerebrovascular
events, movement disorder, dystonia, akathisia, parkinsoniam
movement disorder, tardive dyskinesia, cognitive disorders,
prolactinemia, catalepsy, psychosis, neuroleptic malignant
syndrome, heart problems, pulmonary problems, diabetes, liver
failure, suicidality, sedation, orthostatic hypotension, choking,
dizziness, tachycardia, blood abnormalities, abnormal triglyceride
levels, increased cholesterol levels, dyslipidemia, hyperglycemia,
syncope, seizures, dysphagia, priapism, thrombotic thrombocytopenic
purpura, disruption of body temperature regulation, insomnia,
agitation, anxiety, somnolence, aggressive reaction, headache,
constipation, nausea, dyspepsia, vomiting, abdominal pain, saliva
increase, toothache, rhinitis, coughing, sinusitis, pharyngitis,
dyspnea, back pain, chest pain, fever, rash, dry skin, seborrhea,
increased upper respiratory infection, abnormal vision, arthralgia,
hypoaesthesia, manic reaction, concentration impairment, dry mouth,
pain, fatigue, acne, pruritus, myalgia, skeletal pain,
hypertension, diarrhea, confusion, asthenia, urinary incontinence,
sleepiness, increased duration of sleep, accommodation disturbance,
palpitations, erectile dysfunction, ejaculatory dysfunction,
orgastic dysfunction, lassitude, increased pigmentation, increased
appetite, automatism, increased dream activity, diminished sexual
desire, nervousness, depression, apathy, catatonic reaction,
euphoria, increased libido, amnesia, emotional liability,
nightmares, delirium, yawning, dysarthria, vertigo, stupor,
paraesthesia, aphasia, hypoesthesia, tongue paralysis, leg cramps,
torticollis, hypotonia, coma, migrain, hyperreflexia,
choreoathetosis, anorexia, flatulence, stomatitis, melena,
hemorrhoids, gastritis, fecal incontinence, erutation,
gastroeophageal reflux, gastroenteritis, esophagitis, tongue
discoloration, choleithiasis, tongue edema, diverticulitis,
gingivitis, discolored feces, gastrointestinal hemorrhage,
hematemesis, edema, rigors, malaise, pallor, enlarged abdomen,
ascites, sarcoidosis, flushing, hyperventilation, bronchospasm,
pneumonia, tridor, asthma, increased sputum, aspiration,
photosensitivity, increased sweating, acne, decreased sweating,
alopecia, hyperkeratosis, skin exfoliation, bullous eruption, skin
ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis
lichenoid, hypertrichosis, genital pruritus, urticaria, ventricular
tachycardia, angina pectoris, premature atrial contractions, T wave
inversion, ventricular extrasystoles, ST depression, AV block,
myocarditis, abnormal accommodation, xerophthalmia, diplopia, eye
pain, blepharitis, photopsia, photophobia, abnormal lacrimation,
hyponatremia, creatine phosphokinase increase, thirst, weight
decrease, decreased serum iron, cachexia, dehydration, hypokalemia,
hypoproteinemia, hyperphosphatemia, hypertrigylceridemia,
hyperuricemia, hypoglycemia, polyuria, polydipsia, hemturia,
dysuria, urinary retention, cystitis, renal insufficiency,
arthrosis, synostosis, bursitis, arthritis, menorrhagia, dry
vagina, nonpeurperal lactation, amenorrhea, female breast pain,
leukorrhea, mastitis, dysmenorrhea, female perineal pain,
intermenstrual bleeding, vaginal hemorrhage, increased SGOT,
increased SGPT, cholestatic hepatitis, cholecystitis,
choleithiasis, hepatitis, hepatocellular damage, epistaxis,
superficial phlebitis, thromboplebitis, thrombocytopenia, tinnitus,
hyperacusis, decreased hearing, anemia, hypochromic anemia,
normocytic anemia, granulocytopenia, leukocytosis, lymphadenopathy,
leucopenia, Pelger-Huet anomaly, gynecomastia, male breast pain,
antiduretic hormone disorder, bitter taste, micturition
disturbances, oculogyric crisis, abnormal gait, involuntary muscle
contraction, and increased injury.
[0019] In some embodiments, the condition is psychosis and the
efficacious effect is an antipsychotic effect. In some embodiments,
the psychosis is associated with schizophrenia. In some
embodiments, the psychosis is acute psychotic exacerbation. In some
embodiments, the condition amenable to treatment is selected from
the group consisting of schizophrenia, bipolar disorder, agitation,
psychosis, behavioral disturbances in Alzheimer's disease,
depression with psychotic features or bipolar manifestations,
obsessive compulsive disorder, post traumatic stress syndrome,
anxiety, personality disorders (borderline and schizotypal),
dementia, dementia with agitation, dementia in the elderly,
Tourette's syndrome, restless leg syndrome, insomnia, social
anxiety disorder, dysthymia, ADHD, and autism.
[0020] Another embodiment described herein includes a method of
inducing a rapid onset of an antipsychotic effect, comprising
co-administering a 5-HT2A inverse agonist or antagonist and an
antipsychotic agent to a subject suffering from psychosis such that
there is a rapid onset of antipsychotic effect.
[0021] Another embodiment described herein includes a method of
inducing a rapid onset of an antidepressant effect, comprising
co-administering a 5-HT2A inverse agonist or antagonist and an
antipsychotic agent to a subject suffering from depression such
that there is a rapid onset of antidepressant effect.
[0022] Another embodiment described herein includes a method of
increasing the percentage of patients responding to antipsychotic
therapy, comprising co-administering a 5-HT2A inverse agonist or
antagonist and an antipsychotic agent to a subject suffering from
psychosis such that a greater percentage of patients experience an
efficacious effect than when the antipsychotic agent is
administered alone at an efficacious dose.
[0023] Another embodiment described herein includes a method of
reducing or preventing weight gain associated with administration
of an antipsychotic agent, comprising co-administering a 5-HT2A
inverse agonist or antagonist with the antipsychotic agent to a
subject at risk of or suffering from weight gain associated with
administration of an antipsychotic agent.
[0024] Another embodiment described herein includes a method of
increasing patient compliance during antipsychotic therapy,
comprising co-administering a 5-HT2A inverse agonist or antagonist
with an antipsychotic agent, wherein the doses of co-administration
are such that patient compliance is increased as compared to
compliance when administering an efficacious dose of the
antipsychotic agent alone.
[0025] Another embodiment described herein includes a method of
reducing or preventing increased serum glucose associated with
administration of an antipsychotic agent, comprising
co-administering a 5-HT2A inverse agonist or antagonist with the
antipsychotic agent to a subject at risk of or suffering from
increased serum glucose associated with administration of an
antipsychotic agent.
[0026] Another embodiment described herein includes a method of
reducing or preventing increased serum glucose and reducing or
preventing weight gain associated with administration of an
antipsychotic agent, comprising co-administering a 5-HT2A inverse
agonist or antagonist with the antipsychotic agent to a subject at
risk of or suffering from increased serum glucose and weight gain
associated with administration of an antipsychotic agent.
[0027] Another embodiment disclosed herein includes a
pharmaceutical composition that includes a first amount of a 5-HT2A
inverse agonist or antagonist and a second amount of an
antipsychotic agent, wherein the first and second amounts are such
that when the composition is administered, an efficacious
antipsychotic effect is achieved faster than when the antipsychotic
agent is administered alone at an efficacious dose. In some
embodiments, the second amount is less than a maximal dose of the
antipsychotic agent when it is administered alone. In some
embodiments, the second amount is less than an efficacious dose of
the antipsychotic agent when it is administered alone.
[0028] Another embodiment disclosed herein includes a package that
includes a first amount of a 5-HT2A inverse agonist or antagonist
and instructions for administering the first amount of the 5-HT2A
inverse agonist or antagonist and a second amount of an
antipsychotic agent, wherein the first and second amounts are such
that an efficacious antipsychotic effect is achieved faster than
when the antipsychotic agent is administered alone at an
efficacious dose. In some embodiments, the second amount is less
than a maximal dose of the antipsychotic agent when it is
administered alone. In some embodiments, the second amount is less
than an efficacious dose of the antipsychotic agent when it is
administered alone.
[0029] In some of the above-mentioned embodiments, the
antipsychotic agent is a typical antipsychotic. In some
embodiments, the antipsychotic agent is an atypical antipsychotic.
In some embodiments, the antipsychotic agent is a D2 antagonist. In
some embodiments, the antipsychotic agent is risperidone. In some
embodiments, the antipsychotic agent is haloperidol. In some
embodiments, the antipsychotic agent is selected from the group
consisting of a phenothiazine, a phenylbutylpiperidine, a
dibenzapine, a benzisoxidil, and a salt of lithium. In some
embodiments, the phenothiazine is selected from the group
consisting of chlorpromazine (Thorazine.RTM.), mesoridazine
(Serentil.RTM.), prochlorperazine (Compazine.RTM.), thioridazine
(Mellaril), Fluphenazine (Prolixin.RTM.), Perphenazine
(Trilafon.RTM.), and Trifluoperazine (Stelazine.RTM.). In some
embodiments, the phenylbutylpiperidine is pimozide (Orap.RTM.). In
some embodiments, the dibenzapine is selected from the group
consisting of clozapine (Clozaril.RTM.), loxapine (Loxitane.RTM.),
olanzapine (Zyprexa.RTM.), and quetiapine (Seroquel.RTM.). In some
embodiments, the benzisoxidil is ziprasidone (Geodon.RTM.). In some
embodiments, the salt of lithium is lithium carbonate. In some
embodiments, the antipsychotic agent is selected from the group
consisting of Aripiprazole (Abilify.RTM.), Etrafon.RTM., Droperidol
(Inapsine.RTM.), Thioridazine (Mellaril.RTM.), Thiothixene
(Navane.RTM.), Promethazine (Phenergan.RTM.), Metoclopramide
(Reglan.RTM.), Chlorprothixene (Taractan.RTM.), Triavil.RTM.,
Molindone (Moban.RTM.), Sertindole (Serlect.RTM.), Droperidol,
Amisulpride (Solian.RTM.), Melperone, Paliperidone (Invega.RTM.),
and Tetrabenazine.
[0030] Another embodiment described herein includes a method of
reducing or preventing hyperprolactinemia caused by administration
of risperidone, comprising co-administering a 5-HT2A inverse
agonist or antagonist with less than 6 mg per day of risperidone to
a subject at risk of or suffering from hyperprolactinemia
associated with administration of risperidone.
[0031] In some of any of the above-mentioned embodiments, the
5-HT2A inverse agonist or antagonist is the compound of formula
(I):
##STR00001##
[0032] In other embodiments, the 5-HT2A inverse agonist or
antagonist is a compound selected from the group consisting of:
##STR00002##
[0033] In still other embodiments, the 5-HT2A inverse agonist or
antagonist is selected from the group consisting of Adatanserin,
Altanserin, Benanserin, Blonanserin, Butanserin, Cinanserin,
Eplivanserin, Fananserin, Flibanserin, Glemanserin, Iferanserin,
Ketanserin, Lidanserin, Mianserin, Pelanserin, Pruvanserin,
Ritanserin, Seganserin, and Tropanserin.
[0034] In some of any of the above-mentioned methods, the
administration is to a human less than eighteen years of age.
[0035] Another embodiment described herein includes a method of
treatment that includes determining that a first pharmaceutical
agent modulates a pharmacological property of a second
pharmaceutical agent, determining that the first pharmaceutical
agent has a longer half-life than a second pharmaceutical agent,
and co-administering the first and second pharmaceutical agent to a
patient. In some embodiments, the pharmacological property is
receptor occupancy. In some embodiments, the pharmacological
property is the minimum efficacious dose of the second
pharmaceutical agent. In some embodiments, the half-life of the
first agent is at least about 1.5 times higher than the half-life
of the second agent. In some embodiments, the co-administration
results in the second agent being present at an efficacious level
during at least about 50% of the time between successive dosing of
the second agent. In some embodiments, the co-administration
results in the second agent being present at an efficacious level
during substantially all of the time between successive dosing of
the second agent and wherein said second agent would not have been
present at an efficacious level for substantially all of the period
between successive dosing if first agent had been administered
alone with the same dosing schedule and dosage. In some
embodiments, the first pharmacological agent and said second
pharmacological agent are administered at doses and time intervals
which result in said second pharmacological agent being present at
an efficacious level for a period of time which is longer than the
period of time which said second therapeutic agent would be present
at an efficacious level if said second therapeutic agent had been
administered alone.
[0036] Another embodiment described herein includes a method of
determining whether a test therapeutic agent is a good candidate
for combination therapy with a therapeutic agent having a first
half-life comprising obtaining a test therapeutic agent having a
second half-life that is longer than said first half-life and
evaluating whether administering said test therapeutic agent in
combination with said therapeutic agent allows said therapeutic
agent to be efficacious at a level at which it is not efficacious
when administered alone. Some embodiments include determining
whether said test therapeutic agent enhances a level of receptor
occupancy, wherein said receptor is targeted by said therapeutic
agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIG. 1A is a graph depicting the drug level and therapeutic
window for single agent administration.
[0038] FIG. 1B is a graph depicting the drug level and therapeutic
window for co-administration of two drugs having similar half
lives.
[0039] FIG. 1C is a graph depicting the drug level and therapeutic
window for co-administration of two drugs have different half
lives.
[0040] FIG. 2 is a graph depicting change in PANSS score upon
administration of risperidone and haloperidol alone and in
combination with pimavanserin.
[0041] FIGS. 3A and 3B are bar graphs depicting the percent of
responders to therapy with risperidone and haloperidol alone and in
combination with pimavanserin at Day 15 and Day 43,
respectively.
[0042] FIGS. 4A and 4B are graphs depicting change in PANSS
positive and negative scales, respectively, upon administration of
risperidone and haloperidol alone and in combination with
pimavanserin.
[0043] FIGS. 5A and 5B are graphs depicting change in PANSS
psychopathology and cognition scales, respectively, upon
administration of risperidone and haloperidol alone and in
combination with pimavanserin.
[0044] FIG. 6 is a graph depicting change in the CGI-severity scale
upon administration of risperidone and haloperidol alone and in
combination with pimavanserin.
[0045] FIG. 7A is a bar graph depicting the percent of subjects
experiencing weight gain upon administration of risperidone and
haloperidol alone and in combination with pimavanserin.
[0046] FIG. 7B is a bar graph depicting the mean weight gain in
subjects upon administration of risperidone and haloperidol alone
and in combination with pimavanserin.
[0047] FIGS. 8A and 8B are graphs depicting change in prolactin
levels in males and females, respectively, upon administration of
risperidone and haloperidol alone and in combination with
pimavanserin.
[0048] FIG. 9 is a bar graph depicting glucose levels upon
administration of risperidone alone and in combination with
pimavanserin.
[0049] FIG. 10 is a graph depicting the percent of responders to
therapy with risperidone or haloperidol, alone or in combination
with pimavanserin.
[0050] FIG. 11 is a graph depicting the percent of responders to
therapy with risperidone alone or in combination with
pimavanserin.
[0051] FIG. 12A is graph depicting the distance traveled by mice in
an amphetamine-induced hyperlocomotor assay upon administration of
pimavanserin, haloperidol, or pimavanserin in combination with
haloperidol.
[0052] FIG. 12B is a graph depicting dose response curves for
administration to mice of pimavanserin, haloperidol, or
pimavanserin in combination with haloperidol in an
amphetamine-induced hyperlocomotor assay.
[0053] FIG. 13A is a graph depicting dose response curves for
administration to mice of pimavanserin, haloperidol, or
pimavanserin in combination with haloperidol in a
dizocilpine-induced hyperlocomotor assay.
[0054] FIG. 13B is a graph depicting an isobologram that
demonstrates synergism upon administration of haloperidol in
combination with pimavanserin.
[0055] FIG. 14A is a graph depicting dose response curves for
administration to mice of pimavanserin, risperidone, or
pimavanserin in combination with risperidone in a
dizocilpine-induced hyperlocomotor assay.
[0056] FIG. 14B is a graph depicting an isobologram that
demonstrates synergism upon administration of risperidone in
combination with pimavanserin.
[0057] FIG. 15A is graph illustrating the distance traveled by mice
in an amphetamine-induced hyperlocomotor assay upon administration
of pimavanserin, aripiprazole, or pimavanserin in combination with
aripiprazole.
[0058] FIG. 15B is a graph illustrating dose response curves for
administration to mice of pimavanserin, aripiprazole, or
pimavanserin in combination with aripiprazole in an
amphetamine-induced hyperlocomotor assay.
[0059] FIG. 16A is graph illustrating the distance traveled by mice
in an amphetamine-induced hyperlocomotor assay upon administration
of pimavanserin, quetiapine, or pimavanserin in combination with
quetiapine.
[0060] FIG. 16B is a graph illustrating dose response curves for
administration to mice of pimavanserin, quetiapine, or pimavanserin
in combination with quetiapine in an amphetamine-induced
hyperlocomotor assay.
[0061] FIG. 17 is a graph depicting an isobologram that
demonstrates additivity upon administration of quetiapine in
combination with pimavanserin.
[0062] FIG. 18 is a bar graph depicting percent novel object
recognition upon administration of vehicle, pimavanserin,
risperidone, olanzapine, and combinations of pimavanserin with
risperidone or olanzapine in a novel object recognition assay.
[0063] FIG. 19 is a graph depicting working memory errors after
repeated trials upon administration of vehicle, risperidone,
pimavanserin, and combinations of risperidone with pimavanserin in
a radial arm maze in vivo mouse model of cognition.
[0064] FIG. 20A is a graph depicting serum prolactin levels upon
administration of risperidone, haloperidol, or pimavanserin.
[0065] FIG. 20B is a bar graph depicting serum prolactin levels
upon administration of pimavanserin in combination with risperidone
or haloperidol.
[0066] FIGS. 21A and 21B depict dose response curves for
haloperidol- and risperidone-induced catalepsy in rats,
respectively, upon administration of pimavanserin.
[0067] FIG. 22 is a graph depicting mean changes in prolactin
levels upon administration of risperidone alone and in combination
with pimavanserin.
[0068] FIG. 23 is a graph depicting plasma concentration of
risperidone and pimavanserin upon daily individual
administration.
[0069] FIG. 24 is a graph depicting 5-HT2A and D2 receptor
occupancy upon daily individual administration of risperidone and
pimavanserin.
[0070] FIG. 25 is a graph depicting 5-HT2A and D2 receptor
occupancy upon daily administration of pimavanserin in combination
with 1 mg of risperidone.
[0071] FIGS. 26A and 26B are graphs depicting 5-HT2A and D2
receptor occupancy upon administration of 3 mg risperidone twice
daily alone (FIG. 26A) and in combination (FIG. 26B) with
pimavanserin excluding the contribution from paliperidone.
[0072] FIGS. 27A and 27B are graphs depicting 5-HT2A and D2
receptor occupancy for paliperidone upon administration of 3 mg
risperidone twice daily alone (FIG. 27A) and in combination (FIG.
27B) with pimavanserin.
[0073] FIGS. 28A and 28B are graphs depicting 5-HT2A and D2
receptor occupancy upon administration of 3 mg risperidone twice
daily alone (FIG. 28A) and in combination (FIG. 28B) with
pimavanserin including the contribution from paliperidone.
[0074] FIGS. 29A and 29B are graphs depicting 5-HT2A and D2
receptor occupancy upon administration of 1 mg risperidone twice
daily alone (FIG. 29A) and in combination (FIG. 29B) with
pimavanserin excluding the contribution from paliperidone.
[0075] FIGS. 30A and 30B are graphs depicting 5-HT2A and D2
receptor occupancy upon administration of 1 mg risperidone twice
daily alone (FIG. 30A) and in combination (FIG. 30B) with
pimavanserin including the contribution from paliperidone.
[0076] FIGS. 31A and 31B are graphs depicting 5-HT2A and D2
receptor occupancy upon administration of 1 mg risperidone twice
daily alone (FIG. 31A) and in combination (FIG. 31B) with
pimavanserin including the contribution from paliperidone.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0077] Some embodiments include the co-administration of a 5-HT2A
inverse agonist or antagonist along with an antipsychotic agent. In
some embodiments, the 5-HT2A inverse agonist or antagonist enhances
the efficacy of the antipsychotic agent while decreasing the side
effects caused by the antipsychotic agent. While not being bound by
any particular theory, it is believed that the 5-HT2A inverse
agonist or antagonist can modulate the D2 antagonistic activity of
the antipsychotic agent. Specifically, it is believed that the
5-HT2A inverse agonist or antagonist enhances the D2 antagonistic
activity in regions of the brain responsible for psychotic effects
(e.g., hallucinations) while at the same time diminishing D2
antagonistic activity in regions of the brain which cause adverse
side effects (e.g., cognitive impairment, depression, and
extrapyrmaidal side effects). These two actions, decreasing
undesired effects of D2 receptor blockade in brain regions
associated with motoric control or cognitive function, while
simultaneously increasing the effectiveness of the desired
antipsychotic actions will result in increased antipsychotic
efficacy with diminished side effects.
[0078] By "co-administration" or administration "in combination,"
it is meant that the two or more agents may be found in the
patient's bloodstream at the same time, regardless of when or how
they are actually administered. In one embodiment, the agents are
administered simultaneously. In one such embodiment, administration
in combination is accomplished by combining the agents in a single
dosage form. In another embodiment, the agents are administered
sequentially. In one embodiment the agents are administered through
the same route. For example, in some embodiments, both agents are
administered orally. In another embodiment, the agents are
administered through different routes. For example, in one
embodiment, one agent is administered orally and the other agent is
administered i.v.
[0079] In some embodiments, use of the 5-HT2A inverse agonist or
antagonist allows the dose of the antipsychotic agent to be
reduced. This reduction results in an elimination or reduction in
the severity of side effects caused by the antipsychotic agent. In
addition, in some embodiments, reduction of the dosage of the
antipsychotic agent allows the beneficial regional modulation of D2
antagonism described above to take effect. While not being bound by
any particular theory, it is believed that if the dosage of the
antipsychotic agent is too high, resulting in high D2 antagonistic
activity, then the regional modulation of D2 antagonism described
above will not have a significant efficacious effect.
[0080] In some embodiments, the co-administration described herein
eliminates or reduces the severity of one or more side effects
caused by the antipsychotic when it is administered alone at an
efficacious dose. In various embodiments, the side effects are
selected from the group consisting of stroke, tremors, sedation,
gastrointestinal problems, neurological problems, increased risk of
death, cerebrovascular events, movement disorder, dystonia,
akathisia, parkinsoniam movement disorder, tardive dyskinesia,
cognitive disorders, prolactinemia, catalepsy, psychosis,
neuroleptic malignant syndrome, heart problems, pulmonary problems,
diabetes, liver failure, suicidality, sedation, orthostatic
hypotension, choking, dizziness, tachycardia, blood abnormalities
(including abnormal triglyceride levels, increased cholesterol
levels, dyslipidemia, and hyperglycemia), syncope, seizures,
dysphagia, priapism, thrombotic thrombocytopenic purpura,
disruption of body temperature regulation, insomnia, agitation,
anxiety, somnolence, aggressive reaction, headache, constipation,
nausea, dyspepsia, vomiting, abdominal pain, saliva increase,
toothache, rhinitis, coughing, sinusitis, pharyngitis, dyspnea,
back pain, chest pain, fever, rash, dry skin, seborrhea, increased
upper respiratory infection, abnormal vision, arthralgia,
hypoaesthesia, manic reaction, concentration impairment, dry mouth,
pain, fatigue, acne, pruritus, myalgia, skeletal pain,
hypertension, diarrhea, confusion, asthenia, urinary incontinence,
sleepiness, increased duration of sleep, accommodation disturbance,
palpitations, erectile dysfunction, ejaculatory dysfunction,
orgastic dysfunction, lassitude, increased pigmentation, increased
appetite, automatism, increased dream activity, diminished sexual
desire, nervousness, depression, apathy, catatonic reaction,
euphoria, increased libido, amnesia, emotional liability,
nightmares, delirium, yawning, dysarthria, vertigo, stupor,
paraesthesia, aphasia, hypoesthesia, tongue paralysis, leg cramps,
torticollis, hypotonia, coma, migrain, hyperreflexia,
choreoathetosis, anorexia, flatulence, stomatitis, melena,
hemorrhoids, gastritis, fecal incontinence, erutation,
gastroeophageal reflux, gastroenteritis, esophagitis, tongue
discoloration, choleithiasis, tongue edema, diverticulitis,
gingivitis, discolored feces, gastrointestinal hemorrhage,
hematemesis, edema, rigors, malaise, pallor, enlarged abdomen,
ascites, sarcoidosis, flushing, hyperventilation, bronchospasm,
pneumonia, tridor, asthma, increased sputum, aspiration,
photosensitivity, increased sweating, acne, decreased sweating,
alopecia, hyperkeratosis, skin exfoliation, bullous eruption, skin
ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis
lichenoid, hypertrichosis, genital pruritus, urticaria, ventricular
tachycardia, angina pectoris, premature atrial contractions, T wave
inversion, ventricular extrasystoles, ST depression, AV block,
myocarditis, abnormal accommodation, xerophthalmia, diplopia, eye
pain, blepharitis, photopsia, photophobia, abnormal lacrimation,
hyponatremia, creatine phosphokinase increase, thirst, weight
decrease, decreased serum iron, cachexia, dehydration, hypokalemia,
hypoproteinemia, hyperphosphatemia, hypertrigylceridemia,
hyperuricemia, hypoglycemia, polyuria, polydipsia, hemturia,
dysuria, urinary retention, cystitis, renal insufficiency,
arthrosis, synostosis, bursitis, arthritis, menorrhagia, dry
vagina, nonpeurperal lactation, amenorrhea, female breast pain,
leukorrhea, mastitis, dysmenorrhea, female perineal pain,
intermenstrual bleeding, vaginal hemorrhage, increased SGOT,
increased SGPT, cholestatic hepatitis, cholecystitis,
choleithiasis, hepatitis, hepatocellular damage, epistaxis,
superficial phlebitis, thromboplebitis, thrombocytopenia, tinnitus,
hyperacusis, decreased hearing, anemia, hypochromic anemia,
normocytic anemia, granulocytopenia, leukocytosis, lymphadenopathy,
leucopenia, Pelger-Huet anomaly, gynecomastia, male breast pain,
antiduretic hormone disorder, bitter taste, micturition
disturbances, oculogyric crisis, abnormal gait, involuntary muscle
contraction, and increased injury. In one embodiment, the side
effect is weight gain. In one embodiment, side effect is associated
with administration of the antipsychotic to a child under 18. In
one embodiment, the side effect in the child is selected from
psychosis, schizophrenia, pervasive developmental disorder, autism,
Tourette's syndrome, conduct disorder, aggression, attention and
hyperactivity difficulties (e.g., ADD, ADHD). In some embodiments,
the side effects of weight gain, heart rhythm problems, and
diabetes are more severe in children.
[0081] In some embodiments, due to decreased side effects, the
co-administration described herein can be used to increase patient
compliance during antipsychotic therapy.
[0082] In some embodiments, the antipsychotic agent is administered
at a sub-maximal level. In various such embodiments, the dosage of
the antipsychotic agent is less than about 75%, 60%, 50%, 40%, 30%,
20%, or 10% of the maximal dose. By "maximal dose," it is meant the
minimum dose where further increases in the dose do not result in
any significant increase in therapeutic effect when administering
the agent alone. In some embodiments, the antipsychotic agent is
administered at a dose that is less than an efficacious dose for
the antipsychotic when it is administered alone. In various
embodiments, the dosage is less than about 75%, 60%, 50%, 40%, 30%,
20%, or 10% of an efficacious dose. By "efficacious dose," it is
meant the minimal dosage that is required to achieve a clinically
relevant therapeutic effect when administering the agent alone.
[0083] In some embodiments, co-administration of the 5-HT2A inverse
agonist or antagonist with the antipsychotic agent results in a
rapid onset of an efficacious effect. In other words, in some
embodiments, efficacious activity is achieved faster than when the
antipsychotic agent is administered alone. In various embodiments,
the rapid onset of efficacious activity is demonstrated by a
clinically relevant therapeutic effect being achieved greater than
about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 130%, 150%,
200%, 300%, 400%, or 500% faster than when the antipsychotic agent
is administered alone at an efficacious dose. In some embodiments,
the rapid onset of efficacious activity is demonstrated by a
greater percentage of patients experiencing an efficacious effect
after a specified period of time of therapy when compared to
administration of the antipsychotic agent alone at an efficacious
dose. In various embodiments, the percentage of patients
experiencing an efficacious effect is increased by greater than
about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 130%,
150%, 200%, 300%, 400%, or 500% when compared to administration of
the antipsychotic agent alone at an efficacious dose. In some
embodiments, the specified period of time is two weeks.
[0084] In various embodiments, the co-administration of the 5-HT2A
inverse agonist or antagonist with the antipsychotic agent is used
to treat, prevent, or ameliorate the symptoms of a neuropsychiatric
disorder, including but not limited to schizophrenia,
schizoaffective disorders, mania, depression (including dysthymia,
treatment-resistant depression, and depression associated with
psychosis), cognitive disorders, aggressiveness (including
impulsive aggression), panic attacks, obsessive compulsive
disorders, borderline personality disorder, borderline disorder,
multiplex developmental disorder (MDD), behavioral disorders
(including behavioral disorders associated with age-related
dementia), psychosis (including psychosis associated with dementia,
psychosis associated with Parkinson's disease, psychosis associated
with Alzheimer's disease, induced by treatment, such as treatment
of Parkinson's disease, or associated with post traumatic stress
disorder), suicidal tendency, bipolar disorder, sleep disorder
(including sleep maintenance insomnia, chronic insomnia, transient
insomnia, and periodic limb movements during sleep (PLMS)),
addiction (including drug or alcohol addiction, opioid addiction,
and nicotine addiction), attention deficit hyperactivity disorder
(ADHD), post traumatic stress disorder (PTSD), Tourette's syndrome,
anxiety (including general anxiety disorder (GAD)), autism, Down's
syndrome, learning disorders, psychosomatic disorders, alcohol
withdrawal, epilepsy, pain (including chronic pain, neuropathic
pain, inflammatory pain, diabetic peripheral neuropathy,
fibromyalgia, postherpetic neuralgia, and reflex sympathetic
dystrophy), disorders associated with hypoglutamatergia (including
schizophrenia, childhood autism, and dementia), and serotonin
syndrome.
[0085] In some embodiments, the co-administration of the 5-HT2A
inverse agonist or antagonist with the antipsychotic agent is used
to treat, prevent, or ameliorate the symptoms of a
neurodegenerative disorder, including but not limited to
Alzheimer's disease, Parkinson's disease, Huntington's chorea,
sphinocerebellar atrophy, frontotemporal dementia, supranuclear
palsy, or Lewy body dementia.
[0086] In some embodiments, the co-administration of the 5-HT2A
inverse agonist or antagonist with the antipsychotic agent is used
to treat, prevent, or ameliorate the symptoms of an extrapyramidal
disorder including, but not limited to, dyskinesias (such as
induced by treatment of Parkinson's disease), bradykinesia,
rigidity, psychomotor slowing, tics, akathisia (such as induced by
a neuroleptic or SSRI agent), Friedrich's ataxia, Machado-Joseph's
disease, dystonia, tremor, restless legs syndrome, or
myoclonus.
[0087] In some embodiments, the co-administration of the 5-HT2A
inverse agonist or antagonist with the antipsychotic agent is used
to treat, prevent, or ameliorate the symptoms of
chemotherapy-induced emesis, frailty, on/off phenomena,
non-insulin-dependent diabetes mellitus, metabolic syndrome,
autoimmune disorders (including lupus and multiple sclerosis),
sepsis, increased intraocular pressure, glaucoma, retinal diseases
(including age related macular degeneration), Charles Bonnet
syndrome, substance abuse, sleep apnea, pancreatis, anorexia,
bulimia, disorders associated with alcoholism, cerebral vascular
accidents, amyotrophic lateral sclerosis, AIDS related dementia,
traumatic brain or spinal injury, tinnitus, menopausal symptoms
(such as hot flashes), sexual dysfunction (including female sexual
dysfunction, female sexual arousal dysfunction, hypoactive sexual
desire disorder, decreased libido, pain, aversion, female orgasmic
disorder, and ejaculatory problems), low male fertility, low sperm
motility, hair loss or thinning, incontinence, hemorrhoids,
migraine, hypertension, thrombosis (including thrombosis associated
with myocardial infarction, stroke, idiopathic thrombocytopenic
purpura, thrombotic thrombocytopenic purpura, and peripheral
vascular disease), abnormal hormonal activity (such as abnormal
levels of ACTH, corticosterone, rennin, or prolactin), hormonal
disorders (including Cushing's disease, Addison's disease, and
hyperprolactinemia), a pituitary tumor (including a prolactinoma),
a side effect associated with a pituitary tumor (including
hyperprolactinemia, infertility, changes in menstruation,
amenorrhea, galactorrhea, loss of libido, vaginal dryness,
osteoporosis, impotence, headache, blindness, and double vision),
vasospasm, ischemia, cardiac arrythmias, cardiac insufficiency,
asthma, emphysema, or appetite disorders.
[0088] In some embodiments, the co-administration is used to treat,
prevent, or ameliorate psychosis. Functional causes of the
psychosis may include schizophrenia, Parkinson's disease,
Alzheimer's disease, bipolar disorder, severe clinical depression,
severe psychosocial stress, sleep deprivation, neurological
disorders including brain tumor, dementia with Lewy bodies,
multiple sclerosis, and sarcoidosis, electrolyte disorders
including hypocalcemia, hypernatremia, hyonatremia, hyopkalemia,
hypomagnesemia, hypermagnesemia, hypercalcemia, hypophosphatemia,
and hypoglycemia, lupus, AIDS, leprosy, malaria, flu, mumps,
psychoactive drug intoxication or withdrawal including alcohol,
barbiturates, benzodizepeines, anticholinergics, atropine,
scopolamine, Jimson weed, antihistamines, cocaine, amphetamines,
and hallucinogens including cannabis, LSD, psilocybin, mescaline,
MDMA, and PCP. Psychosis may include symptoms such as delusions,
hallucinations, disorganized speech, disorganized behavior, gross
distortion of reality, impaired mental capacity, impaired affective
response, fluctuating level of consciousness, poor motor
co-ordination, inability to perform simple mental tasks,
disorientation as to person, place or time, confusion, or memory
impairment. In one embodiment, the patient is experiencing acute
exacerbation of psychosis. The rapid onset characteristics of
certain combinations described herein are particularly advantageous
in treating acute exacerbation of psychosis. In some embodiments,
the combination is used to treat or ameliorate schizophrenia and
specifically, psychosis associated with schizophrenia. In one
embodiment, the patient has exhibited a prior response to
antipsychotic therapy. In one embodiment, the patient exhibits a
moderate degree of psychopathology.
[0089] In one embodiment, the co-administration is used to treat
depression. In one embodiment, the co-administration results in a
rapid onset of antidepressant activity as compared to the onset of
activity observed with typical antidepressants (e.g., SSRIs). In
various embodiments, efficacious antidepressant activity is
achieved in less than about 8 weeks, 6 weeks, 4 weeks, or 2
weeks.
[0090] Many antipsychotic agents increase serum glucose levels. It
has been surprisingly discovered that combination of a 5-HT2A
inverse agonist with such an antipsychotic results in a decreased
serum glucose elevation while maintaining efficacy. Accordingly, in
various embodiments, the co-administration of the 5-HT2A inverse
agonist or antagonist with the antipsychotic agent is used to
prevent or reduce increased serum glucose associated with
administration of the antipsychotic agent.
[0091] Many antipsychotic agents also cause weight gain. In some
embodiments, the co-administration of the 5-HT2A inverse agonist or
antagonist with the antipsychotic agent is used to prevent or
reduce increased weight gain associated with administration of the
antipsychotic agent.
[0092] In some embodiments, the 5-HT2A inverse agonist or
antagonist is selective for the 5-HT2A receptor. By "selective," it
is meant that an amount of the compound sufficient to effect the
desired response from the 5-HT2A receptor has little or no effect
upon the activity of other certain receptor types, subtypes,
classes, or subclasses. In some embodiments, the 5-HT2A inverse
agonist or antagonist does not interact strongly with other
serotonin receptors (5-HT 1A, 1B, 1D, 1E, 1F, 2B, 2C, 4A, 6, and 7)
at concentrations where the signaling of the 5-HT2A receptor is
strongly or completely inhibited. In some embodiments, the 5-HT2A
inverse agonist or antagonist is selective with respect to other
monoamine-binding receptors, such as the dopaminergic,
histaminergic, adrenergic and muscarinic receptors. In some
embodiments, the 5-HT2A inverse agonist or antagonist has little or
no activity at D2 receptors.
[0093] In various embodiments, the 5-HT2A inverse agonist or
antagonist is selected from the group consisting of Adatanserin
Hydrochloride, Altanserin Tartrate, Benanserin Hydrochloride,
Blonanserin, Butanserin, Cinanserin Hydrochloride, Eplivanserin,
Fananserin, Flibanserin, Glemanserin, Iferanserin, Ketanserin,
Lidanserin, Mianserin Hydrochloride, Pelanserin Hydrochloride,
Pruvanserin, Ritanserin, Seganserin, Tropanserin Hydrochloride,
Iloperidone, Sertindole, EMR-62218, Org-5222, Zotepine, asenapine,
ocaperidone, APD125, and AVE8488.
[0094] In some embodiments, the 5-HT2A inverse agonist or
antagonist is selected from a compound disclosed in U.S. Pat. No.
6,756,393; 6,911,452; or 6,358,698 or U.S. Application Publication
No. 2004-0106600, all of which are incorporated herein by reference
in their entirety. In some embodiments, the 5-HT2A inverse agonist
or antagonist is selected from one of the following structures or
prodrugs, metabolites, hydrates, solvates, polymorphs, and
pharmaceutically acceptable salts thereof:
##STR00003##
[0095] In one embodiment, the 5-HT2A inverse agonist or antagonist
is pimavanserin or prodrugs, metabolites, hydrates, solvates,
polymorphs, and pharmaceutically acceptable salts thereof.
Pimavanserin, which is also known as
N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyl-
oxy)phenylmethyl)carbamide,
N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N'-[[4-(2-methylpro-
poxy)phenyl]methyl]-urea,
1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzy-
l]urea, or ACP-103 has the structure of Formula (I):
##STR00004##
[0096] Pimavanserin can be obtained in a number of salts and
crystalline forms. Exemplary salts include the tartrate,
hemi-tartrate, citrate, fumarate, maleate, malate, phosphate,
succinate, sulphate, and edisylate (ethanedisulfonate) salts.
Pimavanserin salts including the aforementioned ions, among others,
are described in U.S. Patent Publication No. 2006-0111399, filed
Sep. 26, 2005 and entitled "SALTS OF
N-(4-FLUOROBENZYL)-N-(1-METHYLPIPERIDIN-4-YL)-N'-(4-(2-METHYLPROPYLOXY)PH-
ENYLMETHYL)CARBAMIDE AND THEIR PREPARATION," which is incorporated
herein by reference in its entirety. Several crystalline forms of
the tartrate salt are referred to as crystalline Form A, Form B,
Form C, Form D, Form E and Form F, and are described in U.S. Patent
Publication No. 2006-0106063, filed Sep. 26, 2006 and entitled
"SYNTHESIS OF
N-(4-FLUOROBENZYL)-N-(1-METHYLPIPERIDIN-4-YL)-N'-(4-(2-METHYLPROPYLOXY)PH-
ENYLMETHYL)CARBAMIDE AND ITS TARTRATE SALT AND CRYSTALLINE FORMS,"
which is incorporated herein by reference in its entirety. In an
embodiment, the crystalline form of the tartrate salt of
pimavanserin is Form A. In another embodiment, the crystalline form
of the tartrate salt of pimavanserin is Form C. Pimavanserin
(including, for example, the tartrate salt) may be formulated into
tablets, such as is described in more detail in U.S. Patent
Publication Nos. 2007-0260064, filed May 15, 2007 and 2007-0264330,
filed May 15, 2007, each entitled "PHARMACEUTICAL FORMULATIONS OF
PIMAVANSERIN," which are incorporated herein by reference in their
entireties.
[0097] A "prodrug" refers to an agent that is converted into the
parent drug in vivo. Prodrugs are often useful because, in some
situations, they may be easier to administer than the parent drug.
They may, for instance, be bioavailable by oral administration
whereas the parent is not. The prodrug may also have improved
solubility in pharmaceutical compositions over the parent drug. An
example, without limitation, of a prodrug would be a compound which
is administered as an ester (the "prodrug") to facilitate
transmittal across a cell membrane where water solubility is
detrimental to mobility but which then is metabolically hydrolyzed
to the carboxylic acid, the active entity, once inside the cell
where water-solubility is beneficial. A further example of a
prodrug might be a short peptide (polyaminoacid) bonded to an acid
group where the peptide is metabolized to reveal the active moiety.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in Design
of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby
incorporated herein by reference in its entirety.
[0098] Metabolites include active species that are produced upon
introduction of the parent compound into the biological milieu.
[0099] The term "pharmaceutically acceptable salt" refers to a salt
of a compound that does not cause significant irritation to an
organism to which it is administered and does not abrogate the
biological activity and properties of the compound. In some
embodiments, the salt is an acid addition salt of the compound.
Pharmaceutical salts can be obtained by reacting a compound with
inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or
hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and
the like. Pharmaceutical salts can also be obtained by reacting a
compound with an organic acid such as aliphatic or aromatic
carboxylic or sulfonic acids, for example acetic, succinic, lactic,
malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic,
ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic
acid. Pharmaceutical salts can also be obtained by reacting a
compound with a base to form a salt such as an ammonium salt, an
alkali metal salt, such as a sodium or a potassium salt, an
alkaline earth metal salt, such as a calcium or a magnesium salt, a
salt of organic bases such as dicyclohexylamine,
N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,
C.sub.1-C.sub.7 alkylamine, cyclohexylamine, triethanolamine,
ethylenediamine, and salts with amino acids such as arginine,
lysine, and the like.
[0100] If the manufacture of pharmaceutical formulations involves
intimate mixing of the pharmaceutical excipients and the active
ingredient in its salt form, then it may be desirable to use
pharmaceutical excipients which are non-basic, that is, either
acidic or neutral excipients.
[0101] Pimavanserin exhibits activity at monoamine receptors,
specifically serotonin receptors and specifically acts as an
inverse agonist at the 5-HT2A receptor. The compound shows high
potency as an inverse agonist (and competitive antagonist) at the
5HT.sub.2A receptor using a cell-based in vitro functional assay as
well as using radioligand-binding assays. The compound exhibits
lesser potency at 5-HT.sub.2C receptors as an inverse agonist (and
competitive antagonist) using a cell-based functional assay and in
radioligand-binding assays. The compound lacks activity at dopamine
receptor subtypes. Unlike existing atypical antipsychotics,
pimavanserin does not have significant potency for a variety of
other targets that have been implicated in a range of dose-limiting
side effects of the other antipsychotic drugs. For example, unlike
clozapine and olanzapine, pimavanserin does not have significant
activity at the muscarinic and histaminergic receptors that mediate
sedation and potentially weight gain. The compound also lacks the
alpha-adrenergic antagonist activities of clozapine, olanzapine,
risperidone, and ziprasidone that may contribute to cardiovascular
side effects. Further, the compound lacks potency at the 5HT.sub.2B
receptor that controls gastrointestinal function and myocardial
development.
[0102] Pimavanserin is active in a number of models thought to be
predictive of antipsychotic activity such as DOI
((.+-.)-2,5-dimethoxy-4-iodoamphetamine, a serotonin agonist)
induced head twitches in the rat and attenuation of hyperactivity
in mice induced by the N-methyl-D-aspartate antagonist MK-801. The
compound was effective in these models at oral doses of 3 and 10
mg/kg. In a rat model of deficits in sensory motor gating similar
to those exhibited by schizophrenics, pimavanserin at doses of 1
and 3 mg/kg SC potently reversed the gating deficit induced by DOI.
Pimavanserin also failed to disrupt learning of a simple
auto-shaped response in mice at intraperitoneal doses up to 32
mg/kg. The pharmacological profile of pimavanserin suggests it will
be effective as an antipsychotic agent without the side effects
common to other compounds in this class. Thus, pimavanserin will
have antipsychotic activity when used to treat schizophrenic
subjects.
[0103] Pimavanserin may be synthesized by methods described below,
or by modification of these methods. Ways of modifying the
methodology include, among others, modification in temperature,
solvent, reagents, etc.
[0104] The first step of the synthesis, illustrated below, is
conducted in the presence of acetic acid, NaBH.sub.3CN, and
methanol to produce the compound of formula (II):
##STR00005##
[0105] The compound of formula (IV) can be synthesized by treatment
of the compound of formula (III) with isobutyl bromide and
potassium carbonate in dimethyl formamide (DMF) at about 80.degree.
C.:
##STR00006##
[0106] The compound of formula (IV) can be converted to the
compound of formula (V) by reaction with potassium hydride in
methanol/water:
##STR00007##
[0107] The compound of formula (V) is heated to reflux with
diphenylphosphonyl azide (DPPA) and a proton sponge in
tetrahydrofuran (THF) to produce the compound of formula (VI):
##STR00008##
[0108] Finally, reaction of the compound of formula (II) with the
compound of formula (VI) in methylene chloride produces the
compound of formula (I):
##STR00009##
[0109] Non-limiting examples of suitable antipsychotic agents that
may be co-administered with a 5-HT2A inverse agonist or antagonist
include a phenothiazine, a phenylbutylpiperidine, a dibenzapine, a
benzisoxidil, and a salt of lithium. In some embodiments, the
phenothiazine is selected from the group consisting of
chlorpromazine (Thorazine.RTM.), mesoridazine (Serentil.RTM.),
prochlorperazine (Compazine.RTM.), thioridazine (Mellaril),
Fluphenazine (Prolixin.RTM.), Perphenazine (Trilafon.RTM.), and
Trifluoperazine (Stelazine.RTM.). In some embodiments, the
phenylbutylpiperidine is selected from the group consisting of
haloperidol (Haldol.RTM.) and pimozide (Orap.RTM.). In some
embodiments, the dibenzapine is selected from the group consisting
of clozapine (Clozaril.RTM.), loxapine (Loxitane.RTM.), olanzapine
(Zyprexa.RTM.), and quetiapine (Seroquel.RTM.). In some
embodiments, the benzisoxidil is selected from the group consisting
of risperidone (Risperdal.RTM.) and ziprasidone (Geodon.RTM.). In
some embodiments, the salt of lithium is lithium carbonate. In some
embodiments, the antipsychotic agent is selected from the group
consisting of Aripiprazole (Abilify.RTM.), Etrafon.RTM., Droperidol
(Inapsine.RTM.), Thioridazine (Mellaril.RTM.), Thiothixene
(Navane.RTM.), Promethazine (Phenergan.RTM.), Metoclopramide
(Reglan.RTM.), Chlorprothixene (Taractan.RTM.), Triavil.RTM.,
Molindone (Moban.RTM.), Sertindole (Serlect.RTM.), Droperidol,
Amisulpride (Solian.RTM.), Melperone, Paliperidone (Invega.RTM.),
and Tetrabenazine. In some embodiments, the antipsychotic is a D2
antagonist. In some embodiments, the antipsychotic is a typical
antipsychotic. In some embodiments, the antipsychotic is an
atypical antipsychotic.
[0110] In one embodiment, the pimavanserin is co-administered with
the antipsychotic haloperidol. In another embodiment, pimavanserin
is co-administered with the antipsychotic risperidone. In various
embodiments, the dose of haloperidol administered is less than
about 0.5 mg, 1 mg, 2 mg, or 3 mg per day. In various embodiments,
the dose of risperidone administered is less than about 0.5 mg, 1
mg, 2 mg, 3 mg, 4 mg, 5 mg, or 6 mg per day. In one embodiment, the
dose of risperidone administered is about 2 mg per day. In various
embodiments, the dose of pimavanserin administered is from about 10
mg to about 15 mg, from about 15 mg to about 20 mg, from about 20
mg to about 25 mg, from about 25 mg to about 30 mg, from about 30
mg to about 40 mg, from about 40 mg to about 50 mg, from about 50
mg to about 60 mg, from about 60 mg to about 70 mg, or from about
70 mg to about 80 mg per day. In one embodiment, the dose of
pimavanserin is about 20 mg per day.
[0111] Some embodiments include a pharmaceutical composition
comprising both a 5-HT2A inverse agonist or antagonist and the
antipsychotic agent in a single dosage form. Such pharmaceutical
compositions may comprise physiologically acceptable surface active
agents, carriers, diluents, excipients, smoothing agents,
suspension agents, film forming substances, and coating assistants,
or a combinations thereof. Acceptable carriers or diluents for
therapeutic use are well known in the pharmaceutical art, and are
described, for example, in Remington's Pharmaceutical Sciences,
18th Ed., Mack Publishing Co., Easton, Pa. (1990), which is
incorporated herein by reference in its entirety. Preservatives,
stabilizers, dyes, sweeteners, fragrances, flavoring agents, and
the like may be provided in the pharmaceutical composition. For
example, sodium benzoate, ascorbic acid and esters of
p-hydroxybenzoic acid may be added as preservatives. In addition,
antioxidants and suspending agents may be used. In various
embodiments, alcohols, esters, sulfated aliphatic alcohols, and the
like may be used as surface active agents; sucrose, glucose,
lactose, starch, crystallized cellulose, mannitol, light anhydrous
silicate, magnesium aluminate, magnesium methasilicate aluminate,
synthetic aluminum silicate, calcium carbonate, sodium acid
carbonate, calcium hydrogen phosphate, calcium carboxymethyl
cellulose, and the like may be used as excipients; magnesium
stearate, talc, hardened oil and the like may be used as smoothing
agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be
used as suspension agents or lubricants; cellulose acetate
phthalate as a derivative of a carbohydrate such as cellulose or
sugar, or methylacetate-methacrylate copolymer as a derivative of
polyvinyl may be used as suspension agents; and plasticizers such
as ester phthalates and the like may be used as suspension
agents.
[0112] The term "carrier" defines a chemical compound that
facilitates the incorporation of a compound into cells or tissues.
For example dimethyl sulfoxide (DMSO) is a commonly utilized
carrier as it facilitates the uptake of many organic compounds into
the cells or tissues of an organism.
[0113] The term "diluent" defines chemical compounds diluted in
water that will dissolve the compound of interest as well as
stabilize the biologically active form of the compound. Salts
dissolved in buffered solutions are utilized as diluents in the
art. One commonly used buffered solution is phosphate buffered
saline because it mimics the salt conditions of human blood. Since
buffer salts can control the pH of a solution at low
concentrations, a buffered diluent rarely modifies the biological
activity of a compound.
[0114] The term "physiologically acceptable" defines a carrier or
diluent that does not abrogate the biological activity and
properties of the compound.
[0115] Techniques for formulation and administration of the
compositions described herein may be found in "Remington's
Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 18th
edition, 1990.
[0116] Suitable routes of administration may, for example, include
oral, rectal, transmucosal, topical, or intestinal administration;
parenteral delivery, including intramuscular, subcutaneous,
intravenous, intramedullary injections, as well as intrathecal,
direct intraventricular, intraperitoneal, intranasal, or
intraocular injections. The compounds can also be administered in
sustained or controlled release dosage forms, including depot
injections, osmotic pumps, pills, transdermal (including
electrotransport) patches, and the like, for prolonged and/or
timed, pulsed administration at a predetermined rate.
[0117] The pharmaceutical compositions of the present invention may
be manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or tabletting
processes.
[0118] Pharmaceutical compositions for use as described herein thus
may be formulated in conventional manner using one or more
physiologically acceptable carriers comprising excipients and
auxiliaries which facilitate processing of the active compounds
into preparations which can be used pharmaceutically. Proper
formulation is dependent upon the route of administration chosen.
Any of the well-known techniques, carriers, and excipients may be
used as suitable and as understood in the art; e.g., in Remington's
Pharmaceutical Sciences, above.
[0119] Injectables can be prepared in conventional forms, either as
liquid solutions or suspensions, solid forms suitable for solution
or suspension in liquid prior to injection, or as emulsions.
Suitable excipients are, for example, water, saline, dextrose,
mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine
hydrochloride, and the like. In addition, if desired, the
injectable pharmaceutical compositions may contain minor amounts of
nontoxic auxiliary substances, such as wetting agents, pH buffering
agents, and the like. Physiologically compatible buffers include,
but are not limited to, Hanks's solution, Ringer's solution, or
physiological saline buffer. If desired, absorption enhancing
preparations (for example, liposomes), may be utilized.
[0120] For transmucosal administration, penetrants appropriate to
the barrier to be permeated may be used in the formulation.
[0121] Pharmaceutical formulations for parenteral administration,
e.g. by bolus injection or continuous infusion, include aqueous
solutions of the active compounds in water-soluble form.
Additionally, suspensions of the active compounds may be prepared
as appropriate oily injection suspensions. Suitable lipophilic
solvents or vehicles include fatty oils such as sesame oil, or
other organic oils such as soybean, grapefruit or almond oils, or
synthetic fatty acid esters, such as ethyl oleate or triglycerides,
or liposomes. Aqueous injection suspensions may contain substances
which increase the viscosity of the suspension, such as sodium
carboxymethyl cellulose, sorbitol, or dextran. Optionally, the
suspension may also contain suitable stabilizers or agents that
increase the solubility of the compounds to allow for the
preparation of highly concentrated solutions. Formulations for
injection may be presented in unit dosage form, e.g. in ampoules or
in multi-dose containers, with an added preservative. The
compositions may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain formulatory
agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for
constitution with a suitable vehicle, e.g. sterile pyrogen-free
water, before use.
[0122] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions and
the like, for oral ingestion by a patient to be treated.
Pharmaceutical preparations for oral use can be obtained by
combining the active compounds with solid excipient, optionally
grinding a resulting mixture, and processing the mixture of
granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients are, in particular,
fillers such as sugars, including lactose, sucrose, mannitol, or
sorbitol; cellulose preparations such as, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If
desired, disintegrating agents may be added, such as the
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate. Dragee cores are provided with
suitable coatings. For this purpose, concentrated sugar solutions
may be used, which may optionally contain gum arabic, talc,
polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solutions, and suitable organic solvents
or solvent mixtures. Dyestuffs or pigments may be added to the
tablets or dragee coatings for identification or to characterize
different combinations of active compound doses. For this purpose,
concentrated sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,
polyethylene glycol, and/or titanium dioxide, lacquer solutions,
and suitable organic solvents or solvent mixtures. Dyestuffs or
pigments may be added to the tablets or dragee coatings for
identification or to characterize different combinations of active
compound doses.
[0123] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0124] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0125] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of an aerosol spray presentation from pressurized packs or
a nebulizer, with the use of a suitable propellant, e.g.
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of, e.g. gelatin for use in an inhaler or insulator may
be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0126] Further disclosed herein are various pharmaceutical
compositions well known in the pharmaceutical art for uses that
include intraocular, intranasal, and intraauricular delivery.
Suitable penetrants for these uses are generally known in the art.
Pharmaceutical compositions for intraocular delivery include
aqueous ophthalmic solutions of the active compounds in
water-soluble form, such as eyedrops, or in gellan gum (Shedden et
al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayer et al.,
Opthalmologica, 210(2):101-3 (1996)); ophthalmic ointments;
ophthalmic suspensions, such as microparticulates, drug-containing
small polymeric particles that are suspended in a liquid carrier
medium (Joshi, A., J. Ocil. Pharmacol., 10(1):29-45 (1994)),
lipid-soluble formulations (Alm et al., Prog. Clin. Biol. Res.,
312:447-58 (1989)), and microspheres (Mordenti, Toxicol. Sci.,
52(1):101-6 (1999)); and ocular inserts. All of the above-mentioned
references, are incorporated herein by reference in their
entireties. Such suitable pharmaceutical formulations are most
often and preferably formulated to be sterile, isotonic and
buffered for stability and comfort. Pharmaceutical compositions for
intranasal delivery may also include drops and sprays often
prepared to simulate in many respects nasal secretions to ensure
maintenance of normal ciliary action. As disclosed in Remington's
Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa.
(1990), which is incorporated herein by reference in its entirety,
and well-known to those skilled in the art, suitable formulations
are most often and preferably isotonic, slightly buffered to
maintain a pH of 5.5 to 6.5, and most often and preferably include
antimicrobial preservatives and appropriate drug stabilizers.
Pharmaceutical formulations for intraauricular delivery include
suspensions and ointments for topical application in the ear.
Common solvents for such aural formulations include glycerin and
water.
[0127] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g. containing
conventional suppository bases such as cocoa butter or other
glycerides.
[0128] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for
example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0129] For hydrophobic compounds, a suitable pharmaceutical carrier
may be a cosolvent system comprising benzyl alcohol, a nonpolar
surfactant, a water-miscible organic polymer, and an aqueous phase.
A common cosolvent system used is the VPD co-solvent system, which
is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar
surfactant Polysorbate 80.TM., and 65% w/v polyethylene glycol 300,
made up to volume in absolute ethanol. Naturally, the proportions
of a co-solvent system may be varied considerably without
destroying its solubility and toxicity characteristics.
Furthermore, the identity of the co-solvent components may be
varied: for example, other low-toxicity nonpolar surfactants may be
used instead of POLYSORBATE 80.TM.; the fraction size of
polyethylene glycol may be varied; other biocompatible polymers may
replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other
sugars or polysaccharides may substitute for dextrose.
[0130] Alternatively, other delivery systems for hydrophobic
pharmaceutical compounds may be employed. Liposomes and emulsions
are well known examples of delivery vehicles or carriers for
hydrophobic drugs. Certain organic solvents such as
dimethylsulfoxide also may be employed, although usually at the
cost of greater toxicity. Additionally, the compounds may be
delivered using a sustained-release system, such as semipermeable
matrices of solid hydrophobic polymers containing the therapeutic
agent. Various sustained-release materials have been established
and are well known by those skilled in the art. Sustained-release
capsules may, depending on their chemical nature, release the
compounds for a few weeks up to over 100 days. Depending on the
chemical nature and the biological stability of the therapeutic
reagent, additional strategies for protein stabilization may be
employed.
[0131] Agents intended to be administered intracellularly may be
administered using techniques well known to those of ordinary skill
in the art. For example, such agents may be encapsulated into
liposomes. All molecules present in an aqueous solution at the time
of liposome formation are incorporated into the aqueous interior.
The liposomal contents are both protected from the external
micro-environment and, because liposomes fuse with cell membranes,
are efficiently delivered into the cell cytoplasm. The liposome may
be coated with a tissue-specific antibody. The liposomes will be
targeted to and taken up selectively by the desired organ.
Alternatively, small hydrophobic organic molecules may be directly
administered intracellularly.
[0132] In some embodiments, the 5-HT2A inverse agonist or
antagonist is long acting while the co-administered antipsychotic
is short acting. The long acting or short acting properties may be
due to long and short half lives, respectively. Many antipsychotics
have relatively short occupancy times at D2 receptors. If a
similarly short acting 5-HT2A inverse agonist or antagonist were
used in combination with such antipsychotics, then the modulating
effect of the 5-HT2A inverse agonist or antagonist on D2 activity
would be diminished at the same time that D2 receptor occupancy is
low, potentially resulting in a loss of efficacy, a problem that is
compounded if a low dose of antipsychotic is used. In contrast,
while not being bound by any particular theory, if a 5-HT2A inverse
agonist or antagonist that has relatively long receptor occupancy
compared to the antipsychotic is used, then high 5-HT2A receptor
occupancy and resulting D2 modulating effect is maintained during
the periods when the D2 receptor occupancy is at its lowest.
[0133] The benefits of combining a longer acting drug that improves
the therapeutic window of a shorter acting therapeutic agent is
also applicable to combinations other than 5-HT2A inverse agonists
or antagonists with D2 antagonists. For example, while not being
bound by any particular theory, it is believed that the efficacy of
many drugs is limited to a range of drug levels (therapeutic
window). FIG. 1A is an illustrative graph of the drug level upon
sequential administration of a single drug. The therapeutic window
(shown as the shaded region on the graph) is bounded on the lower
side by the minimum level of the drug that must be present to
achieve a therapeutic benefit and on the higher side by the level
of the drug such that the toxicity would outweigh any therapeutic
benefit above this plasma concentration of the drug. As illustrated
for some drugs with a narrow therapeutic window, even the optimal
dose results in plasma levels outside both the upper and lower
bounds of the therapeutic window (the drug has toxicity limited
efficacy). That is, while not being bound to any particular theory,
it is believed that because the drug causes toxicity when the drug
level reaches a particular concentration, the maximum dosage that
can be administered is limited. Thus, during a period of successive
dosings of a drug administered alone with a given half-life, the
level of the drug can cycle in and out of the therapeutic window
such that between doses, the drug levels can fall below those
levels required for efficacy of the drug.
[0134] While not being bound to any particular theory, it is
believed that a secondary drug that, by lowering the plasma level
associated with efficacy, can increase the therapeutic window for
the primary drug. However, if the half life of the secondary drug
is short, then the beneficial effects on the therapeutic window
will be transient and will be absent at the time when the drug
levels of the primary agent are lowest. Thus the beneficial effects
of the modulatory agent may not be apparent. FIG. 1B illustrates
the widening of the therapeutic window in the case where the
primary and secondary drugs have similar half-lives. Only the drug
level of the primary drug is depicted. FIG. 1B illustrates that,
although the size of the therapeutic window is increased, the time
that the primary drug is within the therapeutic window is not
significantly increased compared to the primary drug administered
alone (see FIG. 1A). For example, if the primary drug is a D2
receptor antagonist and the secondary drug is a 5-HT2A inverse
agonist or antagonist, it is believed that the 5-HT2A antagonist or
inverse agonist would increase the therapeutic window for the D2
antagonist when the level of the secondary drug exceeds its own
required level of efficacy. While the secondary drug lowers the
required level of the primary drug, it does so when the levels of
the primary drug are already high. Consequently, it is believed
that the fraction of time in which there is efficacious therapy may
not be increased through this approach.
[0135] While not being bound to any particular theory, it is
believed that when a secondary drug has a longer half-life than the
primary drug, the enhanced therapeutic window can be maintained
into the next dose. FIG. 1C depicts the resulting sustained
increase in the therapeutic window. Because the secondary drug is
present at high levels throughout each dosing period of the primary
drug, the lower limit of the therapeutic window stays consistently
low. Thus, the primary drug is always within the therapeutic
window, thereby dramatically increasing the fraction of time in
which there is efficacious therapy. Implicit in this is the
opportunity to lower the dose of the primary drug to a level that
diminishes its toxic effects while maintaining its efficacy.
[0136] Accordingly, some embodiments include administering a first
agent in combination with a second agent wherein the first agent
has a higher half-life than the second agent. In some embodiments,
the half-life of the first agent is at least about 1.5, 1.6, 1.7,
1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0,
3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, or more than 4.0
times higher than the half-life of the second agent. In some
embodiments, the first agent modulates the activity of the second
agent. In some embodiments, the first and second agents are
selected such that their relative half-lives and the modulating
effect of the first agent on the second agent results in the second
agent being present at an efficacious dose during at least about
50%, 60%, 70%, 80%, 90%, or 100% of the time between successive
dosing of the second agent.
[0137] Some embodiments include selecting appropriate
pharmaceutical agents to achieve the results indicated above. Some
such embodiments include determining whether a first pharmaceutical
agent modulates a pharmacological property of a second
pharmaceutical agent, such as by in vitro assays or in vivo
measurements. In one embodiment, the pharmacological property that
is modulated is a receptor occupancy. For example, the first
pharmaceutical agent may decrease or increase the occupancy of a
particular receptor. In one embodiment, the pharmacological
property is the minimum dose at which the second pharmaceutical
agent has an efficacious effect. For example, the first
pharmaceutical agent may decrease the minimum efficacious dose of
the second pharmaceutical agent. Some embodiments further include
determining whether the first pharmaceutical agent has a longer
half-life than a second pharmaceutical agent.
[0138] In some embodiments, the first agent has D2 antagonist
activity (e.g., haloperidol or risperidone). In some embodiments,
the second agent is a 5-HT2A inverse agonist or antagonist. For
example, in some embodiments, the second agent is pimavanserin or
any of the 5-HT2A inverse agonists or antagonists described
herein.
EXAMPLES
Example 1
Haloperidol and Risperidone Combinations Administered to
Schizophrenic Patients
[0139] A randomized, double blind, multi-center study of
schizophrenic subjects with an acute exacerbation of psychosis was
conducted. Subjects with a DSM-IV diagnosis of schizophrenia and a
baseline score on the Positive and Negative Syndrome Scale (PANSS)
of at least 65 (high level of psychopathology), and a score of 4 or
higher on two items of the psychosis subscale were enrolled.
Subjects were randomly assigned to be administered haloperidol 2 mg
per day co-administered with placebo, haloperidol 2 mg per day
co-administered with pimavanserin at 20 mg per day, 2 mg
risperidone per day co-administered with a placebo, 2 mg
risperidone per day co-administered with 20 mg of pimavanserin, or
6 mg risperidone per day co-administered with placebo. Subjects
administered 2 mg of risperidone per day received two doses of 1 mg
each. Subjects administered 6 mg of risperidone per day received
two doses of 3 mg each. This study lasted approximately nine weeks
and included a screening period to allow for wash out of prior
antipsychotics (2 to 14 days) followed by six weeks of active fixed
dosing. Subjects were returned to the clinic two weeks later for a
follow up visit. Subjects were treated as in-patients during
screening and for the first 14 days of the trial, and thereafter,
at the discretion of each principal investigator (PI), completed
the trial as outpatients. Subjects were evaluated at screening,
after a drug-free lead-in period (Baseline Day -1), and
periodically thereafter by the PANSS, the Clinical Global
Impression Scale-Severity (CGI-S), the Calgary Depression Scale for
Schizophrenia (CDSS), the Simpson and Angus Scale (SAS), and the
Barnes Akathisia Scale (BAS).
[0140] Male and female subjects, age inclusive from 18-65, with a
clinical diagnosis of schizophrenia (DSM-IV 295.XX), are enrolled.
Subjects are experiencing an acute psychotic exacerbation, and have
at least a moderate degree of psychopathology (total score on the
PANSS of 65 or greater), and a score greater than or equal to 4 on
two of the four following PANSS items: delusions, hallucinatory
behavior, conceptual disorganization or suspiciousness, where at
least one of the two items must be delusions or hallucinatory
behavior. Subjects have a history of a previous psychotic
exacerbation with a positive response to antipsychotic therapy, and
a history of at least 3 months of prior antipsychotic therapy. In
other words, subjects who have a history of being refractory to
antipsychotic therapies, or are experiencing their first episode of
psychosis, are excluded.
[0141] All subjects received twice daily (BID) oral doses of study
medication. Subjects receiving haloperidol received a total of 2 mg
per day in a single am dose followed by a placebo pm dose. Subjects
administered 2 mg of risperidone per day received two doses of 1 mg
each. Subjects administered 6 mg of risperidone per day received
two doses of 3 mg each. Subjects administered pimavanserin received
a total of 20 mg per day in a single am dose followed by a placebo
pm dose. Thus each subject received BID dosing of study medications
in a blinded manner.
[0142] Subjects were evaluated at baseline/enrollment (Study Day
-1), and periodically thereafter throughout the active dosing
portion of the trial (Study Days 1, 8, 15, 22, 29, 36, and 43).
These clinical evaluations included vital signs, medical history
and exam (including psychiatric and brief neurological evaluation),
ECG measurements, the administration of clinical rating scales,
safety evaluations including reported or observed adverse events,
clinical chemistries (except Days 1, 22 and 36), and plasma
sampling for the pimavanserin, haloperidol, and risperidone
concentrations. A final follow-up visit on Day 57, two weeks after
the termination of the active dosing portion of the trial, included
a medical evaluation, safety clinical labs, and plasma sampling for
pimavanserin, haloperidol, and risperidone concentrations.
Prolactin levels, weight gain, and glucose levels were also
monitored.
[0143] The clinical rating scale for psychosis and negative
symptoms is the Positive and Negative Symptom Scale (PANSS). The
Clinical Global Impression Scale (CGI-S) is a global assessment of
clinical severity. Scales for extrapyramidal symptoms (EPS) include
the Simpson and Angus Scale (SAS) and the Barnes Akathisia Scale
(BAS). Finally, the Calgary Depression Scale for Schizophrenia
(CDSS) was included.
[0144] The PANSS is a 30-item, 7-point rating system that was
adapted from the Brief Psychiatric Rating Scale. It has sections
that specifically measure positive symptoms, negative symptoms, and
general psychopathology in schizophrenic subjects. The PANSS is
widely used in trials of antipsychotic drug treatment, and has been
formally validated for such use. The entire scale was administered
at screening, at baseline (Study Day -1), and during each clinical
evaluation except for Study Day 1 and Day 57.
[0145] The CGI-S consists of three subscales. The CGI-S (severity
of illness) has been designed to evaluate global severity of
illness. The CGI-S was administered at baseline (Study Day -1), and
at each clinical evaluation, except for Study Days 1 and 57.
[0146] The SAS is an extrapyramidal motor effect measure. This
10-item, 5-point scale is designed to assess a range of
extrapyramidal symptoms including disturbances in gait, muscle
tone, and tremor. This scale was administered at baseline (Study
Day -1), and at all clinical evaluations, except for Study Day
57.
[0147] The BAS is another extrapyramidal motor effect measure. The
BAS was designed to measure drug-induced akathisia that occurs
specifically with use of antipsychotic agents. The BAS is a
four-item fully anchored scale. Three items (i.e., objective
akathisia, subjective awareness of restlessness, and subjective
distress related to restlessness) are rated on a 4-point scale, and
the global clinical assessment of akathisia uses a 6-point scale.
This scale was administered at baseline (Study Day -1), and at all
clinical evaluations, except for Study Day 57.
[0148] The effect of adjunctive pimavanserin treatment on affective
symptoms was also assessed. The CDSS is a 9-item, 4-point scale
that was specifically designed to measure depressive symptoms in
psychotic subjects, separate from the positive, negative, and
extrapyramidal symptoms observed in this population. It has been
widely used in treatment trials in schizophrenia and has been
validated for such use. This scale was administered at screening
and at all clinical evaluations, except for Study Days 1 and
57.
[0149] During the screening period (from screening to Study Day
-1), all subjects receive only permitted concomitant medication as
deemed necessary. All prior antipsychotic, mood stabilization and
antidepressant therapy are completely washed out at least two days
prior to randomization (Day -1). Thereafter, all investigational
study drugs are administered twice a day for the duration of the
trial.
[0150] FIG. 2 is a graph depicting the total change (mean.+-.SE)
from baseline in the PANSS score for each treatment group. The
pimavanserin/risperidone combination produced a significantly
greater decrease in PANSS score starting at Day 15 as compared to
low dose risperidone (2 mg). FIG. 3A is a bar graph depicting the
percent of subjects with greater than or equal to 20% improvement
in PANSS total at Day 15. FIG. 3B shows the same data at Day 43.
The response to the pimavanserin/risperidone was significantly
greater than low dose (2 mg) and high dose (6 mg) risperidone at
Day 15 (p=0.002 and 0.013, respectively), and significantly greater
than low dose risperidone at Day 43 (p=0.001).
[0151] FIG. 4A is a graph depicting the change from baseline
(mean.+-.SE) in the PANSS positive symptom scale. The response to
the pimavanserin/risperidone combination was significantly greater
than low dose risperidone at Days 15-36 (p<0.05). The
combination was not significantly different from high dose
risperidone. FIG. 4B shows the change in the PANSS negative symptom
scale. The response to the pimavanserin/risperidone combination was
significantly greater than low dose risperidone at Day 15 and later
(p<0.05). The combination was not significantly different from
high dose risperidone.
[0152] FIG. 5A is a graph depicting the change from baseline
(mean.+-.SE) in the PANSS general psychopathology scale. The
response to the pimavanserin/risperidone combination was
significantly greater than low dose risperidone for all time points
from Day 15 on (p<0.005). The combination also showed trends for
greater change compared to high dose risperidone at Days 15 and 20.
FIG. 5B shows the change in the PANSS cognition scale. The response
for the pimavanserin/risperidone combination was significantly
better than low dose risperidone at Day 36 (p<0.05) and trends
for superiority at Days 22 (p<0.05) and 43 (p<0.07).
[0153] FIG. 6 is a graph depicting the change from baseline
(mean.+-.SE) for the CGI-severity scale. The change for the
pimavanserin/risperidone combination was significantly different
from low dose risperidone from Day 15-43. No significant difference
was observed between the combination and high dose risperidone.
[0154] FIG. 7A is a bar graph depicting the percent of subjects
with a weight gain of at least 7% at the end of the study. The
results indicate that fewer patients experienced clinically
significant weight gain when receiving the pimavanserin/risperidone
combination as compared to patients receiving either low dose
(p=0.08) or high dose (p=0.031) of risperidone alone. FIG. 7B is a
bar graph depicting mean weight gain at the end of the study
compared to baseline. Patients receiving a pimavanserin/risperidone
combination had less weight gain than high dose risperidone
(p=0.05).
[0155] FIGS. 8A and 8B are graphs depicting the change from
baseline (mean.+-.SE; ng/mL) of prolactin levels at the end of
treatment for males and females, respectively. The prolactin levels
in both males and females were significantly less for the
pimavanserin/risperidone combination patients than for those
receiving high dose risperidone (p=0.015 for males, p=0.004 for
females).
[0156] FIG. 9 is a bar graph indicating the changes in glucose
levels from baseline. The results indicated that patients receiving
the pimavanserin/risperidone combination had less of an increase in
glucose than those receiving high dose risperidone (p=0.024).
[0157] The results of the study demonstrate that co-administering
pimavanserin with haloperidol provided highly significant
antipsychotic efficacy (p<0.0001) with similar efficacy to
haloperidol administered alone. FIG. 10 is a graph depicting the
percent of responders, defined as those subjects experiencing at
least a 20% reduction in PANSS score. The results indicate that the
combination treatment trended toward a faster onset of efficacy.
Specifically, at two weeks after the start of treatment, the
percent responders for the haloperidol/pimavanserin combination
were higher than for haloperidol alone.
[0158] As Table 1 demonstrates, the haloperidol/pimavanserin
combination also resulted in less weight gain than observed when
administering haloperidol alone.
TABLE-US-00001 TABLE 1 Haloperidol Haloperidol + Pimavanserin
Initial mean weight (kg) 82.993 82.943 Final mean weight (kg)
83.759 83.385 Mean weight gain (kg) 0.7657 0.4426
[0159] Co-administering pimavanserin with risperidone also provided
highly significant antipsychotic efficacy (p<0.0001). Efficacy
enhancement was observed when compared to 2 mg of risperidone
administered alone (mean change in PANNS score of 23.0 vs. 16.6
points) and similar efficacy was observed when compared to 6 mg of
risperidone administered alone. Efficacy of the combination was
observed for both positive and negative symptoms of psychosis. The
co-administration resulted in improved treatment of emotional
withdrawal, lack of spontaneity and flow of conversation, abnormal
mannerisms and posturing, motor retardation, uncooperativeness,
lack of judgment and insight, poor impulse control, and
preoccupation as compared to 6 mg per day of risperidone
administered alone.
[0160] FIG. 11 is a graph depicting the percent of responders for
those subjects receiving risperidone, defined as those subjects
experiencing at least a 20% reduction in PANSS score. The results
indicate that the combination treatment resulted in a faster onset
of efficacy. Specifically, at two weeks after the start of
treatment, the percent responders for the risperidone/pimavanserin
combination were higher than for risperidone alone (both the 2 mg
and 6 mg doses).
[0161] As Table 2 demonstrates, the risperidone/pimavanserin
combination resulted in less weight gain than observed when
administering 6 mg of risperidone alone. The difference was
approaching statistical significance (p=0.0784).
TABLE-US-00002 TABLE 2 2 mg 6 mg Risperidone + Risperidone
Risperidone pimavanserin Initial mean weight (kg) 80.702 79.216
79.533 Final mean weight (kg) 81.856 81.332 80.600 Mean weight gain
(kg) 1.1540 2.1162 1.0667
[0162] Conclusion: The combination of low dose risperidone with
pimavanserin was superior to that of either low dose or high dose
risperidone alone in terms of time of onset of response and percent
of patients with good clinical response. The efficacy of
haloperidol was not potentiated by pimavanserin, perhaps because
with haloperidol alone, the occupancy of D2 receptors is sufficient
to achieve optimal outcome, whereas that of low dose risperidone
alone is not. The advantage of using low doses of
atypicals+pimavanserin extends to reduced side effect burden on
metabolic measures and EPS and, potentially, to a broadened
efficacy.
[0163] The conclusions are summarized as follows: [0164]
Pimavanserin potentiated efficacy of low dose risperidone on
psychopathology while reducing side effects. [0165] Pimavanserin
did not potentiate the efficacy of haloperidol. [0166] Low dose
risperidone was significantly less effective than the other
treatments. [0167] Pimavanserin enhanced the efficacy of low dose
risperidone at all time points from week 2 on with regard to PANSS
Total, POS, NEG, General, and CGI. [0168] Pimavanserin/risperidone
was more effective than high dose risperidone and low dose
risperidone at day 15 with regard to % patients with >20%
decrease in PANSS Total. [0169] Pimavanserin/risperidone was as
effective as high dose risperidone, haloperidol and
pimavanserin/haloperidol at all time points, with all measures.
[0170] Pimavanserin/risperidone had less % of patients with >7%
weight gain than high dose risperidone or low dose risperidone.
[0171] Serum glucose and prolactin levels (PRL) were lower in
pimavanserin/risperidone than high dose risperidone; PRL levels
were lower in haloperidol-treated patients compared to risperidone
patients. [0172] There was a trend to less akathesia in the
pimavanserin co-therapy groups compared to the respective
risperidone and haloperidol arms.
Example 2
Combinations of Haloperidol and Risperidone with Pimavanserin for
Suppressing Drug-Induced Hyperactivity in Mice
[0173] Male non-Swiss albino (NSA) mice and Sprague-Dawley (SD)
rats (Harlan, San Diego, Calif.) served as subjects for the present
investigation. Animals were housed in climate-controlled rooms on a
12/12 light dark cycle with on lights at 0600 hr. Rats were housed
in groups of two and mice were housed in groups of eight. Food and
water was available ad libitum except during experimental
procedures. At the time of testing, mice weighed 20-30 g and the
rats weighed between 275-325 g.
[0174] Amphetamine, dizocilpine (i.e., MK-801), and haloperidol
were obtained from Sigma (St. Louis, Mo.). Risperidone was obtained
from Toronto Research Chemicals (North York, ON, Canada).
Pimavanserin were synthesized by ACADIA Pharmaceuticals, Inc. Drugs
were administered either in a volume of 0.1 mL per 10 g body weight
or of 1.0 mL per kg body weight to mice and rats, respectively. The
vehicle used for amphetamine, dizocilpine, and ACP-103 was saline.
Amphetamine and dizocilpine were administered intraperitoneally
(ip). The vehicle used for haloperidol and risperidone was 10%
Tween 80 in saline unless otherwise specified. Haloperidol and
risperidone were administered subcutaneously (sc), unless otherwise
noted. The doses of pimavanserin are expressed as free-base and
were administered by the sc route.
[0175] Amphetamine-induced Hyperlocomotor Activity Assay:
Hyperlocomotion was produced in mice by administration of
amphetamine (3 mg/kg) 15 min prior to entering motor activity
chambers (AccuScan Instruments, Columbus, Ohio). Dose response
curves were constructed for haloperidol in the presence of vehicle
or a fixed dose of pimavanserin (0.03 mg/kg). Vehicle or
haloperidol was injected 30 min prior to entering activity
chambers. Vehicle or pimavanserin was given 30 min prior to
haloperidol (i.e., 60 min prior to entering activity chambers).
Immediately prior to placing the mice into the activity chambers,
the presence of ataxia and muscle incoordination was determined
using the horizontal wire test (Vanover et al., 2004). Once inside
the chambers, total distance traveled (DT) in cm was determined
across a 15 min session. In order to generate dose-response curves,
raw DT data were converted to % MPI: % MPI=((DT drug or drug
combination-DT amphetamine control)/(DT vehicle control-DT
amphetamine control))*100. The ID.sub.50 values and the
corresponding 95% CI were determined as previously mentioned. Mice
had no prior exposure to the chambers and each dose combination was
tested in separate groups of mice.
[0176] Dizocilpine-induced Hyperlocomotor Activity Assay:
Hyperlocomotion was produced in mice by administration of
dizocilpine (0.3 mg/kg) 15 min prior to entering motor activity
chambers. Dose response curves were constructed for haloperidol,
risperidone and pimavanserin. Haloperidol or risperidone was
injected 30 min prior to, and pimavanserin was administered 60 min
prior to entering the activity chambers. Immediately prior to
placing the mice into the activity chambers the presence of ataxia
and muscle incoordination was determined as previously described
and DT was determined across a 15 min session. Raw data were
transformed to % MPI and ID.sub.50 values and corresponding 95% CI
were determined as previously described. Mice had no prior exposure
to the chambers and each dose combination was tested in separate
groups of mice.
[0177] Drug-interaction Studies: Isobolographic analysis was used
to determine the nature of the drug interaction between either
haloperidol or risperidone and pimavanserin on suppression of
dizocilpine-induced hyperlocomotor activity. This method is based
on the comparison of dose combinations in which the doses of each
individual agent are determined to be equi-efficacious. In this
case, dose-response curves were generated following
co-administration of either haloperidol or risperidone with
pimavanserin in a fixed dose ratio based on the individual
calculated ID.sub.50 values. Therefore, separate groups received:
pimavanserin ID.sub.50+haloperidol or risperidone ID.sub.50;
(pimavanserin ID.sub.50+haloperidol or risperidone ID.sub.50)/2;
(pimavanserin ID.sub.50+haloperidol or risperidone ID.sub.50)/4;
and (pimavanserin ID.sub.50+haloperidol or risperidone
ID.sub.50)/8. Based on the dose-response curves obtained for the
combined agents (i.e., pimavanserin+haloperidol or
pimavanserin+risperidone), ID.sub.50 value and 95% CI for each drug
combination was obtained.
[0178] Effects of haloperidol alone, and in combination with
pimavanserin, on suppression of amphetamine-induced hyperlocomotion
in mice: FIG. 12A is graph illustrating the distance traveled as a
function of haloperidol dose for the various administered agents.
Relative to vehicle controls (open circle), amphetamine (open
triangle) significantly increases hyperlocomotor activity in mice
(increased DT to 2764.+-.230 cm from 876.+-.42 cm obtained in the
vehicle controls). Pimavanserin at a dose of 0.03 mg/kg (filled
circle) failed to suppress hyperlocomotion produced by amphetamine.
In contrast, haloperidol (open squares) dose dependently attenuated
hyperactivity produced by amphetamine. However, haloperidol, when
combined with a fixed dose of pimavanserin (0.03 mg/kg, filled
squares), demonstrated an enhanced suppression of
amphetamine-induced hyperlocomotor activity.
[0179] The raw data contained in FIG. 12A were converted to % MPI
to generate dose-response curves depicted in FIG. 12B. Haloperidol
(open squares) produced a dose-dependent attenuation of
hyperactivity elicited by amphetamine with a calculated ID.sub.50
value of 0.012 mg/kg (0.009-0.016; 95% CI). However, when combine
with a fixed dose of pimavanserin (0.03 mg/kg, filled squares), the
dose-response curve for haloperidol was significantly shifted to
the left by a factor of approximately 10 with a calculated
ID.sub.50 value of 0.0013 mg/kg (0.0005-0.0031; 95% CI). The
combination of pimavanserin and haloperidol resulted in a 9.5-fold
(3.8-23.8; 95% CI) shift in potency. Each data point represents a
minimum n of 8.
[0180] Effects of haloperidol and pimavanserin, alone and in
combination, on suppression of dizocilpine-induced hyperlocomotion
in mice: FIG. 13A is a graph depicting dose response curves for
haloperidol (open squares), pimavanserin (filled squares), and the
combination of haloperidol with pimavanserin in a 1:1 fixed dose
ratio (filled circles) on the suppression of dizocilpine-induced
hyperactivity. Each data point represents a minimum n of 16. As
expected, dizocilpine treatment significantly increased DT to
2227.+-.116 cm from 792.+-.40 cm obtained in the vehicle controls.
Administration of either haloperidol or pimavanserin elicited a
dose-dependent attenuation of dizocilpine-induced hyperlocomotion
achieving ID.sub.50 values of 0.07 mg/kg (0.063-0.087; 95% CI) and
0.09 mg/kg (0.067-0.12; 95% CI), respectively. Given that
haloperidol and pimavanserin were equipotent in this assay, a 1:1
fixed-dose ratio (haloperidol:ACP-103) was administered in
fractions of the approximated ID.sub.50 dose combinations of
0.06+0.06 mg/kg (ID.sub.50/2=0.03+0.03 mg/kg;
ID.sub.50/4=0.015+0.015 mg/kg; ID.sub.50/8=0.0075+0.0075 mg/kg).
Co-administration of haloperidol and pimavanserin produced a
dose-dependent attenuation of hyperlocomotor activity induced by
dizocilpine achieving a % MPI of 103.+-.6%.
[0181] Isobolographic analysis conducted using the equipotent ratio
and the resulting isobologram is presented in FIG. 13B. The
calculated ID.sub.50 (and 95% CI) values for pimavanserin and
haloperidol when administered alone (open squares) are plotted on
the x- and y-axes, respectively. The dashed line connecting these
two points represents the line of theoretical additivity. The
experimental ID.sub.50 (filled circle, B) for the dose combination
was significantly less than the theoretical ID.sub.50 (filled
square, A), indicating a synergistic interaction. The experimental
ID.sub.50 for the dose mixture was significantly less than the
theoretical ID.sub.50, values of 0.04 mg/kg (0.03-0.05; 95% CI) and
0.08 mg/kg (0.68-0.93; 95% CI), respectively. These results
indicate that efficacy is maintained at 50% of haloperidol
dose.
[0182] Effects of risperidone and pimavanserin, alone and in
combination, on suppression of dizocilpine-induced hyperlocomotion
in mice: FIG. 14A is a graph depicting dose response curves for
risperidone (open squares), pimavanserin (filled squares), and the
combination of risperidone with pimavanserin in a 1:18 fixed dose
ratio (filled circles) on the suppression of dizocilpine-induced
hyperactivity. Each data point represents a minimum n of 16. As in
the previous experiment, dizocilpine treatment significantly
increased total DT to 2020.+-.223 cm from 649.+-.67 cm obtained in
the vehicle controls. Administration of either risperidone or
pimavanserin elicited a dose-dependent attenuation of
dizocilpine-induced hyperlocomotion achieving ID.sub.50 values of
0.0045 mg/kg (0.003-0.006; 95% CI) and 0.09 mg/kg (0.067-0.12; 95%
CI), respectively. Given that risperidone was more potent than
pimavanserin in this assay, a 1:18 fixed-dose ratio
(risperidone:pimavanserin) was administered in fractions of the
approximated ID.sub.50 dose combinations of 0.005+0.09 mg/kg
(ID.sub.50/2=0.0025+0.045 mg/kg; ID.sub.50/4=0.00125+0.0225 mg/kg;
ID.sub.50/8=0.000625+0.01125 mg/kg). Co-administration of
risperidone and pimvanserin produced a dose-dependent attenuation
of hyperlocomotor activity induced by dizocilpine achieving a % MPI
of 82.+-.8%.
[0183] Isobolographic analysis was conducted using the fixed dosing
ratio and the resulting isobologram is presented in FIG. 14B. The
calculated ID.sub.50 (and 95% CI) values for pimavanserin and
risperidone when administered alone (open squares) are plotted on
the x- and y-axes, respectively. The dashed line connecting these
two points represents the line of theoretical additivity. The
experimental ID.sub.50 (filled circle, B) for the dose combination
was significantly less than the theoretical ID.sub.50 (filled
square, A), indicating a synergistic interaction. The experimental
ID.sub.50 for the dose mixture was significantly less than the
theoretical ID.sub.50, values of 0.0032 mg/kg (0.0007-0.0058 95%
CI) and of 0.045 mg/kg (0.035-0.054; 95% CI), respectively. These
results indicate that efficacy is maintained at 1/3 of risperidone
dose.
[0184] Conclusion: Pimavanserin, at a dose that does not suppress
amphetamine-induced hyperactivity, when combined with haloperidol,
produced an approximate 10-fold shift in the potency of haloperidol
against amphetamine-induced hyperactivity. Further, pimavanserin
interacted synergistically with haloperidol, and with risperidone,
to reduce dizocilpine-induced hyperactivity. The supra-additive
actions of pimavanserin were not achieved by simply altering the
pharmacokinetics of either haloperidol or risperidone, as brain
exposures for these agents were not significantly altered in the
presence of pimavanserin. For example, Table 3 indicates brain
levels of pimavanserin and haloperidol for various dosages. The
results indicate that full efficacy can be achieved using the
combination with one half haloperidol brain concentration. The
doses used in these studies are consistent with a 5-HT.sub.2A
receptor mechanism of action. These data indicate that even for
compounds that possess high affinity for 5-HT.sub.2A receptors,
complete 5-HT.sub.2A receptor occupancy is not likely achieved at
doses that elicit antipsychotic-like activity.
TABLE-US-00003 TABLE 3 Treatment Pimavanserin brain levels
Haloperidol brain levels conditions (nmol/kg) (nmol/kg) Pim + Veh
23 (.+-.6) Veh + Hal (0.003) <10 Veh + Hal (0.01) 43 (.+-.5) Veh
+ Hal (0.03) 113 (.+-.25) Pim + Hal (0.0003) 17 (.+-.6) <10 Pim
+ Hal (0.001) 14 (.+-.4) 11 (.+-.3) Pim + Hal (0.003) 25 (.+-.5) 12
(.+-.4) Pim + Hal (0.01) 14 (.+-.6) 45 (.+-.7)
[0185] The mechanism by which 5-HT.sub.2A receptor blockade
enhances the action of antipsychotics (APDs) in these models is
unknown, however, microdialysis and other studies suggest several
possibilities. While not being bound by any particular theory, one
possibility is that 5-HT.sub.2A inverse agonists may have
regionally specific effects on dopamine (DA) transmission. Previous
studies have shown that DOI increases DA release and potentiates
amphetamine-induced DA release in the nuclear accumbens (NAC),
suggesting that 5-HT.sub.2A receptor inverse agonists are more apt
to modulate evoked, rather than basal, DA release. Haloperidol,
which potently inhibits amphetamine hyperactivity, has been shown
to paradoxically increase DA release in the NAC, an effect blocked
by pimavanserin. These data suggest that pimavanserin may
potentiate the actions of haloperidol via direct or indirect
modulation of evoked DA release in the NAC. Another possibility is
that 5-HT.sub.2A inverse agonists may block a "pro-psychotic" drive
associated with APD-induced enhanced serotonergic transmission in
limbic or cortical structures. Following systemic administration of
NMDA antagonists, extracellular DA and 5-HT concentrations rise in
the NAC, and medial prefrontal cortex (mPFC). High doses of
atypical APDs, such as clozapine and olanzapine, but not typical
APDs, such as haloperidol, produce preferential increases in DA
release in the mPFC compared to the NAC, a property that may
explain how atypical APDs improve cognition in schizophrenia.
Regardless of the mechanism, these findings indicate that
pimavanserin has dose-sparing actions for APDs in models predictive
of antipsychotic action.
[0186] In conclusion, the above data suggests that pimavanserin,
via 5-HT.sub.2A receptor antagonism or inverse agonism, results in
a significant dose-sparing effect such that antipsychotic efficacy
can be maintained, or improved, while concomitantly reducing the
severity of unwanted side effects mediated via D.sub.2 receptor
antagonism. The findings with risperidone suggest that the
dose-sparing benefits of pimavanserin will be manifested even with
those atypical APDs having an inherently high affinity for
5-HT.sub.2A receptors. This is consistent with clinical findings
indicating that even for those APDs which have relatively high
affinity for 5-HT.sub.2A receptors, 5-HT.sub.2A receptor blockade
is not fully achieved at clinically tolerated doses.
Example 3
Combinations of Aripiprazole and Quetiapine with Pimavanserin for
Suppressing Drug-Induced Hyperactivity in Mice
[0187] The protocol described above in Example 2 was repeated using
aripiprazole and quetiapine antipsychotics. FIG. 15A is graph
illustrating the distance traveled as a function of aripiprazole
dose for the various administered agents. Relative to vehicle
controls (open circle), amphetamine (open triangle) significantly
increases hyperlocomotor activity in mice. Pimavanserin at a dose
of 0.03 mg/kg (filled circle) failed to suppress hyperlocomotion
produced by amphetamine. In contrast, aripiprazole (open squares)
dose dependently attenuated hyperactivity produced by amphetamine.
However, aripiprazole, when combined with a fixed dose of
pimavanserin (0.03 mg/kg, filled squares), demonstrated an enhanced
suppression of amphetamine-induced hyperlocomotor activity.
[0188] The raw data contained in FIG. 15A were converted to % MPI
to generate dose-response curves depicted in FIG. 15B. Aripiprazole
(open squares) produced a dose-dependent attenuation of
hyperactivity elicited by amphetamine. However, when combined with
a fixed dose of pimavanserin (0.03 mg/kg, filled squares), the
dose-response curve for aripiprazole was significantly shifted to
the left.
[0189] FIG. 16A is graph illustrating the distance traveled as a
function of quetiapine dose for the various administered agents.
Relative to vehicle controls (open circle), amphetamine (open
triangle) significantly increases hyperlocomotor activity in mice.
Pimavanserin at a dose of 0.03 mg/kg (filled circle) failed to
suppress hyperlocomotion produced by amphetamine. In contrast,
quetiapine (open squares) dose dependently attenuated hyperactivity
produced by amphetamine. However, quetiapine, when combined with a
fixed dose of pimavanserin (0.03 mg/kg, filled squares),
demonstrated an enhanced suppression of amphetamine-induced
hyperlocomotor activity.
[0190] The raw data contained in FIG. 16A were converted to % MPI
to generate dose-response curves depicted in FIG. 16B. Quetiapine
(open squares) produced a dose-dependent attenuation of
hyperactivity elicited by amphetamine. However, when combined with
a fixed dose of pimavanserin (0.03 mg/kg, filled squares), the
dose-response curve for quetiapine was shifted to the left.
[0191] The effects of quetiapine and pimavanserin, alone and in
combination, on suppression of dizocilpine-induced hyperlocomotion
in mice was also evaluated. Isobolographic analysis was conducted
and the resulting isobologram is presented in FIG. 17. The
calculated ID.sub.50 (and 95% CI) values for pimavanserin and
quetiapine when administered alone (open squares) are plotted on
the x- and y-axes, respectively. The dashed line connecting these
two points represents the line of theoretical additivity. The
experimental ID.sub.50 (filled square, B) for the dose combination
was not significantly different than the theoretical ID.sub.50
(filled circle, A), indicating an additive interaction.
Example 4
Use of Pimavanserin for Reversing Cognitive Impairment in Mice
Administered Anti-Psychotics
[0192] Various antipsychotics were administered alone or in
combination with pimavanserin to mice in an in vivo mouse model of
cognition. Compounds were administered to mice at one hour
post-training (a time-point at which animals normally behaviorally
discriminate between novel and familiar objects) and two hours
post-training (a time-point at which these animals normally no
longer discrimate between objects).
[0193] FIG. 18 is a bar graph of percent novel object recognition
upon administration of vehicle, pimavanserin (0.3 mg/kg),
risperidone, olanzapine, and combinations of pimavanserin with
risperidone or olanzapine. The results indicate that pimavanserin
reverses novel object recognition impairment caused by risperidone
and olanzapine.
[0194] Combinations of pimavanserin and risperidone were also
evaluated in a radial arm maze in vivo mouse model of cognition.
FIG. 19 is a graph indicating working memory errors after repeated
trials upon administration of vehicle, risperidone, pimavanserin (1
mg/kg), and combination of risperidone with pimavanserin. The
results indicated that pimavanserin improved the cognitive deficit
induced by risperidone.
Example 5
Attenuation of Other Side Effects when Pimavanserin is
Co-Administered with Antipsychotics
[0195] Prolactin Assay: Dose response curves were generated for
haloperidol, risperidone and pimavanserin on serum prolactin
levels. Rats were dosed ip with vehicle (100% dimethyl sulfoxide),
haloperidol or risperidone, while pimavanserin or vehicle (saline)
was given sc. Blood samples were collected 30 min following
vehicle, haloperidol or risperidone administration or 60 min after
pimavanserin administration. Rats were deeply anesthetized with
isoflurane and blood samples were obtained by cardiac puncture,
allowed to clot and then centrifuged at 12,000 rpm for 10 min to
yield serum for analysis. Serum prolactin levels were quantified
using a commercially available enzyme immunoassay kit (ALPCO
Diagnostics, Windham, N.H.).
[0196] In order to explore the potential interaction between
haloperidol or risperidone and pimavanserin on serum prolactin
levels, rats were dosed sc with either vehicle or various doses of
pimavanserin, then 30 min later, dosed ip with either vehicle or a
fixed dose of haloperidol or risperidone. Blood samples were
collected 30 min following vehicle, haloperidol or risperidone
administration (i.e., 60 min following vehicle or pimavanserin
administration). The time point for sample collection was chosen
based on our work and that of others (Liegeois et al., 2002b),
which show that 30 min appears to be the time at which peak
prolactin levels can be detected following risperidone or
haloperidol treatment, respectively. The fixed doses of haloperidol
(0.1 mg/kg) and risperidone (0.01 mg/kg) were chosen since they
elicited statistically significant and reproducible, but
sub-maximal, increases in prolactin, thus allowing for the
detection of potential increases as well as decreases.
[0197] Effects of haloperidol and risperidone alone, and in
combination with pimavanserin, on serum prolactin levels in rats:
FIG. 20A is a graph depicting the dose response of prolactin levels
obtained in rats following various doses of risperidone (filled
squares), haloperidol (open squares) and pimavanserin (filled
circles). Serum prolactin levels obtained in vehicle-treated
controls were 24.+-.3 ng/nL and 31.+-.3 ng/nL after 30 min and 60
min, respectively. As expected, 60 min following haloperidol
treatment rats demonstrated a dose-related increase in serum
prolactin levels as compared to vehicle controls. Similarly, 30 min
following risperidone treatment, a dose-dependent increase in serum
prolactin levels was observed. In contrast, pimavanserin treatment,
up to 3 mg/kg, did not significantly elevate serum prolactin levels
as compared to vehicle-treated controls. Rather, rats treated with
pimavanserin demonstrated a significant reduction in serum
prolactin concentrations, as the values obtained were 31.+-.3 ng/mL
and 15.+-.0 ng/mL after vehicle and 3 mg/kg pimavanserin,
respectively. All rats treated with 3 mg/kg pimavanserin had serum
prolactin concentrations below the limit of detection; hence a
value of 15 ng/mL was assigned.
[0198] FIG. 20B depicts the serum prolactin levels obtained in rats
following fixed doses of risperidone (0.01 mg/kg; filled bars) or
haloperidol (0.1 mg/kg; open bars) in the presence of vehicle or
various doses of pimavanserin. Each data point represents a minimum
n of 12. ** denotes p<0.01; * denotes p<0.05. The dose of
haloperidol significantly increased serum prolactin levels from
31.+-.3 ng/mL to 102.+-.12 ng/mL. Similarly, risperidone
significantly increased serum prolactin levels from 24.+-.3 ng/mL
to 102.+-.12 ng/mL. However, in the presence of pimavanserin, at
doses consistent with 5-HT.sub.2A receptor blockade, the magnitude
of prolactinemia induced by either haloperidol or risperidone was
significantly attenuated.
[0199] Catalepsy Assessment: Rats were positioned with their
forepaws on a horizontal bar (diameter 10 mm); elevated 10 cm above
the bench top, and the duration of the cataleptic bout was recorded
up to a maximum catalepsy value of 120 sec. Catalepsy values (CVs)
were obtained at 30 and 60 min following ip administration
risperidone or haloperidol, respectively. Doses of pimavanserin
were administered sc 60 min prior to either haloperidol or
risperidone. In order to generate dose-response curves raw CVs were
converted to percentage maximum possible catalepsy (% MPC): %
MPC=((CV drug or drug combination --CV vehicle control)/(120-CV
vehicle control))*100. The dose that elicits 50% of maximum
catalepsy (CD.sub.50) and the corresponding 95% CI was determined
for each compound as previously mentioned. Each dose or dose
combination was assessed in separate groups of rats.
[0200] Effects of pimavanserin on haloperidol- and
risperidone-induced catalepsy in rats: FIG. 21A depicts dose
response curves as a function of haloperidol dose. As expected,
haloperidol (open circles) produced a dose-dependent increase in
catalepsy time in rats. Pimavanserin failed to potentiate
haloperidol-induced catalepsy at any of the doses tested. The
combination of 1 (filled circles) or 3 mg/kg (open squares) of
pimavanserin with haloperidol did not significantly alter
haloperidol-induced catalepsy, CD.sub.50 values of 0.24 mg/kg
(0.16-0.36; 95% CI) and 0.38 mg/kg (0.24-0.61; 95% CI),
respectively. However, the addition of 10 mg/kg pimavanserin (filed
squares) to haloperidol significantly increased the observed
CD.sub.50 value from 0.27 mg/kg (0.19-0.39; 95% CI) to 0.53 mg/kg
(0.31-0.91; 95% CI) indicating a reduction of catalepsy.
[0201] FIG. 21B depicts dose response curves as a function of
risperidone dose. As expected, risperidone (open circles) produced
a dose-dependent increase in catalepsy time in rats. Each data
point represents a minimum n of 12. Vehicle treatment elicited a
maximum CV of 6.8.+-.0.9 sec. Pimavanserin did not elicit catalepsy
at doses up to 10 mg/kg achieving a maximum CV of 10.5.+-.2.4 sec.
a value that was not significantly different from that obtained in
vehicle treated controls. In contrast, both haloperidol and
risperidone produced dose-dependent and marked increases in CVs
yielding CD.sub.50 values of 0.27 mg/kg (0.19-0.39; 95% CI) and 1.1
mg/kg (0.79-1.62; 95% CI), respectively. Pimavanserin, at all doses
tested, resulted in a dose-dependent and significant rightward
displacement of the risperidone dose response curve for catalepsy.
The calculated CD.sub.50 values for risperidone in the presence of
1 (filled circles), 3 (open squares) or 10 mg/kg (filed squares)
pimavanserin were 2.0 mg/kg (1.3-3.0; 95% CI), 4.4 mg/kg (2.6-7.5;
95% CI) and 5.1 mg/kg (3.2-8.3; 95% CI), respectively, indicating a
reduction of catalepsy.
[0202] Discussion: Antagonism of D.sub.2 receptors produces robust
prolactinemia both experimentally and clinically. Similarly,
risperidone, an atypical APD, has also been shown to elicit
prolactinemia as severe as haloperidol in humans. In the present
investigation, it was demonstrated that while both haloperidol and
risperidone produced robust increases in serum prolactin,
pimavanserin alone did not elevate, and indeed slightly reduced,
serum prolactin levels. Importantly, pimavanserin did not
potentiate, but rather attenuated the hyperprolactinemia produced
by these APDs. Despite the anatomical evidence supporting
expression of 5-HT.sub.2 receptors in the pituitary gland, the
preponderance of data suggests that the regulation of prolactin
secretion mediated by 5-HT.sub.2A receptors occurs at the level of
the hypothalamus. Pituitary D.sub.2 receptors, which lie outside of
the blood brain barrier (BBB), exert tonic inhibition of prolactin
secretion, while activation of 5-HT.sub.2A receptors in the
hypothalamus inhibits DA release resulting in prolactin elevation.
Thus, pure D.sub.2 antagonists elicit prolactinemia by direct
actions in the pituitary, whereas, highly brain penetrating APDs,
especially those which possess high 5-HT.sub.2A/D.sub.2 affinity
ratios (i.e., olanzapine and clozapine), do not elicit marked
hyperprolactinemia because these drugs achieve sufficient
5-HT.sub.2A receptor blockade in the hypothalamus to counteract the
effects of D.sub.2 receptor blockade in the pituitary. This is
critical with respect to risperidone which has been shown to
preferentially occupy D.sub.2 receptors in the pituitary gland, as
compared to the striatum, at doses up to 2.5 mg/kg in rats. If
risperidone does indeed poorly cross the BBB then the profile of
this drug is more consistent with a typical, rather than an
atypical APD, as the direct effects at D.sub.2 in the pituitary are
not likely to be counteracted by 5-HT.sub.2A receptor blockade
inside the BBB. Consistent with this idea are the observations in
the present study in which it was shown that risperidone elevates
prolactin at doses equal to or below those required to attenuate
head twitches produced by DOI. Furthermore, by combining
pimavanserin with risperidone a sufficient level of 5-HT.sub.2A
receptor occupancy was reached inside the BBB to counteract
risperidone-induced hyperprolactinemia. Taken together, these data
indicate that risperidone is not likely to achieve maximum
occupancy of 5-HT.sub.2A receptors inside the BBB, in the absence
of significant D.sub.2 receptor antagonism, in rats or in humans.
These finding have significant clinical relevance, as
hyperprolactinemia is correlated with numerous complications such
as sexual dysfunction, which is a prominent cause of noncompliance,
particularly in men, with these medications.
[0203] Finally, this investigation demonstrated that while both
haloperidol and risperidone produced dose-dependent catalepsy,
pimavanserin alone did not elicit detectable catalepsy at doses as
high as 10 mg/kg, or 50-fold higher than the ID.sub.50 in a DOI
head twitch assay, consistent with its lack of affinity for D.sub.2
receptors. It was demonstrated that although pimavanserin
potentiated the efficacy of haloperidol and risperidone,
pimavanserin clearly did not potentiate the catalepsy produced by
either drug. Instead, a small but significant reduction of
haloperidol-induced catalepsy at a dose of pimavanserin was
observed that would be expected for supramaximal 5-HT.sub.2A
receptor occupancy (i.e., 10 mg/kg). Pimavanserin demonstrates
approximately 50-fold selectivity for 5-HT.sub.2A over 5-HT.sub.2C.
This result suggests that the attenuation of catalepsy by
pimavanserin may be driven by its weaker 5-HT.sub.2C receptor
interactions. Based on the in vivo data, the selectivity of
pimavanserin for 5-HT.sub.2A over 5-HT.sub.2C receptors would be
approximately 50-fold, which is in agreement with previously
published in vitro data. Pimavanserin also produced a significant
attenuation of risperidone-induced catalepsy, however, at doses as
low as 1 mg/kg. The apparent shift in potency shown by pimavanserin
against risperidone-induced catalepsy is likely a function of the
excess of 5-HT.sub.2A antagonist expected to be present at doses of
risperidone that would presumably occupy >70% of striatal
D.sub.2 receptors. Therefore, in a system that is in far excess of
maximal 5-HT.sub.2A receptor occupancy, as would be expected with
these dose combinations, weaker 5-HT.sub.2C antagonist properties
of pimavanserin, and perhaps risperidone, are more likely to
manifest.
Example 6
Prolactin Levels During Co-Administration of Pimavanserin with
Risperidone
[0204] Prolactin levels were measured during a Phase II
schizophrenia co-therapy trial using pimavanserin in combination
with risperidone and compared to administration of risperidone
alone. As depicted in the FIG. 22 graph, patients in the co-therapy
arm with pimavanserin plus risperidone (2 mg) had significantly
lower prolactin levels after 42-days of treatment as compared to
patients in the risperidone (6 mg) plus placebo arm
(p=0.00001).
Example 7
Simulation of Pimavanserin and Risperidone Steady State Plasma
Concentrations and 5-HT2A and D2 Receptor Occupancy Following
Co-Administration
[0205] Plasma Concentration-Time Profile Following Oral
Administration of 20 mg of Pimavanserin Once Daily
[0206] Initial parameters for the simulation were obtained by
fitting mean plasma concentration-time data to a 1-compartment
model (first order input, no lag time and first order elimination).
Mean multiple-dose plasma concentration-time data following the
14.sup.th oral dose of 50 mg of pimavanserin were applied. Based on
the model, the pharmacokinetic parameters shown in Table 4 were
estimated.
TABLE-US-00004 TABLE 4 Pharmacokinetic parameters obtained by
fitting pimavanserin mean plasma concentration-time data (50 mg) to
1-compartment model. Pharmacokinetic parameter Estimate Absorption
rate constant (k01) (1/hr) 0.9197 Elimination rate constant (k10)
(1/hr) 0.0121 CL/F (L/hr) 6.4 Tmax (hr) 4.77 Cmax (ng/mL) 89.27 AUC
(0-24).sub.SS (hr*ng/mL) 1893.2
[0207] The pharmacokinetic parameters provided in Table 4 agreed
well with previous reported pharmacokinetic parameters obtained
following multiple oral doses of pimavanserin. One exception is the
oral clearance for which the estimated parameter is somewhat lower
compared to the previous reported value (25.2 L/hr).
[0208] The plasma concentration-time profile of pimavanserin
following oral administration of 20 mg of pimavanserin once daily
was simulated using the initial parameters provided in Table 5. The
simulated profile for pimavanserin administered alone are shown in
FIG. 23.
TABLE-US-00005 TABLE 5 Initial parameters used in simulation of
plasma concentration-time profile of pimavanserin following oral
administration of 20 mg of pimavanserin once daily. Parameter Value
V/F (mL) 2182727 K01 (1/hr) 0.9197 CL/F (mL/hr) 26411* *Calculated
using D/AUC.sub.(0-24)ss
[0209] Plasma Concentration-Time Profile Following Oral
Administration of 5 mg of Risperidone Once Daily
[0210] Initial parameters for the simulation were obtained by
fitting mean plasma concentration-time data to a 2-compartment
model (first order input, micro-constants, no lag time and first
order elimination). Mean plasma concentration-time data obtained
following administration of a single oral dose of 4 mg of
risperidone were applied. Based on the model, the pharmacokinetic
parameters shown in Table 6 were estimated.
TABLE-US-00006 TABLE 6 Pharmacokinetic parameters obtained by
fitting risperidone mean plasma concentration-time data to a
2-compartment model Pharmacokinetic parameter Estimate Absorption
rate constant 0.4403 (k01) (1/hr) Elimination rate constant 0.2393
(k10) (1/hr) Alpha (1/hr) 0.4314 Beta (1/hr) 0.0349 CL/F (L/hr)
14408.8 V2/F (mL) 157245.7 CLD2/F (mL/hr) 9885.5 Tmax (hr) 2.4 Cmax
(ng/mL) 25.8 AUC (hr*ng/mL) 277.6
[0211] The pharmacokinetic parameters provided in Table 6 agreed
reasonably well with previous reported pharmacokinetic parameters
for risperidone. However, the secondary parameters were poorly
estimated by the model as indicated by the coefficient of variation
of the parameters.
[0212] The plasma concentration-time profile of risperidone
following oral administration of 5 mg of risperidone once daily was
simulated using the initial parameters provided in Table 7. The
simulated profile for risperidone administered alone are shown in
FIG. 23.
TABLE-US-00007 TABLE 7 Initial parameters used in simulation of
plasma concentration-time profile of risperidone following oral
administration of 5 mg of risperidone once daily. Parameter Value
V1/F (mL) 60222 K01 (1/hr) 0.4403 CL/F (mL/hr) 14409 V2/F (mL)
157246 CLD2/F (mL/hr) 9886
[0213] Due to the shorter half-life of risperidone, 19.9 hr
compared to 57.3 for pimavanserin, fluctuations between peak and
trough plasma concentrations are seen to be higher for risperidone.
Steady state concentrations of pimavanserin are reached following
approximately 200 hr corresponding to 8 days. C.sub.min,SS and
C.sub.max,SS for pimavanserin are approximately 27.2 and 34.5 ng/1
mL, respectively. The steady state maximum concentrations are
reached approximately 4 hours post dosing.
[0214] Simulation of the Time Course of Serotonin 5-HT2A and
Dopamine D2 Receptor Occupancy from Plasma Pharmacokinetics of
Pimavanserin and Risperidone
[0215] The receptor occupancy (.PHI.,%) was calculated using
equation 1, .PHI.=(C.sub.R/C.sub.R+Kd)*100, where C.sub.R is the
concentration of unbound drug around the receptor (nM) and Kd is
the dissociation constant (nM).
[0216] C.sub.R is assumed to equal the unbound drug concentration
in plasma implying that equilibrium between plasma and brain is
fast and no active transport of the drug takes place during
distribution to the brain. C.sub.R may then be calculated using
equation 2, C.sub.R=f.sub.u*C.sub.pl(t), where f.sub.u is the free
fraction of drug in plasma and C.sub.pl(t) is the plasma
concentration at time t.
[0217] The 5HT2A and D2 receptor occupancies of pimavanserin and
risperidone were estimated using the parameters in Table 7 and the
C.sub.pl(t) obtained above.
TABLE-US-00008 TABLE 7 Unbound fraction in plasma and Kd of
pimavanserin and risperidone Kd (nM) f.sub.u 5HT2A D2 Pimavanserin
0.05 0.4 Risperidone 0.1 0.2 0.3
[0218] The receptor occupancy-time profile of pimavanserin (20
mg/24 hr) and risperidone (5 mg/24 hr) when administered separately
is shown in FIG. 24. Risperidone, which acts at both D2 and 5HT
receptors, achieved high occupancy at both receptors. Pimavanserin,
which has a longer half life than risperidone, showed less
variability in 5HT receptor occupancy.
[0219] Following the first oral dose of 20 mg of pimavanserin 71%
5HT2A receptor occupancy is achieved 5 hr post dosing (tmax). The
corresponding plasma concentration of pimavanserin (Cmax) is 8.6
ng/mL. Steady state 5HT2A receptor occupancies for pimavanserin
vary between 88 and 91%.
[0220] The calculated occupancy of 5HT2A and D2 receptors 2.4 hours
after the first oral dose of 5 mg of risperidone is 98% and 96%,
respectively. The corresponding plasma concentration of risperidone
is 32.3 ng/mL. The steady state D2 receptor occupancy of
risperidone ranges between 80% and 97%. Occupancy of the 5HT
receptor in steady state is between 86% and 98%. The corresponding
minimum and maximum steady state plasma concentrations of
risperidone are 4.9 ng/mL and 36.6 ng/mL.
[0221] The receptor occupancy-time profile of D2 and 5HT receptors
following combined therapy with pimavanserin and risperidone is
shown in FIG. 25. The pimavanserin dose was maintained at 20 mg
once daily as in FIG. 24, whereas the daily dose of risperidone has
been reduced to 1 mg once daily. The results indicate that D2
receptor occupancy significantly decreases as compared to the
higher dose of risperidone administered alone (see FIG. 24) while
the 5HT receptor occupancy is maintained at high level. These
results support that the combination can lead to a lower incidence
of D2 related side effects without affecting 5HT associated
efficacy.
[0222] The D2 receptor occupancy was calculated using equation 1.
The 5HT receptor occupancy was calculated using equation 3:
.PHI.=(C.sub.R1/(C.sub.R1+Kd.sub.5HT,1(1+C.sub.R2/Kd.sub.5HT,2))+(C.sub.R-
2/(C.sub.R2+Kd.sub.5HT,2(1+C.sub.R1/Kd.sub.5HT,1)))*100, where
C.sub.R1, C.sub.R2, Kd.sub.5HT,1, Kd.sub.5HT,2 is the unbound
concentration of pimavanserin, unbound concentration of
risperidone, dissociation constant of pimavanserin for 5HT2A
receptor and dissociation constant of risperidone for 5HT2A,
respectively.
[0223] Several other doses of risperidone were also evaluated. The
D2 and 5HT receptor occupancy-time profiles following therapy with
3 mg twice daily of risperidone alone is shown in FIG. 26A. The D2
and 5HT receptor occupancy-time profiles following combined therapy
with pimavanserin and risperidone is shown in FIG. 26B. The
pimavanserin dose was maintained at 20 mg daily, and the
risperidone dose was maintained at 3 mg twice daily. The
contribution from paliperidone to the receptor profiles was not
taken into account. FIGS. 26A and 26B illustrate that receptor
occupancy of 5HT was enhanced with combined pimavanserin and
risperidone therapy versus risperidone therapy alone when dosing at
3 mg twice daily. Notably, due to the long action of the low
half-life pimavanserin, the variation in 5HT receptor occupancy
decreased in the combination. The receptor occupancy of D2 remained
substantially unchanged.
[0224] The D2 and 5HT receptor occupancy-time profiles for
paliperidone (a metabolite of risperidone) following therapy with
risperidone alone at 3 mg twice daily is shown in FIG. 27A. The
risperidone dose was maintained at 3 mg twice daily. The D2 and 5HT
receptor occupancy-time profiles for paliperidone following
combined therapy with pimavanserin and risperidone is shown in FIG.
27B. The pimavanserin dose was maintained at 20 mg daily, and the
risperidone dose was maintained at 3 mg twice daily. The
contribution from risperdone to the receptor profiles was not taken
into account. FIGS. 27A and 27B further illustrate that receptor
occupancy of 5HT was slightly enhanced with combined pimavanserin
and risperidone therapy versus risperidone therapy alone when
dosing at 3 mg twice daily. The receptor occupancy of D2 remained
substantially unchanged.
[0225] The D2 and 5HT receptor occupancy-time profiles following
therapy with risperidone with 3 mg twice daily taking into
consideration both risperidone and paliperidone is shown in FIG.
28A. The D2 and 5HT receptor occupancy-time profiles following
combined therapy with pimavanserin and risperidone is shown in FIG.
28B. The pimavanserin dose was maintained at 20 mg daily and the
risperidone dose was maintained at 3 mg twice daily. FIGS. 28A and
28B further illustrate that receptor occupancy of 5HT was slightly
enhanced with combined pimavanserin and risperidone therapy versus
risperidone therapy alone when dosing at 3 mg twice daily. The
receptor occupancy of D2 remained substantially unchanged.
[0226] The D2 and 5HT receptor occupancy-time profiles following
therapy with 1 mg twice daily of risperidone alone is shown in FIG.
29A. The D2 and 5HT receptor occupancy-time profiles following
combined therapy with pimavanserin and risperidone is shown in FIG.
29B. The pimavanserin dose was maintained at 20 mg daily and the
risperidone dose was maintained at 1 mg twice daily. For FIGS. 29A
and 29B, the contribution from paliperidone to the receptor
profiles was not taken into account. FIGS. 29A and 29B illustrate
that receptor occupancy of 5HT was significantly enhanced with
combined pimavanserin and risperidone therapy versus risperidone
therapy alone at 1 mg twice daily dosing. The variation in 5HT
receptor occupancy decreased substantially in the combination,
demonstrating the beneficial effect of combining the long acting
pimavanserin with the short acting risperidone. The receptor
occupancy of D2 remained substantially unchanged. Comparison with
FIG. 26B (illustrating a 3 mg twice daily dose of risperidone)
illustrates a more significant enhancement in 5HT receptor
occupancy with a decreased D2 receptor occupancy.
[0227] The D2 and 5HT receptor occupancy-time profiles for
paliperidone following therapy with 1 mg twice daily risperidone
alone is shown in FIG. 30A. The D2 and 5HT receptor occupancy-time
profiles for paliperidone following combined therapy with
pimavanserin and risperidone is shown in FIG. 30B. The pimavanserin
dose was maintained at 20 mg daily and the risperidone dose was
maintained at 1 mg twice daily. For FIGS. 30A and 30B, the
contribution from risperdone to the receptor profiles was not taken
into account. FIGS. 30A and 30B illustrate that receptor occupancy
of 5HT was significantly enhanced with combined pimavanserin and
risperidone therapy versus risperidone therapy alone at 1 mg twice
daily dosing. A decrease in 5HT receptor occupancy variation was
also observed in the combination. The receptor occupancy of D2
remains substantially unchanged. Comparison with FIG. 27B
(illustrating a 3 mg twice daily dose of risperidone) illustrates a
more significant enhancement in 5HT receptor occupancy with a
decreased D2 receptor occupancy.
[0228] The D2 and 5HT receptor occupancy-time profiles following
therapy with 1 mg twice daily taking both risperidone and
paliperidone into account is shown in FIG. 31A. The D2 and 5HT
receptor occupancy-time profiles following combined therapy with
pimavanserin and risperidone is shown in FIG. 31B. The pimavanserin
dose was maintained at 20 mg daily and the risperidone dose was
maintained at 1 mg twice daily. FIGS. 31A and 31B illustrate that
receptor occupancy of 5HT was significantly enhanced with combined
pimavanserin and risperidone therapy versus risperidone therapy
alone at 1 mg twice daily dosing. A decrease in 5HT receptor
occupancy variation was also observed in the combination. The
receptor occupancy of D2 remained substantially unchanged.
Comparison with FIG. 28B (illustrating a 3 mg twice daily dose of
risperidone) illustrates a more significant enhancement in 5HT
receptor occupancy with a decreased D2 receptor occupancy.
[0229] Taken together, FIGS. 24-31B demonstrate that combinations
of pimavanserin and low doses of risperidone can result in an
enhancement of the receptor occupancy of the 5HT2A receptor
compared with low dose risperidone therapy alone and achieve a
lower D2 receptor occupancy due to the lower dose of risperidone.
Thus, a combined therapy with pimavanserin and risperidone can
increase the efficacy of anti-psychotic treatment without
increasing side effects due to D2 receptor occupancy. Furthermore,
the results demonstrate that combining the long acting drug
pimavanserin with the short acting drug risperidone results in
significantly less variability in 5-HT2A receptor occupancy,
allowing the high levels of occupancy to be maintained between
dosings.
[0230] Although the invention has been described with reference to
embodiments and examples, it should be understood that numerous and
various modifications can be made without departing from the spirit
of the invention. Accordingly, the invention is limited only by the
following claims.
* * * * *