Combinations of 5-ht2a inverse agonists and antagonists with antipsychotics

a technology of inverse agonists and antagonists, applied in the field of chemistry and medicine, can solve the problems of reducing the effect of antipsychotics, reducing the effectiveness of antipsychotics, and reducing the effectiveness of antipsychotics, and achieve the effect of achieving effective effects

Inactive Publication Date: 2009-02-26
ACADIA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[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 ac

Problems solved by technology

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.
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).
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.
However, atypical agents also have the potential for serious side effects including increased risk of stroke, abnormal

Method used

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  • Combinations of 5-ht2a inverse agonists and antagonists with antipsychotics
  • Combinations of 5-ht2a inverse agonists and antagonists with antipsychotics
  • Combinations of 5-ht2a inverse agonists and antagonists with antipsychotics

Examples

Experimental program
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Effect test

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....

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 vehic...

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....

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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.

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-METHYLPROPYLOXY)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 s...

Claims

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Application Information

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IPC IPC(8): A61K33/00A61K31/445A61K31/519A61K31/438A61P25/18A61K31/497A61K31/54A61K31/55
CPCA61K31/00A61K31/4468A61K31/4515A61K31/519A61K31/5513A61K31/554A61K2300/00G16C20/50A61K31/435A61K31/451A61K31/454A61K31/496A61K33/00A61P25/06A61P25/18A61P25/20A61P25/22A61P25/24A61P43/00A61P7/02A61P9/00A61P9/10A61P9/12A61K45/06A61K49/0008
Inventor PETERS, PERRYFURLANO, DAVIDBAHR, DAUNVAN KAMMEN, DANIELBRANN, MARK
Owner ACADIA PHARMA INC
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