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Biotech / Medical : ACADIA Pharmaceuticals Inc (ACAD) -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (414)	5/25/2007 11:49:15 AM
From: tuck	Respond to of 588

[ACP-103 Improves The Antipsychotic Efficacy And Side Effect Profile Of Haloperidol and Risperidone In Experimental Models] >>J Pharmacol Exp Ther. 2007 May 22; [Epub ahead of print] ACP-103, A 5HT2A Receptor Inverse Agonist, Improves The Antipsychotic Efficacy And Side Effect Profile Of Haloperidol and Risperidone In Experimental Models. Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW. ACADIA Pharmaceuticals. Dopamine D2 receptor antagonism contributes to the therapeutic action of antipsychotic drugs (APDs) but also produces undesirable side effects, including extrapyramidal motor deficits, cognitive dulling and prolactinemia. The introduction of atypical APDs was a significant advancement in the treatment of schizophrenia. While these agents are D2 receptor antagonists, they are also potent 5-HT2A receptor inverse agonists, a feature which may explain their improved efficacy and tolerability. Recently, we reported that ACP-103, a novel selective 5-HT2A receptor inverse agonist that fails to bind D2 receptors, is active in several models predictive of antipsychotic activity. Using ACP-103, we tested the hypothesis that combining high levels of 5-HT2A inverse agonism with low levels of D2 antagonism would result in a favorable interaction, such that antipsychotic efficacy could be achieved with reduced D2 receptor-related adverse effects. Here we show that ACP-103: (a) potently inhibited head-twitching produced by the 5-HT2A/2C receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine; (b) increased the potency of haloperidol against amphetamine-induced hyperactivity; (c) interacted synergistically with haloperidol or risperidone to suppress hyperactivity induced by the NMDA receptor antagonist MK-801 and, by contrast; (d) attenuated haloperidol- or risperidone-induced prolactinemia. ACP-103 also attenuated catalepsy produced by haloperidol or risperidone. However, the doses that were required for this effect were higher than would be expected for a 5-HT2A receptor mediated mechanism. These data indicate that utilizing ACP-103 as an adjunctive therapy to currently used APDs may result in enhanced antipsychotic efficacy while reducing adverse effects including those attributable to D2 receptor antagonism.<< Cheers, Tuck