Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

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

To: tuck who wrote (419)	5/31/2007 4:58:28 PM
From: tuck	Respond to of 588

[ACP-104: Partial agonist actions of N-desmethylclozapine at dopamine D(2L) receptors is modified by co-transfection of D(3) receptors: potential role of heterodimer formation] >>J Neurochem. 2007 May 26; [Epub ahead of print] Partial agonist actions of aripiprazole and the candidate antipsychotics S33592, bifeprunox, N-desmethylclozapine and preclamol at dopamine D(2L) receptors are modified by co-transfection of D(3) receptors: potential role of heterodimer formation. Novi F, Millan MJ, Corsini GU, Maggio R. Department of Neuroscience, University of Pisa, Pisa, Italy. Aripiprazole and the candidate antipsychotics, S33592, bifeprunox, N-desmethylclozapine (NDMC) and preclamol, are partial agonists at D(2) receptors. Herein, we examined their actions at D(2L) and D(3) receptors expressed separately or together in COS-7 cells. In D(2L) receptor-expressing cells co-transfected with (D(3) receptor-insensitive) chimeric adenylate cyclase-V/VI, drugs reduced forskolin-stimulated cAMP production by approximately 20% versus quinpirole (48%). Further, quinpirole-induced inhibition was blunted by aripiprazole and S33592, confirming partial agonist properties. In cells co-transfected with equal amounts of D(2L)and D(3) receptors (1 : 1), efficacies of aripiprazole and S33592 were attenuated. Further, in cells co-transfected with D(2L) and an excess of D(3) receptors (1 : 3), aripiprazole and S33592 were completely inactive, and they abolished the actions of quinpirole. Likewise, bifeprunox, NDMC and preclamol lost agonist properties in cells co-transfected with D(2L)and D(3) receptors. Accordingly, at split D(2trunk)/D(3tail) and D(3trunk)/D(2tail) chimeras, agonist actions of quinpirole were blocked by aripiprazole and S33592 that, like bifeprunox, NDMC and preclamol, were inactive alone. Conversely, when a 12 amino acid sequence in the third intracellular loop of D(3) receptors was replaced by the homologous sequence of D(2L) receptors, aripiprazole, S33592, bifeprunox, NDMC and preclamol inhibited cAMP formation by approximately 20% versus quinpirole (42%). Moreover, at D(2L) receptor-expressing cells co-transfected with modified D(3i3(D2)) receptors, drugs behaved as partial agonists. To summarize, low efficacy agonist actions of aripiprazole, S33592, bifeprunox, NDMC and preclamol at D(2L) receptors are abrogated upon co-expression of D(3) receptors, probably due to physical association and weakened coupling efficacy. These findings have implications for the functional profiles of antipsychotics.<< Parking. Not sure what significance, if any. Cheers, Tuck

To: tuck who wrote (419)	6/4/2008 12:54:46 PM
From: tuck	Respond to of 588

[Clozapine: more than 900 mg/day may be needed] >>J Psychopharmacol. 2008 May 30. [Epub ahead of print] Clozapine: more than 900 mg/day may be needed. Maccall C, Billcliff N, Igbrude W, Natynczuk S, Spencer EP, Flanagan RJ. The State Hospital, Carstairs, Lanark ML11 8RP, UK. Abstract Patients may fail to respond to clozapine treatment despite use of the maximum licensed UK dosage (900 mg/day) because of ultra-rapid metabolism of the drug. We present the findings of a study of a national clozapine/norclozapine assay service for the period 1997-2005 and three individual case studies of patients treated with clozapine in doses greater than 900ï¿(1/2)mg/day. Clinicians should be alert to the possibility of treatment failure because of rapid clozapine clearance secondary to genetic factors and heavy cigarette consumption. This may necessitate the use of clozapine in doses up to 1400 mg/day, notably in young male smokers. Doses of greater than 900 mg/day are rarely justified in women. Anyone given relatively high-dose clozapine (600 mg/day or more) should be monitored regularly for adverse events and changes in smoking habit.<< Cheers, Tuck