New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects |
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Authors: | L Peacock Jes Gerlach |
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Institution: | (1) Institute of Biological Psychiatry, St. Hans Hospital, DK-4000 Roskilde, Denmark Fax: +45-46334353, DK |
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Abstract: | Rationale: Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the
ratio EPS liability/antiamphetamine efficacy “therapeutic index” (TI)] has fit well with clinical results. Objectives: 1) To find the TIs of one new (quetiapine), three potential NNC 756 (dopamine (DA) D1 antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT2 serotonergic/DA D1 and D2 antagonist) and DOD 647 (DA D1 and D2 antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to
gain more insight as to clozapine’s neuropharmacology. Methods: Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing
doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine
producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI.
Results: Excepting clozapine and DOD 647, all drugs induced dystonia. At 2–4 mg/kg, clozapine caused uncoordinated movements, myoclonic
jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD
647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3–5 versus 4 for clozapine
and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic
doses.
Received: 31 October 1997/Final version: 9 November 1998 |
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Keywords: | Dopamine D1 antagonist Dopamine D2 antagonist Serotonin antagonist Adrenergic antagonist Clozapine Extrapyramidal side effects Monkey |
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