ANTIPSYCHOTIC DRUG-INDUCED DYSKINESIAS

抗精神病药物引起的运动障碍

• 批准号: 3564445
• 负责人: DANIEL E CASEY
• 金额: $ 21.83万
• 依托单位: OREGON REGIONAL PRIMATE RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3564445
• 关键词: Ceboidea; MAO inhibitors; Parkinson's disease; SCH 23390; adrenergic agents; antiadrenergic agents; apomorphine; blood chemistry; bromocriptine; cholinesterase inhibitors; chordate locomotion; clozapine; combination chemotherapy; dextroamphetamine; dopamine receptor; dosage; drug administration rate /duration; drug adverse effect; drug tolerance; ethology; extrapyramidal disorder; haloperidol; longitudinal animal study; neuropharmacology; nonhuman therapy evaluation; pergolide; tardive dyskinesia; tranquilizer

Neuroleptic drugs are highly efficacious agents in controlling symptoms of schizophrenia and other psychoses, but have undesirable early and late neurological side effects which are poorly understood. Reversible acute extrapyramidal syndromes (EPS) of acute dystonia and parkinsonism occur in up to 95% of patients and are one of the major reasons why schizophrenics discontinue their medication and suffer a psychotic relapse. Tardive dyskinesia (TD), a potentially irreversible syndrome of involuntary movements, may develop in 20% of patients (and up to 50% of high risk elderly). Unfortunately, we are not able to predict who is at risk for these side effects. The pathophysiology of acute EPS and TD is believed to involve dopamine (DA) receptor blockade with early EPS due to reduced DA influences and TD due to overactive DA processes. The specific roles of DA receptor subtypes (D1 D2), serotonin and norepinephrine, are minimally understood. Many new compounds which are potentially antipsychotic offer the opportunity to more precisely study the mechanisms of actions of these drugs and to evaluate their potential for improving the antipsychotic efficacy and reducing the neurological side effect risks. Research in a nonhuman primate model with studies that parallel clinical treatment issues in both the short term and long term can provide both practical and heuristic data. The acute EPS studies will evaluate the contribution of specific drugs which affect D1 and D2 receptor subtypes, investigate their interactions, and assess the prevention/aggravation potentials of new antipsychotic drugs with serotonin antagonist properties. Clozapine, a novel antipsychotic drug, will also be evaluated to identify its mechanism of action and potential side effects. The long-term TD studies will examine the effect of continuous and interrupted haloperidol. The central issues are: 1) individual vulnerability, and 2) time course for developing acute EPS, DA receptor hypersensitivity, and TD during these distinct treatment regimes. Behavioral changes will be assessed by perturbations in DA function with DA agonists (apomorphine, amphetamine, bromocriptine, pergolide, and SKF 38393) and antagonists (haloperidol, SCH 23390) before, during, and after haloperidol.

神经摄影药是控制的高效药物 精神分裂症和其他精神病的症状，但有不良的症状 早期和晚期神经副作用很差 理解。 可逆的急性急性肌锥虫综合征（EPS） 急性肌张力障碍和帕金森氏症发生在多达95％的患者中， 是精神分裂症患者中断他们的主要原因之一 药物治疗并遭受精神病的复发。 迟发性运动障碍 （TD），一种潜在的非自愿运动综合征， 20％的患者可能会出现（高风险的50％ 老年）。 不幸的是，我们无法预测谁处于危险之中 对于这些副作用。 据信，急性EPS和TD的病理生理涉及 由于DA的减少，多巴胺（DA）受体阻滞了早期EPS 由于过度活跃的DA过程而引起的影响和TD。 具体 DA受体亚型（D1 D2），5-羟色胺和 去甲肾上腺素，最少了解。 许多新化合物 潜在的抗精神病药提供了更多机会 精确研究这些药物的作用机制和 评估它们提高抗精神病药能力的潜力 并降低神经副作用的风险。 研究 非人类灵长类动物模型与临床平行的研究 短期和长期的治疗问题都可以提供 实用和启发式数据。 急性EPS研究将评估特定的贡献 影响D1和D2受体亚型的药物，研究其 相互作用，并评估预防/加重潜力 具有5-羟色胺拮抗剂特性的新抗精神病药。 氯氮平是一种新型抗精神病药，也将评估为 确定其作用机理和潜在的副作用。 长期TD研究将研究连续和 中断的氟哌啶醇。 中心问题是：1）个人 脆弱性和2）开发急性EPS的时间课程，DA 在这些独特的处理过程中，受体超敏反应和TD 政权。 行为改变将通过扰动评估 DA激动剂的DA功能（Apomorphine，苯丙胺， Bromocriptine，Pergolide和SKF 38393）和拮抗剂 （Haloperidol，SCH 23390）在氟哌啶醇之前，之中和之后。