CLINICAL PHARMACOLOGY OF ANTIDEPRESSANTS AND ANTIMANIC DRUGS

抗抑郁药和抗躁狂药的临床药理学

• 批准号: 5203693
• 负责人: W Z POTTER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5203693
• 关键词: G protein; alpha antiadrenergic agent; antidepressants; antipsychotic agents; blood pressure; brain injury; brain metabolism; deoxyglucose; female; functional ability; gender difference; hippocampus; human subject; isozymes; laboratory rat; lithium; male; neuropharmacologic agent; neuropharmacology; norepinephrine; positron emission tomography; protein kinase C

a) We have continued to study effects of intravenous idazoxan, a selective alpha-2 antagonist in volunteers using paired FDG PET scans. Robust quantitative and/or qualitative effects of gender have been found: men show a higher catecholamine response whereas, in brain, with regard to metabolic response, men show decreases in frontal cortex and women show increases. b) While the central and peripheral responses we observe following acute idazoxan are consistent with central and peripheral alpha-2 blockade, idazoxan also interacts with the recently described "imidazoline rceptors." To determine whether imidazoline interactions are involved in the observed responses to idazoxan we initiated a set of parallel studies in volunteers with ethoxyidazoxan, a derivative of idazoxan that does not interact with imidazoline sites. We have completed a Phase I dose ranging study of ethoxyidazoxan in healthy males revealing a dose-dependent increase in norepinephrine and blood pressure in the same ranges as those seen with idazoxan. Brain imaging studies will follow. c) Chronic lithium in healthy volunteers has now been found to not only increase pertussis toxin stimulated ribosylation of G(i) in platelets but to decrease the alpha isozyme of protein kinase C, the latter finding consistent with lithium induced decreases in rat hippocampus. This adds to the growing body of evidence that in humans, chronic lithium exerts potent effects both at the level of PKC and G protein, effects which we postulate to be interrelated.

a) 我们继续研究静脉注射咪唑克生的效果，这是一种选择性的药物 使用配对 FDG PET 扫描对志愿者进行 α-2 拮抗剂检测。强壮的 已发现性别的数量和/或质量影响：男性 显示出较高的儿茶酚胺反应，而在大脑中， 代谢反应，男性额叶皮层减少，女性显示 增加。 b) 虽然我们观察到急性发作后的中枢和外周反应 咪唑克生与中枢和外周 α-2 阻断作用一致， 咪唑克生还与 最近描述了“咪唑啉受体”。判断是否 咪唑啉相互作用涉及观察到的反应 我们在志愿者中发起了一系列平行研究 乙氧基达唑生，达唑克生的衍生物，不与 咪唑啉位点。我们已经完成了 I 期剂量范围研究 乙氧基咪唑嗪在健康男性中显示出剂量依赖性增加 去甲肾上腺素和血压与观察到的范围相同 咪唑克生。随后将进行脑成像研究。 c) 现在发现健康志愿者长期摄入锂不仅会 增加百日咳毒素刺激血小板中 G(i) 的核糖基化，但 减少蛋白激酶 C 的 α 同工酶，后者发现 与锂引起的大鼠海马体减少一致。这增加了 越来越多的证据表明，长期服用锂对人类具有强大的作用 在 PKC 和 G 蛋白水平上都有影响，我们假设的影响 是相互关联的。