Sramek J J, Fresquet A, Marion-Landais G, Hourani J, Jhee S S, Martinez L, Jensen C M, Bolles K, Carrington A T, Cutler N R
California Clinical Trials, Beverly Hills, USA.
J Clin Psychopharmacol. 1996 Dec;16(6):454-8. doi: 10.1097/00004714-199612000-00009.
Lesopitron, a 5-hydroxytryptamine 1A agonist, is a new potential anxiolytic of the azapirone class. It has greater potency in animal models of anxiety than buspirone, gepirone, or ipsapirone, and it lacks the antidopaminergic effects associated with buspirone. Lesopitron has been tolerated at single doses up to 50 mg and repeated dosages of 45 mg/day in healthy volunteers. Forty-two patients with generalized anxiety disorder (GAD) were enrolled in this double-blind bridging study to determine the safety and tolerability of fixed doses of lesopitron (20, 25, 30, 40, 45, 50, and 60 mg two times a day) over a 6 1/2-day inpatient administration period. Each of the seven panels included six patients (four drug/two placebo). One patient in the 25-mg, two-times-a-day panel voluntarily withdrew because of increased anxiety symptoms. One patient experienced severe orthostatic hypotension at 60 mg two times a day, and moderate to severe adverse events (dizziness, lightheadedness, nausea, headache) occurred in two other patients at this dosage. The most commonly reported adverse events in all the panels were headache, dizziness, and nausea. Lesopitron is rapidly absorbed in patients, having a time to maximum concentration (Tmax) ranging from 0.5 to 1 hour, and its elimination half-life ranged from 1.1 to 5.6 hours. Peak plasma concentrations showed high interindividual variability for lesopitron, but increased linearly with dose for the main metabolite, 5-hydroxylesopitron. We defined the maximum tolerated dose in GAD patients as 50 mg two times a day, twice as high as the highest dose tested in healthy volunteers.
来索匹隆是一种5-羟色胺1A激动剂，是氮杂螺环癸烷类新型潜在抗焦虑药。在焦虑动物模型中，它比丁螺环酮、吉哌隆或伊沙匹隆效力更强，且没有丁螺环酮相关的抗多巴胺能效应。在健康志愿者中，来索匹隆单次剂量高达50毫克及每日重复剂量45毫克时均可耐受。42例广泛性焦虑障碍（GAD）患者参与了这项双盲衔接研究，以确定在6.5天的住院给药期内，固定剂量（每日两次，20、25、30、40、45、50和60毫克）来索匹隆的安全性和耐受性。七个小组每组包括6名患者（4名用药/2名用安慰剂）。每日两次服用25毫克小组中的1名患者因焦虑症状加重而自愿退出。1名患者每日两次服用60毫克时出现严重直立性低血压，另外2名患者在此剂量下出现中度至重度不良事件（头晕、眩晕、恶心、头痛）。所有小组中最常报告的不良事件是头痛、头晕和恶心。来索匹隆在患者体内吸收迅速，达峰时间（Tmax）为0.5至1小时，消除半衰期为1.1至5.6小时。来索匹隆的血浆峰浓度个体间差异很大，但主要代谢产物5-羟基来索匹隆的血浆峰浓度随剂量呈线性增加。我们将GAD患者的最大耐受剂量定义为每日两次50毫克，是在健康志愿者中测试的最高剂量的两倍。
