摘要
东莨菪碱是当前抗晕动病最强的单药,但有明显的不良反应.根据'抗胆碱药的中枢解胆碱能活性大小并不与其不良反应相平行'的假设,作者设计、合成了一系列氮杂双环醇的羧酸酯类化合物.其中由α-苯基-α-环戊基-α-羟基乙酸甲酯与N-甲基-3-氮杂双环(3,3,1)壬-9α-醇的酯交换反应制得的盐酸苯环壬酯在动物模型上,等效抗晕剂量时,其不良反应较中枢解胆碱能抗晕动病药东莨菪碱和地芬尼多为轻.临床试验表明,志愿者口服该药(每人2～4 mg)后,其预防晕车晕船的总有效率显著高于安慰剂对照组和阳性对照药地芬尼多组(口服每人25～50 mg).在转椅致晕动症的志愿者自身对照试验中,苯环壬酯和地芬尼多都能显著减少旋转引起的眼电震图和胃电图异常改变.在另一组自身对照的旋转致晕动症人体试验中,苯环壬酯和东莨菪碱都能明显减少旋转引起的胃电活动异常,减少急性晕动病的Graybiel得分和抑制视-前庭-内耳反应.苯环壬酯每人2和4 mg的效用相当于东莨菪碱每人0.3和0.6 mg的效用.在易感空晕病的飞行学员中,苯环壬酯(每人3 mg)明显缩短习服空晕病所需的时间,并且在停药后其习服水平没有明显下降.苯环壬酯的不良反应主要是轻度口干(发生率9.7%)和轻度思睡(9.97%,仅发生于晕车晕船试验中).苯环壬酯是一个中枢解胆碱能抗晕动病新药,较地芬尼多和东莨菪碱抗晕效果更好,中枢不良反应更低.
At present scopolamine is the most powerful single antimotion sickness drug, but with prominent unwanted side effects. Many attempts had been made to decrease the unwanted side effects, but no any approach was considered to be successful. Based on our working hypothesis that central ebolinolytic activity of antieholinergies may not be parallel completely to their side effects, a series of alievelie amino alcohol esters were designed, synthesized and evaluated. One of the best compounds, pheneynonate HC1, was obtained by transesteration of methyl α-phenyl-α-eyclopentyl-α-hydmxy acetate with N-methyl-3-azabieyelo（3,3,1 ） nonan-9α-ol. In animal models it was demonstrated that at equivalent anti-motion sickness dose the side effects of pheneynonate were milder than those of two other central antieholinergie anti-motion sickness drugs scopolamine HBr and difenidol HC1. In clinical trials the overall effectiveness rates for prevention of seasickness and carsickness of pheneynonate （oral 2 - 4 mg/person） was very significantly higher than that of placebo, and also significantly higher than that of difenidol （ oral 25 - 50 mg/person）. In self controlled rotatory chair experiments in hospital laboratory, the preventive effeets of pheneynonate and difenidol in redueing the ehanges in eleetronystagmus and electrogastrogram were statistieally significant. In another self eontrolled rotation experiment, pheneynonate （2 - 4 mg/person） and scopolamine （0.3 - 0.6 mg/ person） showed signifieant anti-motion sickness effeets in redueing the gastrie eleetrie cyeles of eleetrogastrogram and the Graybiel scores of aeute motion siekness and significant inhibitory effects on visual-vestibular interaetion dose-dependently. The anti-motion siekness effects of pheneynonate 2 and 4 mg were correspondent with those of scopolamine 0.3 and 0.6 rag, respectively. Student pilots with high susceptibility to airsiekness were stimulated by Corlolis acceleration. The course, of desensitization and habituation to airsick- ness training in pheneynonate group （3 mg/person） was significantly shorter than that of plaeebo. There was no rebounding in sensitivity to Coriohs stimulation after discontinuing pheneynonate, whieh was reported in ease of scopolamine. The side effeets of pheneynonate HC1 were mild dry mouth （9.7%） and drowsiness （9.97%）. The ineidenee of drowsiness is signifieantly lower than that of difenidol. The side effeet of drowsiness was only appeared in aboard ship and bus experiments, but not in Phase Ⅰ trial in hospital or in laboratory rotation tests. The ineidenee of drowsiness of pheneynonate was also lower than that of dramamine in aboard tank experiment. Pheneynonate eould effectively control the aeute attack of vertigo, especially Meniere＇s disease and positional vertigo. In animal models of Parkinson＇s disease and parkinsonism, pheneynonate showed more potent antagonistic effects than clinical common used trihexyphendyl. In summary, pheneynonate is a new eentral antieholinergie anti-motion sickness drag with higher efficacy and lower central inhibitory. side effect than difenidol and scopolamine in prevention of motion sickness. Pheneynonate HCl was appruved on Dec 25, 1993 by State Food and Drug Administration of China a a Class Ⅰ new drug for the prevention and treatment of motion siekness in the market in China.
出处
《中国药理学与毒理学杂志》
CAS
CSCD
北大核心
2005年第4期311-320,共10页
Chinese Journal of Pharmacology and Toxicology
关键词
抗胆碱药
苯环壬酯
晕动病
nholinergic antagonists
phencynonate
motion sickness
