CAJ | 학술논문

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.
동랑탕감시당전항훈동병최강적단약,단유명현적불량반응.근거"항담감약적중추해담감능활성대소병불여기불량반응상평행"적가설,작자설계、합성료일계렬담잡쌍배순적최산지류화합물.기중유α-분기-α-배무기-α-간기을산갑지여N-갑기-3-담잡쌍배(3,3,1)임-9α-순적지교환반응제득적염산분배임지재동물모형상,등효항훈제량시,기불량반응교중추해담감능항훈동병약동랑탕감화지분니다위경.림상시험표명,지원자구복해약(매인2～4 mg)후,기예방훈차훈선적총유효솔현저고우안위제대조조화양성대조약지분니다조(구복매인25～50 mg).재전의치훈동증적지원자자신대조시험중,분배임지화지분니다도능현저감소선전인기적안전진도화위전도이상개변.재령일조자신대조적선전치훈동증인체시험중,분배임지화동랑탕감도능명현감소선전인기적위전활동이상,감소급성훈동병적Graybiel득분화억제시-전정-내이반응.분배임지매인2화4 mg적효용상당우동랑탕감매인0.3화0.6 mg적효용.재역감공훈병적비행학원중,분배임지(매인3 mg)명현축단습복공훈병소수적시간,병차재정약후기습복수평몰유명현하강.분배임지적불량반응주요시경도구간(발생솔9.7%)화경도사수(9.97%,부발생우훈차훈선시험중).분배임지시일개중추해담감능항훈동병신약,교지분니다화동랑탕감항훈효과경호,중추불량반응경저.
At present scopolamine is the most powerful single anti-motion 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 cholinolytic activity of anticholinergics may not be parallel completely to their side effects, a series of alicyclic amino alcohol esters were designed, synthesized and evaluated. One of the best compounds, phencynonate HCl, was obtained by transesteration of methyl α-phenyl-α-cyclopentyl-α-hydroxy acetate with N-methyl-3-azabicyclo(3,3,1)nonan-9α-ol. In animal models it was demonstrated that at equivalent anti-motion sickness dose the side effects of phencynonate were milder than those of two other central anticholinergic anti-motion sickness drugs scopolamine HBr and difenidol HCl. In clinical trials the overall effectiveness rates for prevention of seasickness and carsickness of phencynonate (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 effects of phencynonate and difenidol in reducing the changes in electronystagmus and electrogastrogram were statistically significant. In another self controlled rotation experiment, phencynonate (2-4 mg/person) and scopolamine (0.3-0.6 mg/person) showed significant anti-motion sickness effects in reducing the gastric electric cycles of electrogastrogram and the Graybiel scores of acute motion sickness and significant inhibitory effects on visual-vestibular interaction dose-dependently. The anti-motion sickness effects of phencynonate 2 and 4 mg were correspondent with those of scopolamine 0.3 and 0.6 mg, respectively. Student pilots with high susceptibility to airsickness were stimulated by Coriolis acceleration. The course of desensitization and habituation to airsickness training in phencynonate group (3 mg/person) was significantly shorter than that of placebo. There was no rebounding in sensitivity to Coriolis stimulation after discontinuing phencynonate, which was reported in case of scopolamine. The side effects of phencynonate HCl were mild dry mouth (9.7%) and drowsiness (9.97%). The incidence of drowsiness is significantly lower than that of difenidol. The side effect of drowsiness was only appeared in aboard ship and bus experiments, but not in PhaseⅠ trial in hospital or in laboratory rotation tests. The incidence of drowsiness of phencynonate was also lower than that of dramamine in aboard tank experiment. Phencynonate could effectively control the acute attack of vertigo, especially Meniere′s disease and positional vertigo. In animal models of Parkinson′s disease and parkinsonism, phencynonate showed morepotent antagonistic effects than clinical common used trihexyphendyl. In summary, phencynonate is a new central anticholinergic anti-motion sickness drug with higher efficacy and lower central inhibitory side effect than difenidol and scopolamine in prevention of motion sickness. Phencynonate HCl was approved on Dec 25,1993 by State Food and Drug Administration of China as a Class Ⅰ new drug for the prevention and treatment of motion sickness in the market in China.