Owen K, Hartley K, Tucker M L, Parkinson M M, Tweats D J, Jackson M R
Glaxo Research and Development Ltd, Park Road, Ware, Hertfordshire, UK.
Hum Exp Toxicol. 1995 Dec;14(12):959-73. doi: 10.1177/096032719501401205.
1 Sumatriptan is a potent and selective 5-HT1 receptor agonist marketed for the treatment of migraine by both oral and subcutaneous routes. An extensive toxicological programme employing high doses of sumatriptan was carried out in a range of animal species. The studies evaluated both the local and systemic tolerance to single and repeated dosing, effects on all stages of reproduction, as well as the genotoxic and oncogenic potential of sumatriptan. 2 The administration of relatively high single and repeated doses of sumatriptan was well tolerated by both rodents and dogs by the oral, subcutaneous and intravenous routes. Behavioural effects, suggestive of involvement of the central nervous system, were the most obvious result of such doses and were generally more pronounced in dogs than rodents. The reason for this may be related to the higher plasma concentrations of the drug achievable in dogs. Additional observations restricted to dogs, were transient, and included tachycardia, facial oedema and breaks in the continuity of secretion films on the corneal surface. A tendency for an increase in weight gain was seen for rats, while a slight decrease was usually seen for dogs. The only pathological changes related to treatment with high concentrations of sumatriptan consisted of local reactions at the site of subcutaneous administration. 3 Sumatriptan is an indole; the structures of this chemical class show varying propensities for nitrosation. However, appropriate testing with sumatriptan failed to identify any mutagenic nitroso compounds. 4 Sumatriptan was neither genotoxic nor oncogenic. 5 Reproductive studies demonstrated that sumatriptan was not teratogenic and had no effect on peri- and postnatal development. Some embryotoxicity was observed, but only at maternally toxic doses. A slight decrease in the success of insemination was also noted at high oral doses in rats. 6 Results of the toxicological programme performed in support of migraine therapy with sumatriptan provide good assurance of safety for subcutaneous and oral use.
1 舒马曲坦是一种强效且选择性的5-羟色胺1（5-HT1）受体激动剂，通过口服和皮下途径用于治疗偏头痛。在一系列动物物种中开展了一项使用高剂量舒马曲坦的广泛毒理学研究计划。这些研究评估了对单次和重复给药的局部和全身耐受性、对生殖各阶段的影响，以及舒马曲坦的遗传毒性和致癌潜力。2 啮齿动物和犬类通过口服、皮下和静脉途径给予相对高剂量的单次和重复剂量舒马曲坦后耐受性良好。提示中枢神经系统受累的行为影响是此类剂量最明显的结果，且在犬类中通常比啮齿动物更明显。其原因可能与犬类可达到的较高血浆药物浓度有关。仅限于犬类的其他观察结果是短暂的，包括心动过速、面部水肿和角膜表面分泌膜连续性中断。大鼠有体重增加的趋势，而犬类通常略有下降。与高浓度舒马曲坦治疗相关的唯一病理变化是皮下给药部位的局部反应。3 舒马曲坦是一种吲哚；这类化学结构显示出不同的亚硝化倾向。然而，对舒马曲坦进行的适当测试未能鉴定出任何诱变亚硝基化合物。4 舒马曲坦既无遗传毒性也无致癌性。5 生殖研究表明，舒马曲坦无致畸性，对围产期和产后发育无影响。观察到一些胚胎毒性，但仅在母体中毒剂量时出现。在大鼠中高口服剂量时还注意到受精成功率略有下降。6 为支持舒马曲坦用于偏头痛治疗而开展的毒理学研究结果为皮下和口服使用的安全性提供了有力保证。
