Rupniak N M, Tye S J, Brazell C, Heald A, Iversen S D, Pagella P G
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.
J Neurol Sci. 1992 Feb;107(2):246-9. doi: 10.1016/0022-510x(92)90296-w.
Cholinergic replacement therapy for Alzheimer's disease using existing cholinesterase inhibitors is compromised by short duration, meagre benefits restricted to subgroups of patients, and peripheral toxicity. Heptyl physostigmine is a lipophilic carbamate derivative of physostigmine. In rhesus monkeys, heptyl physostigmine (0.2-0.9 mg/kg i.m.) fully reversed a scopolamine-induced cognitive impairment. Following oral administration in squirrel monkeys, heptyl physostigmine (8 mg/kg) induced long-lasting hypothermia (greater than or equal to 4 h), a centrally-mediated cholinergic effect. Erythrocyte acetylcholinesterase activity was inhibited by 86% at the time of peak hypothermia (180 min). Clinical trials with heptyl physostigmine will enable a more rigorous evaluation of cholinomimetic therapy for dementia.
使用现有胆碱酯酶抑制剂对阿尔茨海默病进行胆碱能替代疗法存在疗程短、益处有限且仅限于部分患者亚组以及外周毒性等问题。庚基毒扁豆碱是毒扁豆碱的一种亲脂性氨基甲酸酯衍生物。在恒河猴中，庚基毒扁豆碱（0.2 - 0.9毫克/千克，肌肉注射）可完全逆转东莨菪碱诱导的认知障碍。在松鼠猴口服给药后，庚基毒扁豆碱（8毫克/千克）可诱导持久的体温过低（大于或等于4小时），这是一种中枢介导的胆碱能效应。在体温过低峰值（180分钟）时，红细胞乙酰胆碱酯酶活性被抑制了86%。庚基毒扁豆碱的临床试验将能够更严格地评估用于痴呆症的拟胆碱能疗法。
