Dematteis M, Lallement G, Mallaret M
Unité de Neuropharmacologie, CRSSA, La Tronche, France.
Fundam Clin Pharmacol. 1998;12(5):526-37. doi: 10.1111/j.1472-8206.1998.tb00982.x.
Dextromethorphan (DM), a widely used and well-tolerated centrally acting antitussive, has been tested in several clinical trials for its antiepileptic and neuroprotective properties. However, the use of DM in these new clinical indications requires higher doses than antitussive doses, which may therefore induce phencyclidine (PCP)-like side-effects (memory and psychotomimetic disturbances) through its metabolic conversion to the active metabolite dextrorphan (DX), a more potent PCP-like non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor than DM. Thus, we compared the behavioural effects in rats of intraperitoneal administration of DM and DX on motor activity in an open field and on learning and memory in the Morris water maze. DM (20, 30, 40 mg/kg) produced a dose-dependent decrease in both locomotion and stereotyped behaviour with a slight ataxia for the highest dose. DX (20, 30, 40 mg/kg) induced a dose-dependent increase in locomotion and stereotypies (swaying, turning) with moderate ataxia. Assessments of learning and memory were performed with lower doses of DM (10, 20, 30 mg/kg) and DX (5, 10, 15 mg/kg) because of motivational deficits (40 mg/kg of DM, 20-40 mg/kg of DX) and motor disorders (30, 40 mg/kg of DX) in the cue learning procedure. DX (10, 15 mg/kg) impaired spatial learning with a long-lasting effect for the highest dose whereas 5 mg/kg of DX and DM (10-30 mg/kg) did not. Only 15 mg/kg of DX appeared to slightly impair working memory. DM (10-30 mg/kg) and DX (5-15 mg/kg) did not impair reference memory. Thus, the two antitussives DM and DX induced different behavioural effects suggesting sedative effects for DM and PCP-like effects for DX. However, PCP-like side-effects with DM remain possible through its metabolic conversion to DX, with very high doses and/or in extensive metabolizers and/or in aged subjects prone to cognitive dysfunction. Therefore, the identification of DM metabolism phenotype, an adapted prescription and a pharmacological modulation of the DM metabolism may avoid adverse effects.
右美沙芬（DM）是一种广泛使用且耐受性良好的中枢性镇咳药，已在多项临床试验中对其抗癫痫和神经保护特性进行了测试。然而，在这些新的临床适应症中使用DM需要比镇咳剂量更高的剂量，因此，它可能通过代谢转化为活性代谢物右啡烷（DX）而诱发苯环己哌啶（PCP）样副作用（记忆和拟精神病性障碍），DX是一种比DM更有效的PCP样非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。因此，我们比较了腹腔注射DM和DX对大鼠在旷场中的运动活动以及在莫里斯水迷宫中的学习和记忆的行为影响。DM（20、30、40mg/kg）使运动和刻板行为呈剂量依赖性减少，最高剂量时伴有轻微共济失调。DX（20、30、40mg/kg）使运动和刻板行为（摇摆、转身）呈剂量依赖性增加，并伴有中度共济失调。由于在线索学习过程中存在动机缺陷（40mg/kg的DM，20 - 40mg/kg的DX）和运动障碍（30、40mg/kg的DX），因此使用较低剂量的DM（10、20、30mg/kg）和DX（5、10、15mg/kg）进行学习和记忆评估。DX（10、15mg/kg）损害空间学习，最高剂量时具有持久效应，而5mg/kg的DX和DM（10 - 30mg/kg）则没有。仅15mg/kg的DX似乎轻微损害工作记忆。DM（10 - 30mg/kg）和DX（5 - 15mg/kg）不损害参考记忆。因此，两种镇咳药DM和DX诱导了不同的行为效应，提示DM有镇静作用，DX有PCP样作用。然而，DM通过代谢转化为DX仍有可能产生PCP样副作用，尤其是在非常高的剂量和/或广泛代谢者和/或易患认知功能障碍的老年受试者中。因此，识别DM代谢表型、调整处方以及对DM代谢进行药理调节可能避免不良反应。
