Löscher W, Hönack D
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Eur J Pharmacol. 1993 Apr 6;234(2-3):237-45. doi: 10.1016/0014-2999(93)90959-l.
The effects of combined treatment with low doses (1-5 mg/kg i.p.) of the competitive NMDA receptor antagonist, CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. CGP 37849, 5 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 80 mg/kg i.p. However, the increase in anticonvulsant activity was parallelled by a marked increase in motor impairment, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, at doses of 2.5-5 mg/kg, CGP 37849 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. In non-kindled rats, combined treatment with CGP 37849 and valproate induced significantly less marked adverse effects than in kindled rats. The data on combined treatment with CGP 37849 and valproate substantiate that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events. Since kindling is thought to be a predictive model of complex partial seizures, these results suggest that competitive NMDA receptor antagonists such as CGP 37849 may be of limited usefulness against this seizure type in humans.
研究了低剂量（腹腔注射1 - 5毫克/千克）竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂CGP 37849（DL-[E]-2-氨基-4-甲基-5-膦酰基-3-戊烯酸）与抗癫痫药物丙戊酸盐联合治疗对杏仁核点燃和未点燃大鼠的影响。5毫克/千克的CGP 37849对完全点燃的大鼠没有抗惊厥作用，但增强了腹腔注射80毫克/千克丙戊酸盐的抗惊厥效力。然而，抗惊厥活性的增加伴随着运动障碍的显著增加，与单独使用丙戊酸盐相比，联合治疗的治疗指数大幅降低。此外，在2.5 - 5毫克/千克的剂量下，CGP 37849增强了50毫克/千克丙戊酸盐的不良反应，但没有增强其抗惊厥活性。在未点燃的大鼠中，CGP 37849和丙戊酸盐联合治疗引起的不良反应明显比点燃大鼠少。关于CGP 37849和丙戊酸盐联合治疗的数据证实，点燃改变了对NMDA受体介导事件操作的易感性。由于点燃被认为是复杂部分性癫痫的预测模型，这些结果表明，竞争性NMDA受体拮抗剂如CGP 37849对人类这种癫痫类型的作用可能有限。
