Wamil A W, Schmutz M, Portet C, Feldmann K F, McLean M J
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212.
Eur J Pharmacol. 1994 Dec 27;271(2-3):301-8. doi: 10.1016/0014-2999(94)90787-0.
The anticonvulsant compound oxcarbazepine and its principal 10-monohydroxy metabolite protected potently against electroshock-induced tonic hindlimb extension. Maximal plasma concentrations depended on dose and were reached < or = 1 h after an oral dose of oxcarbazepine and < 2 h after monohydroxy derivative. In mice, the ED50 was 14 mg/kg for oxcarbazepine and 20.5 mg/kg for the monohydroxy derivative, p.o. In rats, the ED50 was 13.5 mg/kg for oxcarbazepine and 17.0 mg/kg for monohydroxy derivative, p.o. This protective effect compared favorably with the efficacy of carbamazepine, phenytoin, phenobarbital and diazepam in the same test. As observed previously, valproate and ethosuximide were markedly less potent. The effect of oxcarbazepine and its monohydroxy derivative on sustained high frequency repetitive firing of sodium-dependent action potentials of mouse spinal cord neurons in cell culture was also examined using intracellular recording techniques. Both compounds reduced the percentage of neurons capable of sustained action potential firing in concentration-dependent manner. The EC50 for oxcarbazepine was 5 x 10(-8) M and that for monohydroxy derivative was 2 x 10(-8) M (P > 0.05 vs. oxcarbazepine). For comparison, the EC50 for carbamazepine was significantly higher (6 x 10(-7) M, P < 0.001 vs. oxcarbazepine and monohydroxy derivative). Limitation of firing by oxcarbazepine and the monohydroxy derivative depended on firing frequency and membrane potential and was enhanced by depolarization. Input resistance and resting membrane potential were not altered by either drug. The in vitro effect on action potential firing frequency occurred at concentrations below plasma levels of oxcarbazepine and monohydroxy derivative which protected animals against electroshock and were therapeutically effective in patients.(ABSTRACT TRUNCATED AT 250 WORDS)
抗惊厥化合物奥卡西平及其主要的10-单羟基代谢产物对电休克诱发的强直性后肢伸展具有强大的保护作用。最大血浆浓度取决于剂量，口服奥卡西平后1小时内或更短时间达到，单羟基衍生物则在2小时内达到。在小鼠中，奥卡西平的口服半数有效剂量（ED50）为14毫克/千克，单羟基衍生物为20.5毫克/千克。在大鼠中，奥卡西平的口服ED50为13.5毫克/千克，单羟基衍生物为17.0毫克/千克。在同一试验中，这种保护作用与卡马西平、苯妥英、苯巴比妥和地西泮的疗效相比具有优势。如先前观察到的，丙戊酸盐和乙琥胺的效力明显较低。还使用细胞内记录技术研究了奥卡西平及其单羟基衍生物对细胞培养中小鼠脊髓神经元钠依赖性动作电位持续高频重复发放的影响。两种化合物均以浓度依赖性方式降低能够持续动作电位发放的神经元百分比。奥卡西平的半数有效浓度（EC50）为5×10^(-8) M，单羟基衍生物为2×10^(-8) M（与奥卡西平相比，P>0.05）。相比之下，卡马西平的EC50显著更高（6×10^(-7) M，与奥卡西平和单羟基衍生物相比，P<0.001）。奥卡西平和单羟基衍生物对发放的限制取决于发放频率和膜电位，并因去极化而增强。两种药物均未改变输入电阻和静息膜电位。对动作电位发放频率的体外作用发生在低于奥卡西平和单羟基衍生物血浆水平的浓度下，这些浓度可保护动物免受电休克，并且对患者具有治疗效果。（摘要截短于250字）
