Rundfeldt C, Hönack D, Löscher W
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, F.R.G.
Neuropharmacology. 1990 Sep;29(9):845-51. doi: 10.1016/0028-3908(90)90159-o.
Previous studies on the effects of phenytoin in the kindling model have yielded equivocal results, in that some groups reported anticonvulsant effects, while others found the drug to be only weakly active, inactive or even proconvulsant. Although part of these discrepancies might relate to factors such as the time of testing, route of administration, doses and administration vehicles, variable results were also obtained by studies in which these factors were comparable. For further investigation of the reasons of the reported discrepancies in the effectiveness of phenytoin in kindled rats, the influence of current intensity on the effects of phenytoin were examined in this model. In fully amygdala-kindled rats, phenytoin was only weakly active against seizures evoked by a fixed suprathreshold current of 500 microA. However, when the current was decreased to 250 microA, phenytoin exerted potent anticonvulsant effects. Determination of the threshold for focal afterdischarges showed that phenytoin, 12.5-75 mg/kg dose-dependently increased the threshold up to about 600% over controls at 75 mg/kg. Average levels in plasma, determined at this dose were about 30 micrograms/ml. In contrast to the potent effect on the seizure threshold, the severity or duration of seizures, evoked in phenytoin-pretreated rats by increasing the current, was not reduced. These data indicate that the primary effect of phenytoin in kindled rats in an increase in focal seizure threshold, while the ability of phenytoin to reduce the spread of seizures appears to be small. The present data might explain the discrepancy in reports on phenytoin in kindled rats, because most studies which found the drug to be ineffective used current intensities far exceeding the seizure threshold.
先前关于苯妥英在点燃模型中作用的研究结果并不明确，因为一些研究小组报告了抗惊厥作用，而另一些则发现该药物活性较弱、无活性甚至有促惊厥作用。尽管这些差异部分可能与测试时间、给药途径、剂量和给药载体等因素有关，但在这些因素可比的研究中也得到了不同的结果。为了进一步研究报道的苯妥英在点燃大鼠中有效性差异的原因，在该模型中研究了电流强度对苯妥英作用的影响。在完全杏仁核点燃的大鼠中，苯妥英对由500微安固定阈上电流诱发的癫痫发作仅有微弱活性。然而，当电流降至250微安时，苯妥英发挥了强大的抗惊厥作用。局灶性后放电阈值的测定表明，12.5 - 75毫克/千克剂量的苯妥英可使阈值剂量依赖性增加，在75毫克/千克时比对照组高出约600%。该剂量下测定的血浆平均水平约为30微克/毫升。与对癫痫发作阈值的强大作用相反，增加电流在苯妥英预处理大鼠中诱发的癫痫发作严重程度或持续时间并未降低。这些数据表明，苯妥英在点燃大鼠中的主要作用是提高局灶性癫痫发作阈值，而苯妥英减少癫痫发作扩散的能力似乎很小。目前的数据可能解释了关于苯妥英在点燃大鼠中报道的差异，因为大多数发现该药物无效的研究使用的电流强度远远超过癫痫发作阈值。
