虚血脳に対するphenytoinの保護作用およびmannitol, vitamin Eとの併用効果

PROTECTIVE EFFECT OF PHENYTOIN AND ITS ENHANCED ACTION BY COMBINED ADMINISTRATION OF MANNITOL AND VITAMIN E IN CEREBRAL ISCHEMIA

　抄録　抗けいれん剤として広く用いられているphenytoinに脳保護作用があることに着目し，その効果と既報しているradical scavengerとの併用による効果を実験的に検討した。実験モデルとしては既報の"完全虚血脳灌流モデル犬"を用いて，薬剤の虚血前投与後，灌流血流量を正常時の10％に低下させた状態を1時間維持し，再び元の灌流量に戻してその後の脳波の回復，脳腫脹の程度およびEvans blueの漏出を観察することによって薬剤の効果を判定した。実験は無治療群5頭，phenytoin 7mg／kg投与群5頭，10mg／kg投与群5頭，30mg／kg投与群5頭およびphenytoin 10mg／kg, mannitol, vitamin E併用投与群5頭の計5群に分けて行なった。結果はphenytoinの投与量と用量依存性に血流再開後の脳波の回復は良好となり，脳腫脹およびEvans blueの漏出も軽減された。さらにradical scavengerであるmannitol，vitamin Eとの併用投与での脳波の回復は驚異的であり，脳腫脹およびEvans blueの漏出も有意に抑制された。

Phenytoin is well known as the anticonvulsant agent and also said to protect the brain against ischemic damage. The purpose of the present experiment is to study the therapeutic effect of phenytoin on cerebral ischemia and comfirm whe-ther the effectiveness of phenytoin could be enhan-ced by combination of free radical scavengers such as mannitol and vitamin E.

In this experiment, twenty-five dogs were sub-jected to ischemia, using the "canine model of complete ischemic brain regulated with a perfusion method" in which it is possible to control the degree of blood flow to a cerebral hemisphere via a perfusion pump at will. Five animals served as untreated control, fifteen received treatment with phenytoin (7 mg/kg in five dogs, 10 mg/kg in five dogs and 30 mg/kg in five dogs) and five treated with 10 mg/kg phenytoin, 2 g/kg of mannitol and 30 mg/kg of vitamin E. These drugs were adminis-tered intravenously 20 minutes prior to the pro-duction of ischemia, when cerebral blood flow wasreduced to one-tenth its normal volume. After one hour, cerebral blood flow was restored and the recovery of electrical activity of the brain and the degree of brain swelling were observed for three hours.

With regard to the recovery of EEG, no reco-very of EEG was seen subsequent to recirculation except one dog in the control group. Whereas in the group treated with phenytoin, gradual emer-gence of slow wave was observed soon after re-circulation. The higher the administered dosage is, the better the degree of recovery of EEG was seen. Thus, the dose-related recovery of EEG was observed within the dose ranges tested. An in the group treated in combination with phenytoin, mannitol and vitamin E, remarkable recover of EEG was found. With regard to the degree of brain swelling, similar dose-related suppressive effect was seen in phenytoin treated group. Fur-thermore, in the combination therapy group, brain swelling was attenuated significantly.

Based on these results, it is clarified that pheny-toin has protective effect on cerebral ischemia and it shows the most remarkable effect when given together with radical scavengers such as mannitol and vitamin E.