イヌ脳血管攣縮モデルにおけるニカルジピン徐放剤の有効性

Efficacy of Nicardipine Prolonged-release Pellet on Cerebral Vasospasm in Dogs

I．目的

　くも膜下出血に対して早期クリッピングが一般的になった今日，くも膜下出血後脳血管攣縮は予後を決定する大きな因子といえる．このため脳血管攣縮の治療法として様々な薬剤が用いられてきたが，この際，投与方法は有用性を論じる際に重要な要因となる．全身投与であれば効果は弱く，攣縮血管への動注では持続投与は出来ず，手技も繁雑となる．髄腔内投与の場合，効果は期待できるが，くも膜下出血術後，脳槽内にカテーテルを留置し，1-2週間持続して薬剤を投与し続けることは感染等，合併症の危険が大きく，術後管理に難渋することがしばしばである．そこで，われわれは髄腔内に留置できる徐放剤に注目した．

　これまで，われわれはパパベリン徐放剤を開発し，その有用性を報告してきたが^16），今回，髄腔内投与が臨床的に有効との報告がある^15）ニカルジピンを用いて徐放剤を開発し，これによる脳血管攣縮発生予防効果を，イヌくも膜下出血モデルを用いて検討した．本実験の有効性が明らかとなれば，その投与は手術中の1回で済み，本法は臨床的に有用な治療方法となる可能性が高いと考えられた．

A drug delivery system using copoly (lactic/glycolic acid) was developed for the intrathecal administra-tion of nicardipine. This system was tested to determine its efficacy in preventing cerebral vasospasm inclogs. A rod-shaped implant (1-mm diameter, 10-mm long, and which contained approximately 10% ofnicardipine) was prepared by a heat compression method. In in vitro studies, 8% of the actual nicardipineloaded was released during clay 1, 17% within day 2, 62% within clay 4, and 96% within day 10. In in visestudies, 12 clogs were assigned to two groups: the placebo group and the group treated with nicardipine. Angiography before the experiment was performed followed by right craniectomy and induction of subara-chnoid hemorrhage by the placement of a clot in the Sylvian fissure. Eight pellets, either containing 8 mgof nicardipine or without nicardipine were placed in the cistern. On day 7, the angiography was repeatedand cerebrospinal fluid was removed from the cisterna magna. The animals were then sacrificed, and thebrain and blood clot were taken out. Cerebral vessels were measured three times with a calibrated opticalmicrometer, and the mean value was obtained. Average reduction of vessel diameters on the clot side inthe placebo and nicardipine groups were -37% and -10% on the internal carotid (IC), -48% and -3%on the middle cerebral (MC), and -28% and -1% on the anterior cerebral artery (AC), respectively. Therewere significant differences in vessel diameters of IC (p＜0.05), MC (p＜0.005), and AC (p＜0.05) betweenthese groups. No vasospasm was found in the left side. The nicardipine concentration in the clot was deter-mined by high performance liquid chromatography. The mean concentration of nicardipine in the clot was1.5×10^-4M, at which concentration sufficient relaxation is evoked in vitro. The pellets did not last beyondclay 7. Regarding the histological findings, there was a marked difference in vessel diameters between theplacebo and the nicardipine treated groups. The arteries were surrounded with red blood cells and in-flammatory cells. There were no specific changes related to the pellets and no sign of meningoencephalitis.A prolonged-release preparation of nicardipine that can be implanted intracranially at the time of surgeryprevented vasospasm significantly in clogs. These results suggest that this new drug delivery system mightbe put into effect favorably in patients suffering from vasospasm clue to subarachnoid hemorrhage.