Kawashima A, Kasuya H, Shiokawa K, Miyajima M, Izawa M, Takakura K
Department of Neurosurgery, Tokyo Women's Medical College.
No Shinkei Geka. 1998 Jan;26(1):37-43.
A drug delivery system using copoly (lactic/glycolic acid) was developed for the intrathecal administration of nicardipine. This system was tested to determine its efficacy in preventing cerebral vasospasm in dogs. A rod-shaped implant (1-mm diameter, 10-mm long and which contained approximately 10% of nicardipine) was prepared by a heat compression method. In in vitro studies, 8% of the actual nicardipine loaded was released during day 1, 17% within day 2, 62% within day 4, and 96% within day 10. In in vivo studies, 12 dogs 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 subarachnoid hemorrhage by the placement of a clot in the Sylvian fissure. Eight pellets, either containing 8 mg of nicardipine or without nicardipine were placed in the cistern. On day 7, the angiography was repeated and cerebrospinal fluid was removed from the cisterna magna. The animals were then sacrificed, and the brain and blood clot were taken out. Cerebral vessels were measured three times with a calibrated optical micrometer, and the mean value was obtained. Average reduction of vessel diameters on the clot side in the 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. There were significant differences in vessel diameters of IC (p < 0.05), MC (p < 0.005), and AC (p < 0.05) between these groups. No vasospasm was found in the left side. The nicardipine concentration in the clot was determined by high performance liquid chromatography. The mean concentration of nicardipine in the clot was 1.5 x 10(-4)M, at which concentration sufficient relaxation is evoked in vitro. The pellets did not last beyond day 7. Regarding the histological findings, there was a marked difference in vessel diameters between the placebo and the nicardipine treated groups. The arteries were surrounded with red blood cells and inflammatory 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 surgery prevented vasospasm significantly in dogs. These results suggest that this new drug delivery system might be put into effect favorably in patients suffering from vasospasm due to subarachnoid hemorrhage.
开发了一种使用聚（乳酸/乙醇酸）共聚物的药物递送系统用于鞘内注射尼卡地平。对该系统进行了测试，以确定其预防犬脑血管痉挛的功效。通过热压法制备了棒状植入物（直径1毫米，长10毫米，含有约10%的尼卡地平）。在体外研究中，第1天释放了8%的实际负载尼卡地平，第2天内释放了17%，第4天内释放了62%，第10天内释放了96%。在体内研究中，12只犬被分为两组：安慰剂组和尼卡地平治疗组。实验前进行血管造影，随后进行右颅骨切除术，并通过在大脑外侧裂放置血凝块诱导蛛网膜下腔出血。将8个含8毫克尼卡地平或不含尼卡地平的微丸置于脑池中。在第7天，重复血管造影并从枕大池抽取脑脊液。然后处死动物，取出大脑和血凝块。用校准的光学测微计对脑血管测量3次，获得平均值。安慰剂组和尼卡地平组血凝块侧颈内动脉（IC）的血管直径平均减少分别为-37%和-10%，大脑中动脉（MC）为-48%和-3%，大脑前动脉（AC）为-28%和-1%。这些组之间IC（p<0.05）、MC（p<0.005）和AC（p<0.05）的血管直径存在显著差异。左侧未发现血管痉挛。通过高效液相色谱法测定血凝块中的尼卡地平浓度。血凝块中尼卡地平的平均浓度为1.5×10⁻⁴M，在此浓度下体外可引起充分的舒张。微丸在第7天后不再存在。关于组织学结果，安慰剂组和尼卡地平治疗组的血管直径存在明显差异。动脉周围有红细胞和炎性细胞。与微丸无关的特异性变化，也没有脑膜脑炎的迹象。一种可在手术时颅内植入的尼卡地平缓释制剂可显著预防犬的血管痉挛。这些结果表明，这种新的药物递送系统可能会在因蛛网膜下腔出血而发生血管痉挛的患者中良好生效。
