[Efficacy of nicardipine prolonged-release pellet on cerebral vasospasm in dogs]

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.