Prevention of cerebral vasospasm by nicardipine prolonged-release implants in dogs

The purpose of this study was to determine the efficacy of nicardipine prolonged-release implants for preventing vasospasm in a canine SAH model in a dose-escalating placebo-controlled blind fashion. Drug-release kinetics of copoly(lactic/glycolic acid) pellet containing nicardipine were evaluated in vitro. In vivo, 18 dogs were randomly assigned to one of three groups, i.e. placebo, low-dose (0.8 mg), or high-dose (8 mg) nicardipine. Angiography was performed, followed by right craniectomy, the induction of subarachnoid hemorrhage, and the placement of the pellets in the Sylvian fissure. On Day 7 and Day 14, the angiography was repeated. In the first four days, 61.9% of the actual nicardipine loaded was released and within 10 days, 96%. The average percent reductions of vessel diameters in the middle cerebral artery on Day 7 were 43%, 14% and 7% in the placebo, low-dose, and high-dose groups, respectively (p = 0.0319). The mean concentration of nicardipine in the clots on Day 14 was 9.7 x 10(-7) mol-1 l-1 and 5.1 x 10(-6) mol-1 l-1 in the low-dose and high-dose group, respectively. This drug delivery system prevented vasospasm in dogs significantly even at low dose, while maintaining an appropriate concentration of nicardipine in the clot adjacent to the arteries.