Prevention of cerebral vasospasm by nicardipine prolonged-release implantsin dogs

The purpose of this study was to determine the efficacy of nicardipine prol onged-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 (8mg) nicardipine. Angiography was performed followed Dy right craniectomy, the induction of subarachnoid hemorrhage, and the placement of the pellets in the Sylvian fissure. On Da y 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 arte ry on Day 7 were 43%, 14% and 7% in the placebo, low-dose, and high-dose gr oups, respectively (p = 0.0319). The mean concentration of nicardipine in t he clots on Day 14 was 9.7x 10(-7) mol(-1) l(-1) and 5.1x10(-6) mol(-1) l(- 1) in the low-dose and high-dose group, respectively. This drug delivery sy stem prevented vasospasm in dogs significantly even at low dose, while main taining an appropriate concentration of nicardipine in the clot adjacent to the arteries.