Inhibition of experimental vasospasm in rats with the periadventitial administration of ibuprofen using controlled-release polymers

Background and Purpose-The chronic phase of vasospasm after an aneurysmal s ubarachnoid hemorrhage may be mediated in part by early leukocyte-endotheli al cell interactions. Ibuprofen is an anti-inflammatory agent that inhibits expression of certain cell adhesion molecules and therefore disrupts leuko cyte-endothelial cell interactions. Its systemic administration, however, h as dose-limiting side effects. We evaluated the effect of the periadventiti al delivery of ibuprofen using controlled-release polymers in the rat femor al artery model of chronic posthemorrhagic vasospasm. Methods-Before the animal studies, the release pharmacokinetics of the ibup rofen-loaded ethylene-vinyl acetate polymers were determined in vitro. Subs equently, the femoral arteries (n=266) of Fischer 344 rats (n=133) were enc losed in latex pouches bilaterally. In the toxicity study (n=15 rats), the animals were randomized into 5 dose groups in which 0%-, 10%-, 20%-, 30%-, or 50%-loaded ibuprofen polymers were evaluated. In the efficacy study, the animals were randomized into 5 time groups in which 50%-loaded ibuprofan p olymers were inserted at 0 (n=58 rats), 6 (n=16), 12 (n=13), 24 (n=11), or 48 hours (n=12) after blood injection into the pouch. The rats were killed 12 days after blood exposure, at the time of maximal vasospasm in this mode l. Vasospasm was expressed as percent lumen patency. To evaluate the effect of ibuprofen on leukocyte migration, 8 rats were randomized into 2 groups. Macrophages and granulocytes were stained by immunohistochemistry with the use of a mouse OX-41 monoclonal antibody and counted in the periadventitia l space 24 hours after blood exposure. Results-In vitro pharmacokinetics showed that the 50%-loaded ibuprofen poly mer released its total drug load over a 12-day period. In the toxicity stud y, a nonsignificant arterial vasodilatation with ibuprofen treatment was se en at higher doses, and no deleterious effects were noted on the vessel wal l histologically. In the efficacy study, ibuprofen treatment resulted in si gnificant vasospasm inhibition when treatment was initiated at 0 hour (73.7 +/-4.9% versus 94.5+/-3.3% [mean+/-SEM percent lumen patency]; P<0.001) and 6 hours (69.2+/-5.7% versus 98.0+/-3.9%; P=0.002) after blood exposure, bu t not at 12, 24, or 48 hours. Leukocyte immunohistochemistry showed that ib uprofen treatment resulted in significantly lower periadventitial macrophag e and granulocyte counts of 25.0+/-3.9 cells per high-powered field compare d with counts of 140.5+/-18.2 cells per high-powered field in the untreated vessels (P<0.001). Conclusions-The periadventitial, controlled release of ibuprofen from surgi cally implanted polymers significantly inhibits chronic posthemorrhagic vas ospasm in this model when treatment is initiated within 6 hours of blood ex posure. Vasospasm inhibition with ibuprofen correlates with a significant d ecrease in the number of macrophages and granulocytes in the periadventitia l space. This study supports the hypothesis that inflammation mediates in p art the chronic phase of posthemorrhagic vasospasm and suggests a potential alternative treatment for this condition.