Inhibition of Experimental Vasospasm in Rats With the Periadventitial Administration of Ibuprofen Using Controlled-Release Polymers

Abstract

Background and Purpose-The chronic phase of vasospasm after an aneurysmal subarachnoid hemorrhage may be mediated in part by early leukocyte-endothelial cell interactions. Ibuprofen is an anti-inflammatory agent that inhibits expression of certain cell adhesion molecules and therefore disrupts leukocyte-endothelial cell interactions. Its systemic administration, however, has dose-limiting side effects. We evaluated the effect of the periadventitial delivery of ibuprofen using controlled-release polymers in the rat femoral artery model of chronic posthemorrhagic vasospasm. Methods-Before the animal studies, the release pharmacokinetics of the ibuprofen-loaded ethylene-vinyl acetate polymers were determined in vitro. Subsequently, the femoral arteries (nϭ266) of Fischer 344 rats (nϭ133) were enclosed in latex pouches bilaterally. In the toxicity study (nϭ15 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 polymers were inserted at 0 (nϭ58 rats), 6 (nϭ16), 12 (nϭ13), 24 (nϭ11), or 48 hours (nϭ12) after blood injection into the pouch. The rats were killed 12 days after blood exposure, at the time of maximal vasospasm in this model. 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 periadventitial space 24 hours after blood exposure. Results-In vitro pharmacokinetics showed that the 50%-loaded ibuprofen polymer released its total drug load over a 12-day period. In the toxicity study, a nonsignificant arterial vasodilatation with ibuprofen treatment was seen at higher doses, and no deleterious effects were noted on the vessel wall histologically. In the efficacy study, ibuprofen treatment resulted in significant vasospasm inhibition when treatment was initiated at 0 hour (73.7Ϯ4.9% versus 94.5Ϯ3.3% [meanϮSEM percent lumen patency]; PϽ0.001) and 6 hours (69.2Ϯ5.7% versus 98.0Ϯ3.9%; Pϭ0.002) after blood exposure, but not at 12, 24, or 48 hours. Leukocyte immunohistochemistry showed that ibuprofen treatment resulted in significantly lower periadventitial macrophage and granulocyte counts of 25.0Ϯ3.9 cells per high-powered field compared with counts of 140.5Ϯ18.2 cells per high-powered field in the untreated vessels (PϽ0.001). Conclusions-The periadventitial, controlled release of ibuprofen from surgically implanted polymers significantly inhibits chronic posthemorrhagic vasospasm in this model when treatment is initiated within 6 hours of blood exposure. Vasospasm inhibition with ibuprofen correlates with a significant decrease in the number of macrophages and granulocytes in the periadventitial space. This study supports the hypothesis that inflammation mediates in part the chronic phase of posthemorrhagic va...

Haptoglobin 2-2 Genotype Determines Chronic Vasospasm After Experimental Subarachnoid Hemorrhage

“…5,7,8 In addition, the administration of ibuprofen, which decreases intercellular adhesion molecule-l expression, results in decreased macrophage/neutrophil transendothelial migration and subsequently less vasospasm. 4,6 Hp is a serum protein that limits the extent of inflammation following a hemorrhagic event. 18,19 After a hemorrhage, blood is extravasated into the interstitial space, leading to the breakdown of erythrocytes and subsequent release of Hgb.…”

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

“…Another smaller study concluded, on the basis of 50 patients given aspirin suppositories (100 mg) for 21 days after the surgery for aneurysm clipping (at 4 days maximum), that there could be some longterm benefit in the treatment, but a larger trial was necessary to demonstrate it. In experiments on femoral arteries, early application (at <6 h) of ibruprofen to the adventitia inhibited the VS probably by decreasing the periadventitial macrophage and granulocyte count (261). Older animal studies have also shown normalizing effects of ibuprofen and methylprednisolone on VS and CSF PG concentrations (262) and on vasoreactivity of cerebral arteries removed from animals subjected to SAH (263).…”

Inhibitory Effect With Antisense Mitogen-Activated Protein Kinase Oligodeoxynucleotide Against Cerebral Vasospasm in Rats

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