Local delivery of ibuprofen via controlled-release polymers prevents angiographic vasospasm in a monkey model of subarachnoid hemorrhage.
OBJECTIVE
Adhesion and migration of leukocytes into the periadventitial space play a role in the pathophysiology of vasospasm after subarachnoid hemorrhage (SAH). Intercellular adhesion molecule-1 is a determinant cell adhesion molecule involved in this process. Ibuprofen has been shown to inhibit intercellular adhesion molecule-1 upregulation and prevent vasospasm in animal models of SAH. In this study, we report the toxicity and efficacy of locally delivered ibuprofen incorporated into controlled-release polymers to prevent vasospasm in a monkey model of SAH.


METHODS
Ibuprofen was incorporated into ethylene-vinyl acetate (EVAc) polymers at 45% loading (wt:wt). For the toxicity study, cynomolgus monkeys (n = 5) underwent surgical implantation of either blank/EVAc polymers (n = 3) or 45% ibuprofen/EVAc polymers (n = 2) in the subarachnoid space, were followed up for 13 weeks, and were killed for histopathological analysis. For the efficacy study, cynomolgus monkeys (n = 14) underwent cerebral angiography 7 days before and 7 days after surgery and SAH and were randomized to receive either a 45% ibuprofen/EVAc polymer (n = 7; mean dose of ibuprofen, 6 mg/kg) or blank EVAc polymers (n = 7) in the subarachnoid space. Angiographic vasospasm was determined by digital image analysis. Student's t test was used for analysis.


RESULTS
Animals implanted with ibuprofen polymers showed no signs of local or systemic toxicity. Animals treated with ibuprofen polymers had 91 +/- 9% lumen patency of the middle cerebral artery, compared with 53 +/- 11% of animals treated with blank/EVAc polymers (P < 0.001).


CONCLUSIONS
Ibuprofen polymers are safe and prevent angiographic vasospasm after SAH in the monkey model. These findings support the role of cell adhesion molecules and inflammation in the pathophysiology of vasospasm.
Department of Neurosurgery, The Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
Gustavo
G
Pradilla
Quoc-Anh
QA
Thai
Federico G
FG
Legnani
Richard E
RE
Clatterbuck
Philippe
P
Gailloud
Kieran P
KP
Murphy
Rafael J
RJ
Tamargo
D000818:Animals; D002533:Cerebral Angiography; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000009:adverse effects; D004195:Disease Models, Animal; D007052:Ibuprofen / Q000008:administration & dosage* / Q000009:adverse effects; D008252:Macaca fascicularis; D008297:Male; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000009:adverse effects; D011145:Polyvinyls; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000188:drug therapy*; D016896:Treatment Outcome; D020301:Vasospasm, Intracranial / Q000000981:diagnostic imaging / Q000209:etiology* / Q000517:prevention & control*
D003692:Delayed-Action Preparations; D014677:Pharmaceutical Vehicles; D011145:Polyvinyls; C016438:ethylenevinylacetate copolymer; D007052:Ibuprofen