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). CONCLUSION: 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.

[1]  R. Macdonald,et al.  Etiology of cerebral vasospasm. , 1999, Acta neurochirurgica. Supplement.

[2]  K. Fassbender,et al.  Source of Endothelin-1 in Subarachnoid Hemorraghe , 2001, Clinical chemistry and laboratory medicine.

[3]  K. Kröncke,et al.  Nitric Oxide Inhibits Endothelial IL-1β-induced ICAM-1 Gene Expression at the Transcriptional Level Decreasing Sp1 and AP-1 Activity , 2001, Molecular medicine.

[4]  R. Tamargo,et al.  Prevention of cerebral vasospasm by a humanized anti-CD11/CD18 monoclonal antibody administered after experimental subarachnoid hemorrhage in nonhuman primates. , 2003, Journal of neurosurgery.

[5]  R. Macdonald,et al.  Mechanism of Cerebral Vasospasm Following Subarachnoid Hemorrhage in Monkeys , 1992, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[6]  M. Naruszewicz,et al.  Ibuprofen inhibits adhesiveness of monocytes to endothelium and reduces cellular oxidative stress in smokers and non‐smokers , 2000, European journal of clinical investigation.

[7]  R. Tamargo,et al.  Inhibition of experimental vasospasm in rats with the periadventitial administration of ibuprofen using controlled-release polymers. , 1999, Stroke.

[8]  R. Tamargo,et al.  High-dose ibuprofen for reduction of striatal infarcts during middle cerebral artery occlusion in rats. , 2003, Journal of neurosurgery.

[9]  S. Akopov,et al.  The endothelium-dependent relaxation of human middle cerebral artery: Effects of activated neutrophils , 1992, Experientia.

[10]  D. Harrison,et al.  Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. Mocco,et al.  Outcome prediction with serum intercellular adhesion molecule-1 levels after aneurysmal subarachnoid hemorrhage. , 2002, Journal of neurosurgery.

[12]  Henry Brem,et al.  Drug delivery to tumors of the central nervous system , 2001, Current neurology and neuroscience reports.

[13]  M. Hennerici,et al.  Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries , 2001, Journal of neurology, neurosurgery, and psychiatry.

[14]  M. Hennerici,et al.  Endothelin-1 in Subarachnoid Hemorrhage: An Acute-Phase Reactant Produced by Cerebrospinal Fluid Leukocytes , 2000, Stroke.

[15]  T. Springer,et al.  Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. , 1995, Annual review of physiology.

[16]  R. Tamargo,et al.  Endothelial cell expression of intercellular adhesion molecule 1 in experimental posthemorrhagic vasospasm. , 1997, Neurosurgery.

[17]  B. Weir,et al.  Effect of clot removal at 24 hours on chronic vasospasm after SAH in the primate model. , 1987, Journal of neurosurgery.

[18]  Betty M Tyler,et al.  The intracerebral administration of phenytoin using controlled-release polymers reduces experimental seizures in rats , 2002, Epilepsy Research.

[19]  T. Sundt,et al.  Prevention of chronic experimental cerebral vasospasm with ibuprofen and high-dose methylprednisolone. , 1983, Journal of neurosurgery.

[20]  A. Olivi,et al.  Local delivery of antineoplastic agents using biodegradable polymers for the treatment of malignant brain tumors , 2003, Expert review of neurotherapeutics.

[21]  R. Tamargo,et al.  Prevention of vasospasm by anti-CD11/CD18 monoclonal antibody therapy following subarachnoid hemorrhage in rabbits. , 2004, Journal of neurosurgery.

[22]  T. Shike,et al.  Animal models. , 2001, Contributions to nephrology.

[23]  James L. Frazier,et al.  Pharmacokinetics of controlled-release polymers in the subarachnoid space after subarachnoid hemorrhage in rabbits. , 2004, Journal of neurosurgery.

[24]  R. Tamargo,et al.  Brain biocompatibility of a biodegradable, controlled-release polymer in rats. , 1989, Journal of biomedical materials research.

[25]  R. J. Dumont,et al.  Cerebral Vasospasm after Subarachnoid Hemorrhage: Putative Role of Inflammation , 2003, Neurosurgery.

[26]  R. Sercombe,et al.  Cerebrovascular inflammation following subarachnoid hemorrhage. , 2002, Japanese journal of pharmacology.

[27]  J. M. Findlay,et al.  Safety and efficacy of intrathecal thrombolytic therapy in a primate model of cerebral vasospasm. , 1989, Neurosurgery.

[28]  R. Macdonald.  Chapter 11 – Animal Models , 2001 .

[29]  Grace H. Kim,et al.  Rise in serum soluble intercellular adhesion molecule-1 levels with vasospasm following aneurysmal subarachnoid hemorrhage. , 2002, Journal of neurosurgery.

[30]  E. Oldfield,et al.  Neuropeptide Y in the primate model of subarachnoid hemorrhage. , 1992, Journal of neurosurgery.

[31]  R. Tamargo,et al.  Inhibition of vasospasm with lymphocyte function-associated antigen-1 monoclonal antibody in a femoral artery model in rats. , 2002, Journal of neurosurgery.

[32]  Michael Loran Dustin,et al.  Primary structure of ICAM-1 demonstrates interaction between members of the immunoglobulin and integrin supergene families , 1988, Cell.

[33]  J. McIntyre,et al.  Vasospasm in response to repeated subarachnoid hemorrhages in the monkey. , 1970, Journal of neurosurgery.

[34]  R. Tamargo,et al.  Prevention and Reversal of Experimental Posthemorrhagic Vasospasm by the Periadventitial Administration of Nitric Oxide from a Controlled-release Polymer , 2001, Neurosurgery.

[35]  M. Shaffrey,et al.  Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage. , 1998, Journal of neurosurgery.

[36]  R J Tamargo,et al.  Inhibition of experimental vasospasm with anti-intercellular adhesion molecule-1 monoclonal antibody in rats. , 1997, Stroke.

[37]  R. Webster,et al.  Inhibition of human polymorphonuclear leukocyte functions by ibuprofen. , 1987, Immunopharmacology.

[38]  T. Hori,et al.  Quantitative Analysis of Gene Expressions Related to Inflammation in Canine Spastic Artery After Subarachnoid Hemorrhage , 2001, Stroke.

[39]  D. Long,et al.  Interstitial delivery of dexamethasone in the brain for the reduction of peritumoral edema. , 1991, Journal of neurosurgery.

[40]  B. Weir,et al.  Cerebral arterial responses to induced hypertension following subarachnoid hemorrhage in the monkey. , 1978, Journal of neurosurgery.

[41]  P. Valent,et al.  Ibuprofen inhibits pyrogen-dependent expression of VCAM-1 and ICAM-1 on human endothelial cells. , 1996, Life sciences.

[42]  R. Tamargo,et al.  Prevention of Experimental Cerebral Vasospasm by Intracranial Delivery of a Nitric Oxide Donor From a Controlled-Release Polymer: Toxicity and Efficacy Studies in Rabbits and Rats , 2002, Stroke.

[43]  A. Tsuchida,et al.  Expression of intercellular adhesion molecule 1 (ICAM-1) on the cerebral artery following subarachnoid haemorrhage in rats , 2005, Acta Neurochirurgica.

[44]  R. Baughman,et al.  Intrathecal Fibrinolytic Therapy after Subarachnoid Hemorrhage: Dosage Study in a Primate Model and Review of the Literature , 1989, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[45]  A. Arthur,et al.  Monoclonal antibodies against ICAM-1 and CD18 attenuate cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits. , 1998, Stroke.

[46]  J. M. Findlay,et al.  Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH. , 1988, Journal of neurosurgery.

[47]  R. Macdonald,et al.  Morphometric analysis of monkey cerebral arteries exposed in vivo to whole blood, oxyhemoglobin, methemoglobin, and bilirubin. , 1991, Blood vessels.

[48]  D. Chyatte.  Prevention of chronic cerebral vasospasm in dogs with ibuprofen and high-dose methylprednisolone. , 1989, Stroke.

[49]  Gustavo Pradilla,et al.  Inhibition of cerebral vasospasm by intracranial delivery of ibuprofen from a controlled-release polymer in a rabbit model of subarachnoid hemorrhage. , 2004, Journal of neurosurgery.