Local delivery of ibuprofen via controlled-release polymers prevents angiographic vasospasm in a monkey model of subarachnoid hemorrhage

Gustavo Pradilla, Quoc Anh Thai, Federico G. Legnani, Richard E. Clatterbuck, Philippe Gailloud, Kieran P. Murphy, Rafael J. Tamargo

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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 angiographie vasospasm after SAH in the monkey model. These findings support the role of cell adhesion molecules and inflammation in the pathophysiology of vasospasm.

Original languageEnglish
JournalNeurosurgery
Volume57
Issue number1 SUPPL.
DOIs
Publication statusPublished - Jul 2005

Fingerprint

Ibuprofen
Subarachnoid Hemorrhage
Haplorhini
Polymers
Subarachnoid Space
Macaca fascicularis
Cell Adhesion Molecules
Intercellular Adhesion Molecule-1
Cerebral Angiography
Middle Cerebral Artery
Ambulatory Surgical Procedures
ethylene
vinyl acetate
Leukocytes
Up-Regulation
Animal Models
Students
Inflammation

Keywords

  • Controlled release
  • Ibuprofen
  • Monkey
  • Polymer
  • Vasospasm

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

Local delivery of ibuprofen via controlled-release polymers prevents angiographic vasospasm in a monkey model of subarachnoid hemorrhage. / Pradilla, Gustavo; Thai, Quoc Anh; Legnani, Federico G.; Clatterbuck, Richard E.; Gailloud, Philippe; Murphy, Kieran P.; Tamargo, Rafael J.

In: Neurosurgery, Vol. 57, No. 1 SUPPL., 07.2005.

Research output: Contribution to journalArticle

Pradilla, Gustavo ; Thai, Quoc Anh ; Legnani, Federico G. ; Clatterbuck, Richard E. ; Gailloud, Philippe ; Murphy, Kieran P. ; Tamargo, Rafael J. / Local delivery of ibuprofen via controlled-release polymers prevents angiographic vasospasm in a monkey model of subarachnoid hemorrhage. In: Neurosurgery. 2005 ; Vol. 57, No. 1 SUPPL.
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abstract = "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 angiographie vasospasm after SAH in the monkey model. These findings support the role of cell adhesion molecules and inflammation in the pathophysiology of vasospasm.",
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AU - Pradilla, Gustavo

AU - Thai, Quoc Anh

AU - Legnani, Federico G.

AU - Clatterbuck, Richard E.

AU - Gailloud, Philippe

AU - Murphy, Kieran P.

AU - Tamargo, Rafael J.

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N2 - 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 angiographie vasospasm after SAH in the monkey model. These findings support the role of cell adhesion molecules and inflammation in the pathophysiology of vasospasm.

AB - 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 angiographie vasospasm after SAH in the monkey model. These findings support the role of cell adhesion molecules and inflammation in the pathophysiology of vasospasm.

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