Document Detail

Prevention and reversal of experimental posthemorrhagic vasospasm by the periadventitial administration of nitric oxide from a controlled-release polymer.
MedLine Citation:
PMID:  11564257     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Despite improvements in the care of patients with aneurysmal subarachnoid hemorrhage, delayed cerebral vasospasm remains a major cause of morbidity and death. There is now evidence that a decrease in the local availability of nitric oxide (NO) plays a role in delayed cerebral vasospasm. We evaluated a controlled-release polymer containing the NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) for the treatment of chronic posthemorrhagic vasospasm in the rat femoral artery model. METHODS: The release kinetics of ethylene/vinyl acetate copolymers loaded with 20% (w/w) DETA/NO were determined in vitro. Chronic vasospasm was induced in the left femoral artery of adult male Fischer 344 rats (n = 35) by exposure to autologous blood. At 1, 3, or 7 days after blood exposure, either a 5-mg polymer loaded with 20% (w/w) DETA/NO or an empty 5-mg polymer was placed in the periadventitial space next to the left femoral artery. At the same time, an empty 5-mg polymer was placed next to the right femoral artery. On the 8th day after blood exposure (at the peak of vasospasm in this model), rats were transcardially perfused with 4% paraformaldehyde, and the left and right femoral arteries were removed for histological processing and morphometric analyses. Vasospasm was expressed as the percent lumen patency of the treated left artery, compared with the control right artery. RESULTS: The in vitro release kinetics demonstrated that the 20% DETA/NO-loaded polymers released up to 15% of their total drug load during a 9-day period. DETA/NO treatments initiated at 1, 3, or 7 days after blood deposition all significantly inhibited vasospasm, compared with control values (94.6 +/- 7.2% versus 67.6 +/- 5.8%, 104.6 +/- 5.5% versus 64.9 +/- 1.7%, and 102.4 +/- 5.1% versus 73.6 +/- 1.4%, respectively; mean +/- standard error of the mean percent lumen patency; P < 0.001). No adverse effects of treatment were observed. CONCLUSION: The diazeniumdiolate NO donor DETA/NO can be effectively released from ethylene/vinyl acetate polymers. Administration of DETA/NO into the periadventitial space can prevent the development of chronic posthemorrhagic vasospasm in the rat femoral artery and can reverse established vasospasm. No adverse effects of DETA/NO were observed in this model.
T S Tierney; R E Clatterbuck; C Lawson; Q A Thai; L D Rhines; R J Tamargo
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Neurosurgery     Volume:  49     ISSN:  0148-396X     ISO Abbreviation:  Neurosurgery     Publication Date:  2001 Oct 
Date Detail:
Created Date:  2001-09-20     Completed Date:  2001-12-04     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  7802914     Medline TA:  Neurosurgery     Country:  United States    
Other Details:
Languages:  eng     Pagination:  945-51; discussion 951-3     Citation Subset:  IM    
Department of Neurological Surgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287-7713, USA.
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MeSH Terms
Biological Availability
Delayed-Action Preparations
Drug Implants*
Nitric Oxide / administration & dosage*,  pharmacokinetics
Rats, Inbred F344
Subarachnoid Hemorrhage / blood,  drug therapy
Vasodilation / drug effects
Vasospasm, Intracranial / blood,  drug therapy*
Reg. No./Substance:
0/1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; 0/Delayed-Action Preparations; 0/Drug Implants; 0/Triazenes; 10102-43-9/Nitric Oxide

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