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.

Abstract

BACKGROUND AND PURPOSE:

A reduction in the local availability of nitric oxide (NO) may play a role in the etiology of chronic cerebral vasospasm after subarachnoid hemorrhage (SAH). We investigated the toxicity and efficacy of a locally delivered NO donor from a controlled-release polymer in preventing experimental cerebral vasospasm in rats and rabbits, respectively.

METHODS:

Diethylenetriamine/NO (DETA/NO) was incorporated into controlled release ethylene-vinyl acetate (EVAc) polymers. Twenty-eight rats were used in a dose-escalation toxicity study to establish a maximally tolerated dose of DETA/NO-EVAc polymer. In the efficacy experiment, 20 rabbits were assigned to 4 experimental groups (n=5 per group): sham operation; SAH only; SAH+empty EVAc polymer; and SAH+DETA/NO-EVAc polymer. Treatment was initiated 30 minutes after blood deposition. Basilar artery lumen patency was assessed 72 hours after hemorrhage to evaluate the efficacy of DETA/NO in preventing cerebral vasospasm.

RESULTS:

In the toxicity study, a dose of 3.4 mg/kg was identified as the LD(20) (dose with 20% mortality during the study period) of this DETA/NO formulation. Brain histology revealed hemorrhage and ischemic changes at the implantation site associated with high concentrations of DETA/NO. In the efficacy study, treatment with DETA/NO-EVAc polymer resulted in a significant decrease in basilar artery vasospasm compared with no treatment (93.0+/-4.9% versus 71.4+/-11.9%; P=0.035) or compared with treatment with blank EVAc polymer (93.0+/-4.9% versus 73.2+/-6.4%; P=0.003).

CONCLUSIONS:

Local delivery of DETA/NO prevents vasospasm in the rabbit basilar artery. Local delivery of DETA/NO via polymers is a safe and effective strategy for preventing cerebral vasospasm after SAH in this model.

• Authors: Patrik Gabikian, Richard E Clatterbuck, Charles G Eberhart, Betty M Tyler, Travis S Tierney, Rafael J Tamargo
• Journal: Stroke (Stroke) Vol. 33 Issue 11 Pg. 2681-6 (Nov 2002) ISSN: 1524-4628 [Electronic] United States
• PMID: 12411661 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Delayed-Action Preparations
• Drug Implants
• Nitric Oxide Donors
• Polyamines
• Polyvinyls
• diethylenetriamine
• ethylenevinylacetate copolymer

Topics

• Animals
• Basilar Artery (drug effects, physiopathology)
• Brain (blood supply, drug effects, pathology, surgery)
• Cisterna Magna
• Delayed-Action Preparations (administration & dosage, adverse effects, chemistry)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Drug Implants (administration & dosage, adverse effects, chemistry)
• Female
• Male
• Maximum Tolerated Dose
• Nitric Oxide Donors (administration & dosage, adverse effects, chemistry)
• Polyamines (administration & dosage, adverse effects, chemistry)
• Polyvinyls (administration & dosage, adverse effects, chemistry)
• Rabbits
• Rats
• Rats, Inbred F344
• Subarachnoid Hemorrhage (complications, physiopathology)
• Survival Rate
• Treatment Outcome
• Vasospasm, Intracranial (etiology, physiopathology, prevention & control)