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.
OBJECTIVE
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.
Gabikian
Patrik
P
Department of Neurological Surgery, Johns Hopkins University School of Medicine, Baltimore, Md, USA.
Clatterbuck
Richard E
RE
Eberhart
Charles G
CG
Tyler
Betty M
BM
Tierney
Travis S
TS
Tamargo
Rafael J
RJ
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D002946:Cisterna Magna; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004343:Drug Implants / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D005260:Female; D008297:Male; D020714:Maximum Tolerated Dose; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D011073:Polyamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D011145:Polyvinyls / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000503:physiopathology; D015996:Survival Rate; D016896:Treatment Outcome; D020301:Vasospasm, Intracranial / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*
D003692:Delayed-Action Preparations; D004343:Drug Implants; D020030:Nitric Oxide Donors; D011073:Polyamines; D011145:Polyvinyls; C005391:diethylenetriamine; C016438:ethylenevinylacetate copolymer