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
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
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DOI：
10.1161/01.str.0000033931.62992.b1
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发表时间：
2002-11
期刊：
影响因子：
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通讯作者：
P. Gabikian;R. Clatterbuck;C. Eberhart;B. Tyler;T. Tierney;R. Tamargo
中科院分区：
文献类型：
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作者：
P. Gabikian;R. Clatterbuck;C. Eberhart;B. Tyler;T. Tierney;R. Tamargo
背景和目的：一氧化氮（NO）局部可用性的降低可能在蛛网膜下腔出血（SAH）后慢性脑血管痉挛的病因学中起作用。我们研究了局部释放的一氧化氮供体从一个控制释放聚合物在预防大鼠和兔实验性脑血管痉挛的毒性和有效性，分别。方法-将二亚乙基三胺/NO（DETA/NO）掺入控释乙烯-乙酸乙烯酯（EVAc）聚合物中。在剂量递增毒性研究中使用28只大鼠以建立DETA/NO-EVAc聚合物的最大耐受剂量。在有效性实验中，将20只兔子分配到4个实验组（每组n=5）：假手术;仅SAH; SAH+空EVAc聚合物;和SAH+DETA/NO-EVAc聚合物。在血液沉积后30分钟开始治疗。出血后72小时评估基底动脉管腔通畅性，以评价DETA/NO预防脑血管痉挛的有效性。结果-在毒性研究中，3.4 mg/kg的剂量被确定为该DETA/NO制剂的LD 20（研究期间死亡率为20%的剂量）。脑组织学显示与高浓度DETA/NO相关的植入部位出血和缺血性变化。在疗效研究中，与未治疗相比，DETA/NO-EVAc聚合物治疗导致基底动脉血管痉挛显著减少（93.0±4.9%对71.4±11.9%;P =0.035）或与用空白EVAc聚合物处理相比（93.0±4.9%对73.2±6.4%;P =0.003）。结论：局部注射DETA/NO可预防兔基底动脉血管痉挛。在该模型中，通过聚合物局部递送DETA/NO是预防SAH后脑血管痉挛的安全有效的策略。
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 LD20 (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.