A re-examination of tetrodotoxin for prolonged duration local anesthesia
A re-examination of tetrodotoxin for prolonged duration local anesthesia
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DOI：
10.1097/00000542-199807000-00019
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发表时间：
1998-07-01
期刊：
影响因子：
8.8
通讯作者：
Berde, CB
中科院分区：
文献类型：
--
作者：
Kohane, DS;Yieh, J;Berde, CB
背景资料：具有高度特异性阻断钠通道的高效毒素（如河豚毒素）已研究多年，当与血管收缩剂或常规局部麻醉剂联合给药时，可提供延长的阻断。然而，它们的效用受到全身毒性的限制。作者研究了河豚毒素与肾上腺素或布比卡因联合应用对大鼠坐骨神经阻滞持续时间延长的有效性，并评估了伴随毒性的程度。方法：大鼠接受了河豚毒素与肾上腺素或布比卡因联合应用的经皮坐骨神经阻滞。一个子集接受皮下注射在颈部中线，伤害性，本体感受，和运动阻滞进行了定量使用对侧腿的反应作为控制全身effects.Results：河豚毒素无肾上腺素产生坐骨神经阻滞，但在最有效的剂量相当大的毒性。肾上腺素使河豚毒素的半数有效伤害浓度从37.6 μ M降低到11.5 μ M，并延长其持续时间，从而实现了持续>13小时的可逆阻断。肾上腺素减少了全身分布的措施，并增加了河豚毒素的半数致死剂量从40至53.6 nmole/kg，从而超过四倍的治疗指数。布比卡因增加了河豚毒素的局部麻醉效力，降低了其全身毒性，并且，当皮下共同注射时，将半数致死剂量从43.7 nmole/kg增加到47.7 nmole/kg，添加肾上腺素没有进一步提高布比卡因-河豚毒素组合的有效性。应检查肾上腺素或布比卡因与河豚毒素或其他对钠通道有活性的高效毒素的组合是否有可能提供临床有用的，延长神经阻滞
Background: Highly potent toxins such as tetrodotoxin that block sodium channels with great specificity have been studied for many years and can provide prolonged blockade when coadministered with vasoconstrictors or conventional local anesthetics. Their utility has been constrained, however, by systemic toxicity. The authors examined the efficacy of tetrodotoxin with and without epinephrine or bupivacaine for producing prolonged-duration sciatic nerve blockade in the rat, and they assessed the degree of concomitant toxicity,Methods: Rats received percutaneous sciatic nerve blockade using tetrodotoxin with and without epinephrine or bupivacaine. A subset received subcutaneous injections at the nuchal midline, Nociceptive, proprioceptive, and motor blockade were quantified using contralateral leg responses as controls for systemic effects.Results: Tetrodotoxin without epinephrine produced sciatic nerve blockade, but with considerable toxicity at most effective doses. Epinephrine reduced the median effective concentration of tetrodotoxin for nociception from 37.6 to 11.5 mu M and prolonged its duration, such that reversible blocks lasting >13 h were achieved. Epinephrine reduced measures of systemic distribution and increased the median lethal dose of tetrodotoxin from 40 to 53.6 nmole/kg, thus more than quadrupling the therapeutic index. Bupivacaine increased the local anesthetic potency of tetrodotoxin, reduced its systemic toxicity, and, when coinjected subcutaneously, increased the median lethal dose from 43.7 to 47.7 nmole/kg, The addition of epinephrine did not further improve the effectiveness of the bupivacaine-tetrodotoxin combination.Conclusion: Combinations of epinephrine or bupivacaine with tetrodotoxin or with other high-potency toxins active on sodium channels should be examined for the potential to provide clinically useful, prolonged nerve blockade.