Kohane D S, Yieh J, Lu N T, Langer R, Strichartz G R, Berde C B
Massachusetts General Hospital and Harvard Medical School, Boston, USA.
Anesthesiology. 1998 Jul;89(1):119-31. doi: 10.1097/00000542-199807000-00019.
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.
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.
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 microM 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.
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.
诸如河豚毒素这类能高度特异性阻断钠通道的高效毒素已被研究多年，与血管收缩剂或传统局部麻醉药合用时可产生持久的阻滞作用。然而，其应用受到全身毒性的限制。作者研究了有或没有肾上腺素或布比卡因时河豚毒素在大鼠中产生长时间坐骨神经阻滞的效果，并评估了伴随的毒性程度。
大鼠接受使用有或没有肾上腺素或布比卡因的河豚毒素进行经皮坐骨神经阻滞。一部分大鼠在颈部中线接受皮下注射。使用对侧腿部反应作为全身效应的对照来量化伤害性感受、本体感觉和运动阻滞。
没有肾上腺素的河豚毒素可产生坐骨神经阻滞，但在最有效剂量时具有相当大的毒性。肾上腺素将河豚毒素产生伤害性感受的半数有效浓度从37.6微摩尔降至11.5微摩尔，并延长了其作用持续时间，从而实现了持续超过13小时的可逆性阻滞。肾上腺素减少了全身分布的指标，并将河豚毒素的半数致死剂量从40纳摩尔/千克提高到53.6纳摩尔/千克，从而使治疗指数增加了四倍多。布比卡因增加了河豚毒素的局部麻醉效能，降低了其全身毒性，并且当皮下联合注射时，将半数致死剂量从43.7纳摩尔/千克提高到47.7纳摩尔/千克。添加肾上腺素并未进一步提高布比卡因 - 河豚毒素组合的有效性。
应研究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，以探讨其提供临床上有用的长时间神经阻滞的潜力。
