High-frequency, low-intensity ultrasound and microbubbles enhance nerve blockade.
High-frequency, low-intensity ultrasound and microbubbles enhance nerve blockade.
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DOI：
10.1016/j.jconrel.2018.02.027
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发表时间：
2018-04-28
期刊：
影响因子：
--
通讯作者：
Kohane DS
中科院分区：
文献类型：
--
作者：
Cullion K;Santamaria CM;Zhan C;Zurakowski D;Sun T;Pemberton GL;McDannold NJ;Kohane DS
Site1钠通道阻滞剂(S1SCB，如河豚毒素[TTX]和岩藻毒素)是一种超强的局部麻醉剂，可结合电压依赖性钠通道的胞外域[1]。S1SCB不容易穿过血脑屏障，对心脏钠通道亚型[2，3]亲和力低，因此不会导致癫痫[4]或心律失常，使TTX成为传统局部麻醉药的有吸引力的替代品[5，6]。S1SCB的局部麻醉在动物模型[[7]、[8]、[9]、[10]、[11]]中已有大量报道，现在已开始应用于人类[[12]、[13]]。然而，由于S1SCB的亲水性，即使局部注射，S1SCB对周围神经的渗透也有限，需要相对较高的浓度才能实现持续的神经阻断[9]。这些高浓度可能与全身毒性有关。增强S1SCB效果的一种方法是将它们与第二种或第三种具有佐剂作用的药物共同注射[7，8，14，15]。然而，这种偶联药物可能会引起第二种药物的副作用，如“常规”氨基酰胺和氨基酯局部麻醉剂的局部组织毒性，或肾上腺素引起的血管收缩和/或心动过速。另一种方法是增强S1SCB对神经元表面的穿透。以前我们已经证明，TTX与化学渗透促进剂联合注射可以增强S1SCBS的效果，尽管在高浓度时会有一些不良组织反应[16，17]。超声介导的药物传递具有增强神经阻滞的潜力，而不会产生不良组织反应。声波可以增强药物通过巩膜[18]、角质层[19，20]、跨越胃肠道内屏障[21，22]和血脑屏障[23，24]的输送。外源性微泡可以增强高频超声波对药物透过皮肤的影响(超声导入)[25，26]。
Site 1 sodium channel blockers (S1SCBs such as tetrodotoxin [TTX] and the saxitoxins) are ultrapotent local anesthetics that bind extracellular domains of voltage-dependent sodium channels [1]. S1SCBs do not cross the blood brain barrier readily and have low affinity for the cardiac sodium channel isoform [2, 3], and so do not cause seizures [4] or arrhythmias, making TTX an attractive alternative to conventional local anesthetics [5, 6]. Local anesthesia with S1SCBs has been described in numerous reports in animal models [[7],[8],[9],[10],[11]], and is now starting to be applied in humans [[12],[13]]. However, due to their very hydrophilic nature S1SCBs have limited penetration to peripheral nerves even with local injection, and require relatively high concentrations to achieve consistent nerve blockade [9]. Those high concentrations can be associated with systemic toxicity. One approach to enhancing the effect of S1SCBs has been to co-inject them with second or third drugs with adjuvantic effects [7, 8, 14, 15]. However, such couplings can entail the side-effects of the second drugs, such as the local tissue toxicity of “conventional” amino-amide and amino-ester local anesthetics or the vasoconstriction and/or tachycardia seen with epinephrine. An alternative approach is to enhance the penetration of S1SCBs to the neuronal surface. Previously we have shown that co-injection of TTX with chemical permeation enhancers could enhance the effect of S1SCBs, albeit with some adverse tissue reaction at high concentrations [16, 17].Ultrasound-mediated drug delivery has the potential to enhance nerve blockade without adverse tissue reaction. Acoustic waves can enhance drug delivery through the sclera [18], the stratum corneum [19, 20], across barriers within the gastrointestinal tract [21, 22], and the blood brain barrier [23, 24]. The effect of high-frequency ultrasound on drug flux across skin (sonophoresis) can be enhanced by exogenous microbubbles [25, 26].
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影响因子：
5.4
作者：
Berde CB;Athiraman U;Yahalom B;Zurakowski D;Corfas G;Bognet C
通讯作者：
Bognet C
影响因子：
8.8
作者：
Kohane, DS;Sankar, WN;Berde, CB
通讯作者：
Berde, CB
影响因子：
8.8
作者：
Kohane, DS;Yieh, J;Berde, CB
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Berde, CB
影响因子：
5.7
作者：
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Kohane DS
影响因子：
46.9
作者：
Prausnitz, Mark R.;Langer, Robert
通讯作者：
Langer, Robert