體外震波治療對於大鼠尾部神經經皮導入藥物之效果

The Effects of Extracorporeal Shockwave Mediated Transdermal Drug Delivery in Rat Caudal Nerves

黃琬葶(Wan-Ting Huang)

指導教授 ： 陸哲駒

共同指導教授 ： 林光華 ； 陳文翔(Wen-Shiang Chen)

國立臺灣大學/醫學院/物理治療學研究所/碩士(2012年)

https://doi.org/10.6342/NTU.2012.10896

摘要

背景與目的: 傳統上低頻超音波應用於超音波導入法(sonophoresis)已被認為是增進藥物經皮傳輸之有效方式。目前普遍認為超音波導入法中增加皮膚通透性的機轉為空泡效應(cavitation effect)。體外震波(extracorporeal shockwave)相對於其他形式的醫用超音波更能有效地產生短暫的空泡效應且熱效應較低，故使用體外震波應可較超音波在聲波導藥上有更好效果。然而體外震波有可能造成神經受損，使用時震波可能造成人體皮膚不舒服的感覺。因此找出安全有效的震波導藥劑量可減少不適感而使病人有較好的順從度，並提昇導藥的安全性。目前仍無研究探討震波經皮導入麻醉藥物的效果。本研究目的為: (1)利用先驅實驗找到之合適震波參數，經由震波輔助預先導入及同時導入安麻樂(Eutectic Mixture of Local Anaesthetics, EMLA cream)局部麻醉乳膏的動物實驗，同時與超音波導入法、直接塗抹EMLA法比較，探討體外震波經皮導入麻醉藥之效果。(2)用較低強度或較低脈衝數之震波，探討體外震波經皮導入EMLA之劑量反應。
方法: 本研究使用二十四隻平均年齡20.9週之成年雄性 Wistar 大鼠為實驗對象。在震波經皮導藥研究中，大鼠被隨機分配至以下的組別：局部塗藥組、超音波導藥組(1MHz)、震波預先導藥組及震波同時導藥組，於大鼠尾巴進行經皮導入EMLA，每次實驗時間為六十分鐘。過程中以神經傳導研究在每次治療前五分鐘及治療後一小時內每五分鐘測量所得之感覺神經動作電位的振幅和潛伏時間來評估麻醉程度。一週後的劑量反應研究中，大鼠被分配至四個組別，接受較低脈衝數和強度的震波輔助 EMLA局部麻醉藥物導入，來測定此應用的最小劑量。
結果: 震波預先導藥組和震波同時導藥組，比超音波導藥組更能於大鼠尾巴提供較好的經皮導藥效果(p<0.05)。此外，震波同時導藥組的經皮導藥效果又明顯優於震波預先導藥組(p<0.05)。震波同時導藥組在五分鐘內就有明顯的效果，顯著快於震波預先導藥組。而較低強度(0.055 mJ/mm2)和較低脈衝數(500 pulse)的震波，也明顯比EMLA局部塗藥組有好的經皮導藥效果(p<0.05)。
結論:本研究使用之震波導藥安全參數，其導入EMLA的效果比超音波導入法好，不僅有更好的麻醉程度而且顯著縮短了EMLA在健康成年雄性大鼠尾巴神經發揮麻醉效果的時間，而震波同時導入法比震波預先導入法為更好的導藥方式。此外，較低強度(0.055mJ/mm2)或脈衝數(500 pulse)之震波可能為震波導藥所需的最小閾值，其導藥效果雖然略微下降，但是其結果仍然比直接塗抹EMLA為佳。

關鍵字

聲波導藥 ； 體外震波 ； 空泡效應 ； 麻醉藥物 ； 感覺神經傳導

並列摘要

Background and Purpose: Traditionally, low-frequency ultrasound is used for sonophoresis and has been found to be an effective method in enhancing transdermal drug transport. The generally accepted mechanism responsible for skin permeability enhancement by sonophoresis is the cavitation effect. Extracorporeal shockwave can provide more transient cavitation than most other forms of medical ultrasound, with less thermal effect. Thus, it might have better clinical effects than ultrasound in sonophoresis. However, extracorporeal shockwave might induce nerve damage and cause uncomfortable sense on human skin. Therefore to determine the reasonable dosage of shockwave to reduce the uncomfortableness and induce better compliance of patients is crucial for safety consideration. There is no study founded to explore the sonophoretic effect of shockwave on transdermal delivery of anesthetic drug. Therefore, the purposes of this study were (1) to use the determined suitable parameters of shockwave to identify the sonophoretic effect of extracorporeal shockwave by using the pre- or concurrent shockwave-aided EMLA(eutectic mixture of local anesthetics) application, and simultaneously compared with the sonophoresis-aided EMLA application and topical EMLA application via an animal study. (2) to determine the dose-response of the sonophoretic effect of extracorporeal shockwave with lower intensities or pulses.
Methods: Twenty-four Wistar rats with a mean age of 20.9 weeks were used as the experimental subject in this study. In the shockwave sonophoresis study, the rats were assigned to following groups randomly: topical, sonophoresis-aided (1MHz ultrasound), pre- and concurrent shockwave-aided EMLA application on the rat tails for 60 minutes. The degree of anesthesia was assessed using the amplitude and latency of sensory nerve action potential which were evaluated by nerve conduction study (VikingQuest, Nicolet, VIASYS Healthcare, USA) before and every 5 minutes after treatment for 60 min. One week later, in the dose-response study, rats were divided into four groups to received shockwave mediated EMLA delivery with different pulse number and intensity to determine the possible minimal dosage in this application.
Results: The pre-treated and concurrent shockwave could provide better effectiveness on transdermal delivery of EMLA cream on the nerve of tail than pre-treated 1 MHz ultrasound (p<0.05). Besides, the concurrent shockwave mediated drug delivery was superior to pre-treated shockwave (p<0.05). After the concurrent shockwave application, the effects of EMLA were evident within 5 minutes, which is much quicker than pre-treatment shockwave application (p<0.05). The concurrent extracorporeal shockwave with lower intensity of 0.055 mJ/mm2 or lower 500 pulse could also show better effectiveness on transdermal delivery of EMLA cream on caudal nerve in healthy male adult rats than topical EMLA application (p<0.05).
Conclusions: The safety parameters of 4Hz, 1000 pulses with 0.089mJ/mm2 intensity of extracorporeal shockwave could show better effectiveness on transdermal delivery of EMLA cream than sonophoresis-aided EMLA application, and resulted in better degree of anesthesia and shortening the onset time of anesthetic effect to 5 minutes on caudal nerve in healthy male adult rats. It would be that the concurrent shockwave-aided EMLA application was superior to the pre shockwave-aided EMLA application. Lower intensities (0.055mJ/mm2) or pulses (500 pulse) of extracorporeal shockwave might be the minimal threshold for shockwave sonophoresis and could show better effectiveness on transdermal delivery of EMLA cream than the topical EMLA application.

並列關鍵字

Sonophoresis ； Extracorporeal shockwave ； Cavitation effect ； Analgesic drug ； Sensory nerve conduction

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