Electropulsation mediated drug therapy for Onychomycosis

甲真菌病(申请人提供)：甲真菌病是指甲和脚趾甲的真菌感染，占所有指甲疾病的50%。他们目前正在接受口服和外用抗真菌药物的治疗。口服抗真菌治疗通常与严重的不良反应有关，独立于或与许多重要的药物相互作用有关。局部单一疗法在治疗甲真菌病方面“不太成功”，这是因为抗真菌药物的经甲渗透性差。药物在甲板上的吸收不良可能是由于药物的不良物理化学性质、缺乏能够克服甲板屏障性能的制剂、局部制剂的停留时间短以及药物与角蛋白的广泛结合等原因。局部单一疗法只有在治疗过程中甲层中保持一致的游离药物水平和MIC时才会成功。这需要一种药物输送方法，能够快速地将有效量的药物驱动到指甲板上。我们建议开发一种新的“电脉冲”方法来治疗甲真菌病。我们相信，电脉冲将显著提高局部单一疗法的成功率，并缩短甲真菌病的治疗时间。体外甲板电脉冲(10V/cm2，1赫兹脉冲宽度50ms)提供的药物量(在20分钟的治疗期内)比传统局部应用(在24小时内)高出数量级。我们假设，应用适当的电脉冲方案可以通过药物分子的运动以及通过渗透甲板来快速地将治疗有效量的药物输送到甲板上。在我们的目标1中，我们建议研究不同的电脉冲方案对药物经甲给药的影响，并探讨经甲向药物转运促进的机制。我们进一步假设，电脉冲方案不会对受试者造成任何明显的不适。在我们的目标2中，我们建议评估应用于健康受试者甲板上的电脉冲方案的耐受性。这些特定目标的完成将导致临床应用更有效和更安全的电脉冲方案。 公共卫生相关性：目前，指甲真菌感染(甲真菌病)是通过口服和局部抗真菌药物治疗的。口服抗真菌治疗与严重的副作用有关，而局部单一治疗由于药物对甲板的渗透性差而不太成功。我们建议开发一种新技术，即通过甲板快速给药的“电脉冲”，这反过来可能显著提高局部单一疗法的成功率，并缩短甲真菌病的治疗时间。

DESCRIPTION (provided by applicant): Onychomycoses are fungal infections of both the fingernails and the toenails accounting for up to 50% of all the nail disorders. They are currently treated by oral and topical administration of the antifungal drugs. Oral antifungal therapy is generally associated with serious adverse effects independent of or associated with a number of significant drug interactions. Topical monotherapy is "less successful" in treating onychomycosis due to poor trans-nail permeation of antifungal drugs. The poor drug absorption across the nail plate could be attributed to reasons such as unfavorable physicochemical properties of the drugs, lack of formulations that can overcome the barrier properties of the nail plate, short residence time of topical formulations and extensive binding of drug to keratin. Topical monotherapy would be successful only when consistent free drug level >MIC is maintained in the nail stratums during the course of treatment. This requires a drug delivery method that can rapidly drive an effective quantity of drug across the nail plate. We propose to develop a novel "Electropulsation" method for the treatment of onychomycosis. We believe that Electropulsation will significantly improve the success rate of topical monotherapy and shorten the duration of treatment of onychomycosis. Electropulsation of the nail plate, in vitro (at 10V/cm2, 50ms pulse duration at 1Hz) delivered an order of magnitude higher amount of drugs (within a 20 minutes treatment period) as opposed to that achieved by conventional topical application (in 24 hours duration). We hypothesize that application of an appropriate Electropulsation protocol can rapidly deliver therapeutically effective quantity of drugs across the nail plate by kinesis of the drug molecules and also by permeabilizing the nail plate as well. In our Aim 1, we propose to study the effect of different Electropulsation protocols on the trans-nail delivery of drugs and to investigate the mechanisms of trans-nail drug transport enhancement. We further hypothesize that the Electropulsation protocols do not cause any significant discomfort in human subjects. In our Aim 2, we propose to assess the tolerability of Electropulsation protocols applied on the nail plate in the healthy human subjects. The completion of these Specific Aims will result in Electropulsation protocols that are effective and safer for clinical applications. PUBLIC HEALTH RELEVANCE: Currently the fungal infection of nails (onychomycosis) is treated with oral and topical antifungal drugs. Oral antifungal therapy is associated with severe side effects and topical monotherapy is less successful due to poor drug penetration into the nail plate. We propose to develop a novel technique; the "Electropulsation" for rapid delivery of drugs across the nail plate, which in turn is likely to significantly improve the success rate of topical monotherapy and shorten the duration of treatment of onychomycosis as well.