Electropulsation mediated drug therapy for Onychomycosis

描述（由申请方提供）：甲真菌病是指指甲和脚趾甲的真菌感染，占所有指甲疾病的50%。他们目前通过口服和局部给药的抗真菌药物治疗。口服抗真菌治疗通常与严重不良反应相关，这些不良反应独立于或与许多重要的药物相互作用相关。局部单药治疗甲真菌病“不太成功”，因为抗真菌药物的甲渗透性差。穿过指甲盖的差的药物吸收可以归因于诸如药物的不利的物理化学性质、缺乏可以克服指甲盖的屏障性质的制剂、局部制剂的短停留时间和药物与角蛋白的广泛结合的原因。局部单药治疗只有在治疗过程中甲层中保持一致的游离药物水平>MIC时才是成功的。这需要一种药物递送方法，该方法可以快速驱动有效量的药物穿过指甲盖。我们建议开发一种新的“电脉冲”方法治疗甲真菌病。我们相信，电脉冲将显着提高局部单药治疗的成功率，并缩短治疗甲癣的持续时间。与常规局部应用（24小时持续时间）相比，体外（10 V/cm 2，50 ms脉冲持续时间，1 Hz）甲盖电脉冲输送的药物量（20分钟治疗期内）高出一个数量级。我们假设，适当的电脉冲方案的应用可以通过药物分子的动力学以及通过透化指甲板来快速递送治疗有效量的药物穿过指甲板。在我们的目标1中，我们提出了研究不同的电脉冲方案对药物的跨甲输送的影响，并探讨跨甲药物转运增强的机制。我们进一步假设，电脉冲方案不会引起人类受试者的任何显著不适。在我们的目标2中，我们建议评估在健康人类受试者中施加在指甲上的电脉冲方案的耐受性。这些特定目标的完成将导致电脉冲协议，是有效的，更安全的临床应用。 公共卫生相关性：目前，甲真菌感染（甲真菌病）采用口服和外用抗真菌药物治疗。口服抗真菌治疗与严重的副作用有关，局部单药治疗由于药物渗透到指甲板中的效果较差而不太成功。我们建议开发一种新的技术，“电脉冲”快速输送药物通过指甲盖，这反过来又可能显着提高局部单药治疗的成功率，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.