Treatment of cutaneous leishmaniasis using Pentalinon andrieuxii root extract

描述（由申请人提供）：利什曼原虫是专性细胞内寄生虫，可引起广泛的疾病，如皮肤，粘膜和内脏利什曼原虫病。目前有1 200多万人患有这些疾病，每年约有200万人受到感染。皮肤利什曼病表现为局部皮肤病变，可愈合或导致显著的组织破坏和毁容。显然需要局部治疗，因为目前的治疗包括每日注射锑类药物（GlucantimeTM或penttostamtm），时间较长，这些药物有毒且患者依从性差。在尤卡坦半岛，玛雅传统治疗师使用喷特利草根局部治疗CL，这表明喷特利草有可能用作治疗利什曼病的局部药物。我们已经发现，对迭香根己烷提取物（PARHE）显示出有效的抗利什曼原虫活性。我们发表的数据表明PARHE在体外杀灭利什曼原虫的效率与葡聚糖metm一样高。此外，我们新的初步数据表明，PARHE在墨西哥乳杆菌感染期间有效地限制寄生虫在感染皮肤中的生长。PARHE还能增加巨噬细胞的利什曼尼杀灭活性，对哺乳动物细胞无毒。本项目将利用小鼠模型评估PARHE作为局部药物治疗CL的疗效（目标1），并确定PARHE的化学成分，以便将来开发生物活性化合物的质量控制程序（目标2）。我们假设PARHE将是一种有效的局部药物治疗旧大陆和新世界皮肤利什曼病。由于在利什曼病（Satoskar）和植物化学和天然产物开发（Kinghorn）方面的互补专业知识，我们的团队在开展这些研究方面具有独特的优势。该项目产生的数据将为后期的R01应用奠定基础，重点是对PARHE及其有效成分在不同形式的利什曼病的局部或全身治疗中的更全面研究，并确定从PARHE分离的抗利什曼分子的作用机制。我们的研究很重要，因为它们将确定局部应用PARHE是否可以防止病变发展和/或促进CL的治愈，以及确定PARHE中的生物活性分子，这对未来的临床应用很重要。

DESCRIPTION (provided by applicant): Leishmania are obligate intracellular parasites that cause a wide range of diseases such as cutaneous, mucocutaneous and visceral leishmaniasis. Over 12 million people currently suffer from these diseases and approximately 2 million are infected annually. Cutaneous leishmaniasis (CL) manifests as localized skin lesions which may heal or lead to significant tissue destruction and disfigurement. There is a clear need for a topical treatment against CL because current therapy involves daily injections of antimonials (GlucantimeTM or PentostamTM) for prolonged periods, which are toxic and have poor patient compliance. In the Yucatan Peninsula, Mayan traditional healers use Pentalinon andrieuxii root for topical treatment of CL, which suggests that P. andrieuxii has a potential for use as a topical agent for the treatment of leishmaniasis. We have found that Pentalinon andrieuxii root hexane extract (PARHE) exhibits potent antileishmanial activity. Our published data indicate that PARHE kills Leishmania in vitro as efficiently as GlucantimeTM. In addition, our new preliminary data suggest that PARHE is effective in restricting parasite growth in the infected skin during L. mexicana infection. PARHE also increases leishmanicidal activity in macrophages and is not toxic to mammalian cells. This project will seek to evaluate the efficacy of PARHE as a topical agent to treat CL using mouse models (Aim 1) and to determine the chemical composition of PARHE for the future development of quality control procedures for the bioactive compound(s) (Aim 2). We hypothesize that PARHE will be an effective topical agent in the treatment of both Old world and New world cutaneous leishmaniasis. Our team is uniquely poised to perform these studies due to the complementary expertise in leishmaniasis (Satoskar), and phytochemistry and natural products development (Kinghorn). The data generated from this project will lay the foundations for a later R01 application focused on a more comprehensive study of PARHE and its active components in local or systemic treatment of the different forms of leishmaniasis, and for determining mechanisms of action of the antileishmanial molecules isolated from PARHE. Our studies are important because they will determine if a local application of PARHE prevents lesion development and/or promotes the cure of CL as well as identify bioactive molecules in PARHE which are important for future clinical applications. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to develop a natural product as a potential topical agent to treat cutaneous leishmaniasis.