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，可引起多种疾病，如皮肤、粘膜皮肤和内脏利什曼病。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（CL）表现为局部皮肤病变，可能愈合或导致显着的组织破坏和毁容。由于目前的治疗方法涉及长期每日注射锑剂（Glucantime ™或Pentostam ™），因此显然需要针对CL的局部治疗，这些锑剂具有毒性且患者依从性差。在尤卡坦半岛，玛雅传统的治疗师使用Pentalinon pneuuxii根局部治疗CL，这表明P. pneuuxii有可能用作治疗利什曼病的局部药物。我们已经发现，Pentalinon penteuxii根己烷提取物（PARHE）表现出有效的抗利什曼原虫活性。我们发表的数据表明，PARHE在体外杀死利什曼原虫的效率与GlucantimeTM一样。此外，我们的新的初步数据表明，PARHE是有效的限制寄生虫生长在感染的皮肤在L。墨西哥感染。PARHE还增加巨噬细胞中的杀利什曼原虫活性，并且对哺乳动物细胞没有毒性。本项目将寻求使用小鼠模型评价PARHE作为局部药物治疗CL的有效性（目的1），并确定PARHE的化学组成，用于生物活性化合物质量控制程序的未来开发（目的2）。我们假设PARHE将是治疗旧世界和新世界皮肤利什曼病的有效外用药物。由于我们在利什曼病（Satoskar）、植物化学和天然产品开发（Kinghorn）方面的互补专业知识，我们的团队能够独一无二地进行这些研究。该项目产生的数据将为以后的R 01应用奠定基础，该应用侧重于更全面地研究PARHE及其活性成分在不同形式的利什曼病的局部或全身治疗中的作用，并确定从PARHE中分离的抗利什曼病分子的作用机制。我们的研究很重要，因为它们将确定PARHE的局部应用是否能预防病变发展和/或促进CL的治愈，以及确定PARHE中对未来临床应用很重要的生物活性分子。 公共卫生相关性：该项目的总体目标是开发一种天然产品作为治疗皮肤利什曼病的潜在局部制剂。

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.