Treatment of cutaneous leishmaniasis using Pentalinon andrieuxii root extract

描述(申请人提供)：利什曼原虫是一种专性细胞内寄生虫，可引起多种疾病，如皮肤、粘膜皮肤和内脏利什曼病。目前有超过1200万人患有这些疾病，每年约有200万人受到感染。皮肤利什曼病(CL)表现为局部皮肤损害，可愈合或导致严重的组织破坏和毁容。显然有必要对CL进行局部治疗，因为目前的治疗方法是每天长时间注射锑(GLucantimeTM或PentostaTM)，这是有毒的，患者依从性很差。在尤卡坦半岛，玛雅人的传统治疗师使用五倍子的根来局部治疗CL，这表明五倍子有可能作为局部药物用于治疗利什曼病。我们发现，五羟色胺根正己烷提取物(PARHE)具有很强的抗利什曼活性。我们公布的数据表明，PARHE在体外对利什曼原虫的杀灭效果与GLucantimeTM一样有效。此外，我们新的初步数据表明，在墨西哥血吸虫感染期间，PARHE有效地限制了受感染皮肤中的寄生虫生长。PARHE还可增加巨噬细胞的利什曼杀伤力，对哺乳动物细胞无毒。该项目将寻求评估PARHE作为外用药物在小鼠模型上治疗CL的有效性(目标1)，并为未来开发生物活性化合物(S)的质量控制程序确定PARHE的化学成分(目标2)。我们推测，PARHE将是治疗旧大陆和新世界皮肤利什曼病的有效外用药物。我们的团队在利什曼病(Satoskar)、植物化学和天然产品开发(Kinghorn)方面拥有互补的专业知识，因此能够进行这些研究是独一无二的。该项目产生的数据将为后来的R01应用奠定基础，重点是更全面地研究PARHE及其活性成分在不同形式的利什曼病局部或系统治疗中的作用，并确定从PARHE中分离的抗利什曼分子的作用机制。我们的研究很重要，因为他们将确定局部应用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是重要的。 公共卫生相关性：该项目的总体目标是开发一种天然产品，作为一种潜在的局部药物来治疗皮肤利什曼病。

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.