Pre-Clinical Evaluation of Antimalarial Natural Products from Carica papaya L.

描述(申请人提供)：该项目的长期目标是开发一种廉价、口服有效、无毒并能治愈恶性疟疾的新药(新化学实体[NCE])。从番木瓜叶中分离纯化了两种天然产物，并对其化学结构进行了鉴定。这些化合物对氯喹敏感和耐药疟疾菌株都显示出同样强的抑制活性。半数抑制浓度(IC_(50))S优于阳性对照氯喹和甲氟喹。这些化合物对成人肝上皮细胞和新鲜分离的大鼠肝细胞也表现出低毒作用。此外，这些化合物还被发现具有理想的ADME(吸附、分布、代谢和排泄)特性。这些化合物有可能干扰血球蛋白的合成，这是疟疾寄生虫不可或缺的过程。在这些初步研究的基础上，这一第一阶段项目的总体目标是为候选人建立临床前档案。在第一阶段的支持下，我们将对这些化合物进行扩大分离和提纯，并开始在啮齿动物模型中进行临床前研究，以获得疗效、药代动力学和毒性数据。将进行以下互动研究，以有效和有效地获得啮齿动物临床前概况：(I)将更大规模地分离和提纯这两种天然产物(每种化合物1-2公斤)。(Ii)将获得感染人类疟疾品系的免疫受损的BXN小鼠和感染啮齿动物疟疾品系P.berghei的瑞士雄性白化小鼠的抗疟疾疗效数据。(Iii)对大鼠静脉或口服试验化合物，并计算药代动力学参数。(4)测试化合物将在啮齿动物模型中进行测试，以获得急性毒性、胎儿毒性、厌食毒性和神经毒性信息。在第一阶段研究完成后，具有口服活性和良好治疗指数的化合物(S)将被选为第二阶段的进一步开发。第二阶段的工作将包括在Aotus猴子身上进行临床前研究，随后进行GMP分离/纯化和GLP评估。随后将向FDA提交研究用新药(IND)申请。与公共卫生相关：疟疾是世界上最常见的传染病之一。它影响了大约3亿人，每年导致200多万人死亡。前往中南美洲、非洲、亚洲(包括印度次大陆、东南亚和中东)、东欧和南太平洋的美国游客可能面临这种潜在致命疾病的风险。抗疟疾药物的市场每年价值数亿美元。发现新的有效的抗疟疾药物具有为国家经济和人民健康作出重大贡献的潜力。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a new drug (new chemical entity [NCE]) that is inexpensive, orally active, non-toxic and can provide cure for P. falciparum malaria. Radix Pharmaceuticals has isolated and purified two natural products from the leaves of Carica papaya L. The chemical structures of both compounds were determined. These compounds showed equally potent inhibitory activity against both chloroquine sensitive and resistant malaria strains. The IC50's (concentration of compound that affords 50% of inhibition) were superior to the positive controls, chloroquine and mefloquine. These compounds also demonstrated low toxicity in human adult liver epithelial cells and freshly isolated rat hepatocytes. Additionally, these compounds were found to possess desirable ADME (adsorption, distribution, metabolism, and excretion) characteristics. These compounds possess the potential to interfere hemozoin synthesis, an indispensable process for the malaria parasite. Based on these preliminary studies, the overall goal of this Phase I project is to establish pre-clinical profiles for the candidates. Under Phase I support, we will perform the scale up isolation and purification of these compounds and begin pre-clinical studies in rodent models to obtain efficacy, pharmacokinetics and toxicity data. The following interactive studies will be performed to obtain rodent pre-clinical profiles efficiently and effectively: (I) The two natural products will be isolated and purified in a larger scale (1-2 kg per compound). (II) Antimalarial efficacy data will be obtained in immunocompromised BXN mice infected with human malaria strains and male Swiss albino mice infected with rodent malaria strain P. berghei. (III) Test compounds will be administered intravenously or orally to rats and pharmacokinetic parameters will be calculated. (IV) Test compounds will be tested in rodent models to obtain acute toxicity, fetotoxicity, anorectic toxicity, and neurotoxicity information. On completion of the Phase I studies, compound(s) that are orally active and possess good therapeutic index will be selected for further development in Phase II. The efforts in Phase II would include pre-clinical studies in Aotus monkey, followed by GMP isolation/purification and GLP evaluation. Investigational new drug (IND) application will then be filed with FDA. PUBLIC HEALTH RELEVANCE: Malaria is one of the most common infectious diseases in the world. It affects approximately 300 million people and leads to more than 2 million death a year. American travelers to Central and South America, Africa, Asia (including the Indian Subcontinent, Southeast Asia, and the Middle East), Eastern Europe, and the South Pacific may be at risk for this potentially deadly disease. The market for anti-malarial drugs is a couple of hundred million dollars annually. Discovering new and effective anti-malarial drugs possesses potential to contribute significantly to the economy of the nation and to the health of her people.