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

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 an d 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 I C50'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 parasi te. 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-clini cal 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 p urified 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 compou nds 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 co mpletion 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 isolati on/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 t o 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 dis ease. 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.