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 roots and rhizomes of Nardostachys chinensis Batalin. The chemical structures of both compounds were determined. These compounds showed equally potent inhibitory activity against both chloroquine sensitive malaria strain (D-6) and chloroquine resistant malaria strain (W-2). 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, in silico modeling has confirmed that these compounds possess desirable ADME (adsorption, distribution, metabolism, and excretion) characteristics and good oral bioavailability. 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 toxicity and efficacy 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) Compounds will be tested in rodent models to obtain acute and sub-acute toxicity, fetotoxicity, anorectic toxicity, and neurotoxicity information. (iii) 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. 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 successful completion of rodent pre-clinical studies will enable Radix Pharmaceuticals to raise additional funding and attract a commercial partner to push the drug candidate to clinical stage. The efforts in Phase II would include pre-clinical studies (pharmacokinetics, toxicity, and efficacy) in Rhesus monkey, followed by GMP manufacturing and GLP evaluation. Investigational new drug (IND) application will then be filed with FDA.
Project Terms: Acute; Adsorption; Adult; Adverse effects; Affect; African; albino mouse; analytical method; Animal Model; Animals; Antimalarials; Appetite Depressants; Attention; base; Biological Availability; Biological Factors; capsule (pharmacologic); Cell Line; Cessation of life; Characteristics; Chemical Structure; chemical synthesis; Chemicals; Chloroquine; Chloroquine resistance; Clinical; Clinical Research; Communicable Diseases; Computer Simulation; Cyclic GMP; Data; day; Development; Dose; Drug Formulations; Drug Kinetics; Drug resistance; efficacy evaluation; Epidemic; Epithelial Cells; Evaluation; Excipients; Excretory function; Exhibits; Falciparum Malaria; follow-up; Funding; Generations; Goals; Growth; Guanosine Monophosphate; hemozoin; Hepatocyte; Human; Immunocompromised Host; in vivo; Investigational Drugs; Investigational New Drug Application; Investments; Killings; Left; Lethal Dose 50; Liver; Macaca mulatta; Malaria; male; Mefloquine; Metabolism; Modeling; Molecular; Mortality Vital Statistics; Mus; Nardostachys; neurotoxicity; novel; Numbers; Oral; Parasite resistance; Parasites; Parasitic infection; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plant Roots; Plasmodium; Plasmodium falciparum; pre-clinical; preclinical study; Primates; Process; prophylactic; Radiolabeled; radiotracer; Rattus; Recrudescences; Relative (related person); Research; Resistance; Rhizome; Rodent; Rodent Model; Route; scale up; Singapore; Sprague-Dawley Rats; Staging; Swiss Mice; Testing; Thailand; Therapeutic; Therapeutic Index; Time; Toxic effect; Toxicity Tests; Tuberculosis; United States Food and Drug Administration; Work
