Disulfiram for Entameoba histolytica Enteric Diarrhea [DEED] Trial

项目总结/文摘

PROJECT SUMMARY/ABSTRACT This proposal is in response to PAR-20-270, whose funding purpose is to support the planning of a future trial. Protozoan parasites pose significant global health burden, yet therapies are limited and new drug discovery remains costly. Drug repurposing can drastically cut these costs by rapidly finding new indications for existing drugs. For example, amebiasis, caused by Entamoeba histolytica, is a leading cause of severe diarrhea and death from parasitic infection worldwide. Globalization, immigration, travel to and from endemic areas, and sexual practices are contributing to re-emergence in developed countries.The work is significant because amebiasis treatment options are inadequate relying on only one drug class. Therefore, we are not prepared for intolerable side effects or emerging drug resistance, which is a real concern and there are no alternatives. Hence, identification of new anti-parasitic drugs is priority. We found that zinc ditiocarb, a metabolite of the inexpensive, globally available, oral FDA-approved drug disulfiram, was 1000-fold more potent than metronidazole and was an effective anti- amebic agent in pre-clinical animal studies of amebic colitis. Zinc ditiocarb is safely given as disulfiram plus nutritional zinc supplement. We propose to test the hypothesis that oral disulfiram plus zinc supplement effectively treats Entamoeba histolytica diarrhea. Our proposed approach, the Disulfiram for Entamoeba histolytica Enteric Diarrhea (DEED) Trial is an international phase 2a, double-blind, randomized control trial of patients with symptomatic diarrhea due to E. histolytica. If our hypothesis holds true, the proposed trial could result in an innovative repurposed indication for the first new drug treatment for amebiasis in over 60 years. Also of significance, zinc ditiocarb may prove to be a novel broad-spectrum anti-parasitic agent for other difficult-to-treat parasites such as Leishmania and Trypanosoma, as in vitro efficacy against these parasites has also been shown. This R34 planning grant will allow completion of the critical planning, rigorous design and essential preparation of the documents needed to ensure the successful conduct of the DEED trial.