Disulfiram for Entameoba histolytica Enteric Diarrhea [DEED] Trial

项目总结/摘要 本提案是对PAR-20-270的回应，其供资目的是支持规划 未来的审判。原生动物寄生虫造成重大的全球健康负担，但治疗方法 有限的和新的药物发现仍然是昂贵的。药物再利用可以大幅降低这些成本 通过快速找到现有药物的新适应症。例如，阿米巴病，由 溶组织内阿米巴是寄生虫感染引起严重腹泻和死亡的主要原因 国际吧全球化、移民、出入流行地区的旅行和性行为 正在为发达国家的重新崛起做出贡献。这项工作意义重大，因为 仅依赖一种药物类别的阿米巴病治疗选择是不够的。因此我们 没有为无法忍受的副作用或新出现的耐药性做好准备，这是一个真实的问题 而且别无选择因此，确定新的抗寄生虫药物是优先事项。我们 发现二硫卡锌是FDA批准的廉价、全球可用的口服药物的代谢物 药物双硫仑，比甲硝唑强1000倍，是一种有效的抗- 阿米巴制剂在阿米巴结肠炎临床前动物研究中的应用。二硫卡锌安全地作为 双硫仑加营养锌补充剂。我们建议测试的假设，口头 双硫仑加补锌可有效治疗溶组织内阿米巴腹泻。我们提出的 双硫仑治疗溶组织内阿米巴肠腹泻（DEED）试验是一项 一项在有症状的乳腺癌患者中进行的国际2a期、双盲、随机对照试验 E.溶组织剂如果我们的假设成立，拟议中的试验可能会导致 60多年来首个治疗阿米巴病的新药的创新再用途适应症。 同样重要的是，二硫威锌可能被证明是一种新的广谱抗寄生虫剂 对于其他难以治疗的寄生虫，如利什曼原虫和锥虫，作为体外疗效 对这些寄生虫也有很好的效果。这一R34规划赠款将允许完成 所需文件的严格规划、严格设计和必要准备， 确保DEED试验的成功进行。

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.