Disulfiram for Entameoba histolytica Enteric Diarrhea [DEED] Trial

项目摘要/摘要 这项建议是对PAR-20-270的响应，其资金目的是支持规划 一场未来的审判。原生动物寄生虫造成了巨大的全球健康负担，然而治疗方法却是 有限的新药发现仍然代价高昂。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 溶组织内阿米巴是导致严重腹泻和寄生虫感染死亡的主要原因。 全世界。全球化、移民、往返流行地区的旅行和性行为 有助于在发达国家重新崛起。这项工作意义重大，因为 阿米巴病的治疗选择仅依靠一种药物类别是不够的。因此，我们正在 没有为无法忍受的副作用或新出现的耐药性做好准备，这是一个真正令人担忧的问题 而且也没有其他选择。因此，寻找新的抗寄生虫药物是当务之急。我们 发现二硫代森锌是FDA批准的廉价的、全球可用的口服药物的代谢物 药物双硫兰，效力是甲硝唑的1000倍，是一种有效的抗肿瘤药物 阿米巴制剂在阿米巴结肠炎临床前动物研究中的应用。二硫代碳酸锌安全地作为 双硫兰加营养锌补充剂。我们建议检验口述的假设 双硫仑加补锌有效治疗溶组织内阿米巴腹泻。我们的建议 方法，二硫仑治疗溶组织内阿米巴肠源性腹泻(DED)试验是一项 国际2a期，有症状患者的双盲随机对照试验 由溶组织性肠杆菌引起的腹泻。如果我们的假设成立，拟议的试验可能会导致 为60多年来第一个治疗阿米巴病的新药提供创新的重新用途的适应症。 同样重要的是，二硫代氨基甲酸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，如体外疗效 针对这些寄生虫的研究也得到了证实。这项R34规划拨款将允许完成 关键的规划、严格的设计和必要的文件准备 确保契约审判的成功进行。

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.