Disulfiram for Entameoba histolytica Enteric Diarrhea [DEED] Trial

双硫仑治疗溶组织内阿米巴肠腹泻 [DEED] 试验

• 批准号: 10328369
• 负责人: Cirle Alcantara Warren
• 金额: $ 24.39万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-13 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328369
• 关键词: 18 year old; Adverse event; Amebiasis; Amebic colitis; Animals; Antibiotics; Antiparasitic Agents; Area; Case Report Form; Cessation of life; Clinic; Clinical; Clinical Trials; Clinical Trials Data Monitoring Committees; Colitis; Communicable Diseases; Conduct Clinical Trials; Consumption; Developed Countries; Development; Diarrhea; Disulfiram; Ditiocarb; Dose; Double-Blind Method; Drug resistance; Ensure; Entamoeba histolytica; Enteral; Environment; FDA approved; Feces; Fright; Funding; Future; Giardia; Gluconates; Grant; Health Sciences; Hour; Human Resources; Immigration; In Vitro; Infection; Institutional Review Boards; International; Intervention; Investigation; Laboratories; Lead; Left; Leishmania; Manuals; Medical; Metronidazole; Metronidazole resistance; Microscopy; Morbidity - disease rate; Nitroimidazoles; Nutritional; Oral; Parasites; Parasitic infection; Participant; Patients; Pharmaceutical Preparations; Phase; Philippines; Preparation; Protocols documentation; Protozoa; Public Health; Randomized; Randomized Controlled Trials; Research; Research Personnel; Resistance; Resolution; Resources; Risk; Running; Safety; Secure; Sexual Transmission; Site; Statistical Data Interpretation; Testing; Therapeutic; Time; Training; Travel; Trichomonas vaginalis; Trypanosoma; Universities; Virginia; Work; Zinc; Zinc supplementation; active control; alcohol abuse therapy; alcohol use disorder; arm; cost; data management; design; drug discovery; drug repurposing; efficacy evaluation; enteric infection; experience; global health; in vivo; innovation; mortality; novel; novel therapeutics; operation; pre-clinical; pressure; primary endpoint; response; secondary endpoint; side effect; success; trend; trial design

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.

项目概要/摘要 该提案是对 PAR-20-270 的回应，其资助目的是支持规划 未来的审判。原生动物寄生虫造成严重的全球健康负担，但治疗方法尚不成熟 有限且新药发现的成本仍然很高。药物再利用可以大大降低这些成本 通过快速寻找现有药物的新适应症。例如，阿米巴病是由 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以及性行为 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 仅依靠一种药物来治疗阿米巴病是不够的。因此，我们是 没有准备好应对无法忍受的副作用或新出现的耐药性，这是一个真正令人担忧的问题 并且没有其他选择。因此，鉴定新的抗寄生虫药物是当务之急。我们 发现二硫威锌是 FDA 批准的廉价、全球可用的口服药物的代谢物 双硫仑是一种有效的抗病毒药物，其药效是甲硝唑的 1000 倍。 阿米巴制剂在阿米巴结肠炎临床前动物研究中的应用。二硫威锌的安全给药方式为 双硫仑加营养锌补充剂。我们建议检验以下假设：口头 双硫仑加锌补充剂可有效治疗溶组织内阿米巴腹泻。我们提出的 双硫仑治疗溶组织阿米巴肠腹泻 (DEED) 试验是一项 国际 2a 期、双盲、随机对照试验，对象为有症状的患者 溶组织内阿米巴引起的腹泻。如果我们的假设成立，拟议的试验可能会导致 60 多年来首个治疗阿米巴病的新药的创新适应症。 同样重要的是，二硫威锌可能被证明是一种新型广谱抗寄生虫剂 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 也已显示出对抗这些寄生虫的作用。这笔 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DEED试验的成功进行。

项目成果

Alcohol Abuse Drug Disulfiram Is Effective against Cyst Stages of Entamoeba histolytica Parasite.

• DOI: 10.1128/aac.00832-22
• 发表时间: 2022-11-15
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9