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.

项目摘要/摘要 该提案是对Par-20-270的回应，其资金目的是支持计划 未来的审判。原生动物寄生虫造成了巨大的全球健康负担，但疗法是 有限和新药物发现仍然昂贵。药物重新利用可以大大削减这些费用 通过迅速找到现有药物的新迹象。例如，由 Entamoeba Histolictica是严重腹泻和寄生虫死亡的主要原因 全世界。全球化，移民，往返地方性地区以及性行为 在发达国家的重新出现。这项工作很重要，因为 Amebiasis治疗方案仅依靠一个药物类别不足。因此，我们是 不准备无法忍受的副作用或新兴耐药性，这是一个真正的问题 而且别无选择。因此，确定新的抗寄生液是优先的。我们 发现锌ditiocarb是一种廉价，全球可用的口服FDA批准的代谢物 药物二硫酸酯，比甲硝唑高1000倍，是一种有效的抗 - 阿米比克结肠炎前动物研究中的Amebic剂。锌ditiocarb被安全地赋予 二硫仑和营养锌补充。我们建议检验口头的假设 二硫仑加锌补充剂有效地治疗了溶血性腹泻。我们提出的 方法，distamoeba Histolictica肠胃腹泻（契据）试验的二硫仑试验是一个 国际阶段2A，有症状的患者的双盲，随机对照试验 腹泻是由于组织溶液性的。如果我们的假设是正确的，则拟议的试验可能会导致 60多年来，对阿米巴病的首次新药物治疗的创新重新定义。 同样重要的是，锌ditiocarb可能被证明是一种新型的广谱抗寄生虫 对于其他难以治疗的寄生虫，例如利什曼原虫和锥虫，作为体外功效 还显示了针对这些寄生虫。 R34计划赠款将允许完成 批判性计划，严格的设计以及所需的文件的基本准备 确保契据审判的成功进行。

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