Planning Grant for the Efficacy of Auranofin for the Treatment of Amebiasis

描述（由申请人提供）：阿米巴病是继疟疾和血吸虫病之后全球第三大寄生虫感染致死原因。咪唑，特别是甲硝唑，是世界范围内用于治疗的一类药物。甲硝唑耐药是多种原生动物日益关注的问题，包括贾第鞭毛虫、阴道毛滴虫和溶组织芽胞杆菌。因此，鉴定新药是当务之急。这项拟议的临床试验是基于U01拨款的重要发现，以确定B类原生动物的新药物靶点。通过筛选FDA批准的所有抗溶组织梭菌滋养体的药物，我们发现一种药物，即1985年批准用于治疗类风湿性关节炎的口服含金化合物，其IC50为0.5¿M，比甲硝唑（5.2¿M）低10倍。口服金糠蛋白在阿米巴结肠炎和肝脓肿的啮齿类动物模型中也有效，因此被批准为治疗阿米巴病的孤儿药。我们建议验证口服金糠蛋白与甲硝唑治疗阿米巴性结肠炎具有同等疗效的假设。我们提出的临床试验是一项IIa期、3个平行组、随机、双盲治疗研究，比较主动对照（甲硝唑）和每日1次或2次剂量的金糠蛋白治疗成人急性阿米巴性结肠炎。我们将重点关注18岁伴有溶组织大肠杆菌症状性腹泻（24小时稀便）的患者（通过O&P检查+特异性抗原、血清学或PCR检测）。他们将被随机分配到标准甲硝唑治疗组（每天500毫克，持续10天）、低剂量金糠芬（每天3毫克，持续10天）或高剂量金糠芬（每天3毫克，持续10天）。主要终点将是腹泻消退的时间（24小时内无稀便），其次终点是通过显微镜和定量PCR观察寄生虫学反应。这项拟议的临床试验使用一种重新分析的FDA药物可能导致

DESCRIPTION (provided by applicant): Amebiasis is the third leading cause of death from parasitic infection worldwide, following malaria and schistosomiasis. Imidazoles, particularly metronidazole, are the single class of drugs used worldwide for treatment. Resistance to metronidazole is a growing concern in multiple protozoa, including Giardia, Trichomonas vaginalis, and E. histolytica. Therefore, the identification of new drugs is a priority. This proposed clinical trial is based on important findings from a U01 grant to identify new drug targets in Class B protozoa. By screening all FDA approved drugs against E. histolytica trophozoites, we found one drug, auranofin, an oral gold-containing compound approved in 1985 to treat rheumatoid arthritis, had an IC50 of 0.5 ¿M, 10-fold lower than metronidazole (5.2 ¿M). Oral auranofin was also effective in rodent models of amebic colitis and liver abscesses, leading to approval of Orphan Drug status for the treatment of amebiasis. We propose to test the hypothesis that oral auranofin has equivalent efficacy to metronidazole for the treatment of amebic colitis. Our proposed clinical trial is a Phase IIa, 3 parallel arm, randomized, double blin treatment study comparing an active control (metronidazole) to once or twice daily doses of auranofin for treatment of adults with acute amebic colitis. We will focus on patients > 18 years old with symptomatic diarrhea (> 2 loose stools for 24 hrs) with E. histolytica (by O&P exam + specific antigen, serology, or PCR testing). They will be randomized to standard metronidazole therapy (500 mg tid for 10d), low dose auranofin (3 mg daily for 10d), or high dose auranofin, 3 mg bid daily for 10 d). The primary end-point will be time to resolution of diarrhea (no loose stools for 24 hrs) with a secondary end-point of time to parasitologic response by microscopy and quantitative PCR. This proposed clinical trial using a re-profiled FDA drug could result in the first new drug and target for the treatment of amebiasis in 52 years. PUBLIC HEALTH RELEVANCE: Amebiasis is a major cause of morbidity and mortality worldwide with only one class of drugs available for treatment. We have identified an FDA-approved drug, auranofin, which is highly active against the parasite causing amebiasis. We now propose to plan a clinical trial to test its efficacy compared to current therapy, which could lead to the first new drug and drug target to treat this neglected disease in 52 years.