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寄生虫感染导致死亡的第三大原因。咪唑类药物，特别是甲硝唑，是世界范围内用于治疗的唯一一类药物。多种原生动物对甲硝唑的耐药性越来越受到关注，包括贾第虫、阴道毛滴虫和大肠杆菌。溶组织剂因此，确定新药是一个优先事项。这项拟议的临床试验是基于U01资助的重要发现，以确定B类原生动物中的新药物靶点。通过对所有FDA批准的药物进行抗E.我们发现一种药物，金诺芬，一种1985年批准用于治疗类风湿性关节炎的口服含金化合物，其IC 50为0.5 μ M，比甲硝唑（5.2 μ M）低10倍。口服金诺芬在阿米巴结肠炎和肝脓肿的啮齿动物模型中也有效，导致批准孤儿药状态用于治疗阿米巴病。我们建议检验口服金诺芬治疗阿米巴结肠炎与甲硝唑疗效相当的假设。我们提出的临床试验是一项IIa期、3个平行臂、随机、双盲治疗研究，比较了活性对照（甲硝唑）与每日一次或两次剂量的金诺芬治疗成人急性阿米巴结肠炎。我们将重点关注年龄> 18岁的有症状腹泻（> 2次稀便24小时）的E。溶组织（通过O&P检查+特异性抗原、血清学或PCR检测）。他们将随机接受标准甲硝唑治疗（500 mg tid，持续10 d）、低剂量金诺芬（3 mg每日1次，持续10 d）或高剂量金诺芬（3 mg每日2次，持续10 d）。主要终点是至腹泻消退的时间（24小时内无稀便），次要终点是通过显微镜检查和定量PCR获得寄生虫学应答的时间。这项使用重新描述的FDA药物的拟议临床试验可能会导致 52年来首个治疗阿米巴病的新药和靶点。 公共卫生相关性：阿米巴病是全球发病率和死亡率的主要原因，只有一类药物可用于治疗。我们已经确定了一种FDA批准的药物，金诺芬，它对引起阿米巴病的寄生虫具有高度活性。我们现在计划进行一项临床试验，以测试其与目前疗法相比的疗效，这可能导致52年来治疗这种被忽视的疾病的第一种新药和药物靶点。

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.