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

描述(申请人提供)：阿米巴病是全球第三大寄生虫感染致死原因，仅次于疟疾和血吸虫病。咪唑类药物，特别是甲硝唑，是全世界用于治疗的唯一一类药物。对甲硝唑的耐药性在包括贾第虫、阴道毛滴虫和溶组织性肠杆菌在内的多种原虫中日益受到关注。因此，新药的鉴定是当务之急。这项拟议的临床试验是基于U01拨款的重要发现，以确定B类原生动物的新药靶标。通过筛选FDA批准的所有抗组织滋养体药物，我们发现一种药物Auranofin，一种1985年批准用于治疗类风湿性关节炎的含金口服化合物，其IC50为0.5M，比甲硝唑(5.2M)低10倍。口服金诺芬对阿米巴结肠炎和肝脓肿的啮齿动物模型也有效，导致孤儿药物地位被批准用于治疗阿米巴病。我们建议验证口服金诺芬与甲硝唑治疗阿米巴结肠炎具有同等疗效的假设。我们建议的临床试验是一项IIa期、3个平行臂、随机、双盲治疗研究，比较主动对照(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的疗效。我们将重点关注患有症状性腹泻(两次排便24小时)的患者(通过O&P检测特异性抗原、血清学或聚合酶链式反应)。他们将随机接受标准甲硝唑治疗(500 mg tid，共10d)、小剂量金诺芬(每日3 mg，共10d)或大剂量金诺芬(每日3 mg，每日2次，共10d)。主要终点是腹泻消失的时间(24小时内没有大便)，其次是寄生虫学反应的时间终点，通过显微镜和定量聚合酶链式反应。这项拟议的临床试验使用的是FDA重新配置的药物，可能导致 52年来首个治疗阿米巴病的新药和靶点。 公共卫生相关性：阿米巴病是全世界发病率和死亡率的主要原因，只有一类药物可供治疗。我们已经确定了一种FDA批准的药物Auranofin，它对引起阿米巴病的寄生虫非常有效。我们现在提议计划进行一项临床试验，以测试其与目前治疗方法的有效性，这可能导致52年来第一个治疗这种被忽视疾病的新药和药物靶点。

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.