Entamoeba histolytica and Giardia lamblia are major causes of water- and foodborne outbreaks. Imidazoles, particularly metronidazole, are the primary class of drugs used worldwide for treatment. Resistance to metronidazole is a growing concern in Giardia and Entamoeba as cross resistance also occurs to the newer drugs, tinidazole and nitazoxanide. The NIH has made the identification of new drugs for Class B agents a priority. Under a UO1 grant, we developed high throughput screens using Entamoeba and Giardia trophozoites. We found one drug, auranofin, an oral gold-containing compound approved by the FDA in 1985 to treat rheumatoid arthritis, had an IC50 significantly lower for Entamoeba and equivalent for Giardia to metronidazole. Most importantly, oral auranofin was effective in vitro and in vivo against E. histolytica and both metronidazole-sensitive and resistan strains of Giardia. Based on these findings, we will test the hypothesis that oral auranofin is effective treatment of amebiasis and giardiasis. Our proposed clinical trial is a Phase IIa, 2 parallel arms, randomized, controlled, double blinded, superiority treatment study comparing short course auranofin (5 days for Giardia and 7 days for Entamoeba) to placebo for treatment of amebiasis and giardiasis in adults. Our experienced co-investigators from the International Center for Diarrheal Diseases in Bangladesh and University of Virginia, Drs. Haque and Petri, will identify asymptomatic patients =18 years old with E. histolytica or Giardia detected in their stools by microscopy, antigen testing, or positive stool PCR, in a highly endemic area. The primary end-point will be the proportion of patients with resolution of amebiasis (no detectable cysts or trophozoites on microscopic examination) by day 7 of therapy. Secondary outcomes include proportion of patients with resolution of giardiasis or amebiasis by days 3 or 5 of therapy, rate of decrease of trophozoites/cyst load by qPCR in stools by Days 3, 5, and 7, and proportion of patients with negative stool antigen test by Days 3, 5, and 7. Because initial studies show auranofin is also active against cysts, we will follow the proportion of patients with sustained cure at 28 days and determine relapse or re-infection by genotyping of strains. This proposed clinical trial using a re- profiled FDA drug could result in the first new drug and define target for the treatment of amebiasis and giardiasis in 52 years. In addition, auranofin may prove to be a future broad spectrum antiparasitic drug as in vitro efficacy has also been demonstrated against Cryptosporidium, Trichomonas, toxoplasmosis, T. brucei, filariasis, and schistosomiasis.
Amebiasis and giardiasis are major causes of morbidity from diarrheal disease worldwide, and resistance to the one class of drugs used to treat most patients is of increasing concern. We have identified an FDA-approved drug, auranofin, which is highly active against Entamoeba and both drug-sensitive and resistant Giardia parasites. We now propose a clinical trial to test its efficacy, which could lead to the first new drug and drug target to treat these neglected diseases in 52 years.
|Capparelli, Edmund V; Bricker-Ford, Robin; Rogers, M John et al. (2017) Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent. Antimicrob Agents Chemother 61:|
|Parsonage, Derek; Sheng, Fang; Hirata, Ken et al. (2016) X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action. J Struct Biol 194:180-90|