Oral Pyronaridine\nTetraphosphate Reduces Tissue Presence\nof Parasites in a Mouse Model of Chagas Disease

The eukaryotic parasite <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>) is responsible for Chagas disease, which\nresults\nin heart failure in patients. The disease is more common in Latin\nAmerica, and is an emerging infection with The Centers for Disease\nControl estimating that greater than 300,000 people are currently\ninfected in the United States. This disease has also spread from\nSouth and Central America, where it is endemic to many other countries,\nincluding Australia, Japan, and Spain. Current therapy for Chagas\ndisease is inadequate due to limited efficacy in the indeterminate\nand chronic phases of the disease, in addition to the adverse effects\nfrom nifurtimox and benznidazole, which are nitro-containing drugs\nused for therapy. There is a clear need for new therapies for the\nChagas disease. Using a computational machine learning approach, we\nhave previously shown that the antimalarial pyronaridine tetraphosphate\nis active against <i>T. cruzi</i> Brazil-luc <i>in\nvitro</i> against parasites infecting a myoblast cell line and\nis also active <i>in vivo</i> in an acute mouse model of\nChagas disease when dosed i.p. We now further evaluated oral pyronaridine\nas a monotherapy to determine the minimum effective dose to treat\nacute and chronic models of Chagas disease. Our results for <i>T. cruzi</i> Brazil-luc demonstrated daily oral dosing with\npyronaridine from 150 to 600 mg/kg resulted in statistically significant\ninhibition in the 7 day acute mouse model. Combination therapy with\ndaily dosing of benznidazole and pyronaridine in the acute infection\nmodel demonstrated that 300 mg/kg pyronaridine could return statistically\nsignificant antiparasitic activity to a subtherapetic 10 mg/kg benznidazole.\nIn contrast, pyronaridine as monotherapy or combined with benznidazole\nlacked efficacy in the chronic mouse model, whereas 100 mg/kg benznidazole\nalone demonstrated undetectable parasites in the heart of mice. Pyronaridine\nrequires further assessment in other chronic models to identify if\nit can be used beyond the acute stage of <i>T. cruzi</i> infection.