Nitazoxanide: In vitro and in vivo drug effects against Trichuris muris and Ancylostoma ceylanicum, alone or in combination

Soil-transmitted helminths cause more than 1 billion human infections globally, mostly in the poorest regions of the world. Control relies essentially on a limited panel of four drugs, and drug resistance might be inescapable. Nitazoxanide, an anti-infective drug, has been shown to exert anthelmintic activity in human clinical trials. In the present work, nitazoxanide was tested alone or combined with commercialized anthelmintics on Trichuris muris, a whipworm mouse model, and Ancylostoma ceylanicum, a hookworm hamster model, in vitro and in vivo. IC50s of ⩽1 and 12.87 μg/ml were achieved with nitazoxanide on T. muris third-stage larvae (L3) and adult worms in vitro, respectively. An IC50 of ⩽1 μg/ml was obtained exposing A. ceylanicum adults worms to nitazoxanide, whereas A. ceylanicum L3 were not affected. Using scanning electron microscopy, the tegument of adult T. muris appeared unchanged following nitazoxanide treatment, whereas swellings were seen on the tegument of the anterior region of half of the A. ceylanicum specimen analyzed. Synergism was observed in vitro when nitazoxanide was combined with levamisole or ivermectin on T. muris adult worms, and when combined with levamisole, pyrantel pamoate, or ivermectin on A. ceylanicum adult worms. In T. muris-infected mice, oral nitazoxanide achieved worm burden reductions of 56.09% and 17.37% following a single dose of 100 mg/kg and three doses of 50 mg/kg, respectively. None of the tested drug combinations displayed activity on T. muris in vivo. In A. ceylanicum-infected hamsters, no effect was observed for oral nitazoxanide alone, and none of the tested combinations reached the threshold for additive effect. In conclusion, nitazoxanide failed to demonstrate promising activity against T. muris and A. ceylanicum in vivo, regardless whether tested as monotherapy or combined with standard drugs. Reasons for the discrepancy of these findings compared to results obtained in clinical trials remain to be elucidated.

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• Nitazoxanide showed activity on Trichuris muris L3 and adult worms in vitro.
• Ancylostoma ceylanicum adult worms were affected by nitazoxanide in vitro.
• Nitazoxanide combined with levamisole or ivermectin displayed synergism in vitro on T. muris.
• Nitazoxanide plus pyrantel pamoate was synergistic in vitro on A. ceylanicum.
• In vivo nitazoxanide achieved unsatisfactory anthelmintic efficacy.