Effects of miconazole/clotrimazole and praziquantel combinations against the liver fluke Opisthorchis felineus in vivo and in vitro
The liver fluke Opisthorchis felineus (Rivolta, 1884) is the causative agent of opisthorchiasis felinea in Eurasia. Opisthorchiasis is a serious human and fish-eating animal’s disease affecting bile ducts and the gall bladder. Currently, the main drug for specific therapy of opisthorchiasis is praziquantel. We have previously shown that azole inhibitors of O. felineus cytochrome P450 significantly reduced survival of the worms in vitro. Here, we studied in vitro anthelmintic effects of drug combinations involving azole substances approved by the US Food and Drug Administration together with praziquantel against adult or juvenile O. felineus liver flukes. A synergistic interaction was shown for praziquantel-clotrimazole (CI = 0.68) combination and for praziquantel-miconazole (CI = 0.68) combination against adult helminths in vitro. Praziquantel-miconazole (CI = 0.30) had a strongly synergistic effect against newly excysted metacercariae. We also tested anthelmintic effects of azole substances and their combinations with praziquantel in vivo in an animal model of chemotherapy. The treatment of juvenile worms (1 day postinfection) with 100 mg/kg miconazole resulted in a worm burden reduction (WBR) of 37.5% (P = 0.049), with 100 mg/kg clotrimazole causing a WBR of 31.25% (P = 0.025). The treatment of adult worms (5–6 weeks postinfection) with 100 mg/kg or 200 mg/kg miconazole yielded a WBR of 23.8% (P = 0.01) and 21.4% (P = 0.006), respectively. When praziquantel was administered together with clotrimazole or with miconazole, a WBR slightly greater than the effect of ED50 praziquantel was observed (WBR of 59.5 and 54.7%, respectively).
In conclusion, the synergistic effect of the praziquantel-clotrimazole and praziquantel-miconazole combinations observed in vitro was not confirmed in vivo. Thus, this combination chemotherapy revealed no benefits over praziquantel monotherapy in the treatment of opisthorchiasis felinea.
KeywordsFoodborne trematodes Combination chemotherapy Opisthorchis felineus Praziquantel Miconazole Clotrimazole
We acknowledge the support and collaboration of members of the TOPIC (Tomsk OPIsthorchiasis Consortium). This work was supported by the Russian Foundation for Basic Research [grant numbers 16-04-00356a (MYP), 18-04-00417a (VAM)] and the state project of the Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences, [project No. 0324-2018-0016] (MYP, VAM). The studies were partly implemented using the equipment of the Center for Genetic Resources of Laboratory Animals at ICG SB RAS, supported by the Ministry of Education and Science of Russia (project number RFMEFI62117X0015). The funder had no role in this study such as study design, data collection, or decision to publish.
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Conflict of interest
The authors declare that they have no conflict of interest.
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