Abstract
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.
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References
Bartley DJ, Morrison AA, Dupuy J, Bartley Y, Sutra JF, Menez C, Alvinerie M, Jackson F, Devin L, Lespine A (2012) Influence of Pluronic 85 and ketoconazole on disposition and efficacy of ivermectin in sheep infected with a multiple resistant Haemonchus contortus isolate. Vet Parasitol 187:464–472. https://doi.org/10.1016/j.vetpar.2012.02.011
Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70:440–446. https://doi.org/10.1158/0008-5472.CAN-09-1947
Cowan N, Keiser J (2015) Repurposing of anticancer drugs: in vitro and in vivo activities against Schistosoma mansoni. Parasit Vectors 8:417
Day TA, Botros S (2006) Drug resistance in schistosomes. In: Maule AG, Marks NJ (eds) Parasitic flatworms: molecular biology, biochemistry, immunology and physiology. CABI, London, pp 256–265
Devine C, Brennan GP, Lanusse CE, Alvarez LI, Trudgett A, Hoey E, Fairweather I (2010) Enhancement of the drug susceptibility of a triclabendazole resistant isolate of Fasciola hepatica using the metabolic inhibitor ketoconazole. Parasitol Res 107:337–353. https://doi.org/10.1007/s00436-010-1866-2
Doenhoff MJ, Cioli D, Utzinger J (2008) Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis 21:659–667. https://doi.org/10.1097/QCO.0b013e328318978f
Gouveia MJ, Pakharukova MY, Laha T, Sripa B, Maksimova GA, Rinaldi G, Brindley PJ, Mordvinov VA, Amaro T, Santos LL, Correia da Costa JM, Vale N (2017) Infection with Opisthorchis felineus induces intraepithelial neoplasia of the biliary tract in a rodent model. Carcinogenesis 38:929–937. https://doi.org/10.1093/carcin/bgx042
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2012) Biological agents. Volume 100 B. A review of human carcinogens. In: IARC monographs on the evaluation of carcinogenic risks. International Agency for Research on Cancer, Lyon, p 1–441
Keiser J, Tritten L, Silbereisen A, Speich B, Adelfio R, Vargas M (2013) Activity of oxantel palmoate monotherapy and combination chemotherapy against Trichuris muris and hookworms: revival of an old drug. PLoS Negl Trop Dis 7:e2119. https://doi.org/10.1371/journal.pntd.0002119
Maksimova GA, Pakharukova MY, Kashina EV, Zhukova NA, Kovner AV, Lvova MN, Katokhin AV, Tolstikova TG, Sripa B, Mordvinov VA (2017) Effect of Opisthorchis felineus infection and dimethylnitrosamine administration on the induction of cholangiocarcinoma in Syrian hamsters. Parasitol Int 66:458–463. https://doi.org/10.1016/j.parint.2015.10.002
Mordvinov VA, Shilov AG, Pakharukova MY (2017) Anthelmintic activity of cytochrome P450 inhibitors MIC and CLZ: in-vitro effect on the liver fluke Opisthorchis felineus. Int J Antimicrob Agents 50:97–100. https://doi.org/10.1016/j.ijantimicag.2017.01.037
Pakharukova MY, Mordvinov VA (2016) The liver fluke Opisthorchis felineus: biology, epidemiology, and carcinogenic potential. Trans R Soc Trop Med Hyg 110:28–36. https://doi.org/10.1093/trstmh/trv085
Pakharukova MY, Ershov NI, Vorontsova EV, Katokhin AV, Merkulova TI, Mordvinov VA (2012) Cytochrome P450 in fluke Opisthorchis felineus: identification and characterization. Mol Biochem Parasitol 181:190–194. https://doi.org/10.1016/j.molbiopara.2011.11.005
Pakharukova MY, Shilov AG, Pirozhkova DS, Katokhin AV, Mordvinov VA (2015a) The first comprehensive study of praziquantel effects in vivo and in vitro on European liver fluke Opisthorchis felineus (Trematoda). Int J Antimicrob Agents 46:94–100
Pakharukova MY, Vavilin VA, Sripa B, Laha T, Brindley PJ, Mordvinov VA (2015b) Functional analysis of the unique cytochrome P450 of the liver fluke Opisthorchis felineus. PLoS Negl Trop Dis 9:e0004258
Pospísil J, Postupa J, Otcenásek M, Vejbora O (1990) Pathogenicity of Trichosporon capitatum for normal and irradiated mice and the efficacy of MIC on experimental systemic trichosporosis in mice. Mycoses 33:559–566. https://doi.org/10.1111/myc.1990.33.11-12.559
Prichard RK, Basanez MG, Boatin BA, McCarthy JS, Garcia HH, Yang GJ, Sripa B, Lustigman S (2012) A research agenda for helminth diseases of humans: intervention for control and elimination. PLoS Negl Trop Dis 6:e1549. https://doi.org/10.1371/journal.pntd.0001549
Rifai N, Sakamoto M, Law T, Platt O, Mikati M, Armsby CC, Brugnara C (1995) HPLC measurement, blood distribution, and pharmacokinetics of oral CLZ, potentially useful antisickling agent. Clin Chem 41:387–391
Sripa B, Brindley PJ, Mulvenna J, Laha T, Smout MJ, Mairiang E, Bethony JM, Loukas A (2012) The tumorigenic liver fluke Opisthorchis viverrini multiple pathways to cancer. Trends Parasitol 28:395–407. https://doi.org/10.1016/j.pt.2012.07.006
Wiebe VJ (2015) Drug therapy for infectious diseases of the dog and cat. John Wiley & Sons, Ames. https://doi.org/10.1016/j.jcin.2015.07.040
Funding
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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Pakharukova, M.Y., Pakharukov, Y.V. & Mordvinov, V.A. Effects of miconazole/clotrimazole and praziquantel combinations against the liver fluke Opisthorchis felineus in vivo and in vitro. Parasitol Res 117, 2327–2331 (2018). https://doi.org/10.1007/s00436-018-5895-6
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DOI: https://doi.org/10.1007/s00436-018-5895-6