Abstract
Alveolar echinococcosis (AE) caused by the cestode Echinococcus multilocularis (E. multilocularis) is endemic in wide areas of the Northern hemisphere. Untreated AE progresses and leads to death in more than 90 % of cases. Until the advent of benzimidazoles, no antihelminthic drugs were available to cure AE. Benzimidazoles have greatly improved the prognosis of patients with AE. However, benzimidazoles have only a parasitostatic effect on E. multilocularis. Albendazole (ABZ) must sometimes be withdrawn because of adverse events. Alternative drugs are urgently needed. The antihelminthic triclabendazole (TCZ) and clorsulon (CLS) are more effective than ABZ to cure infections by the liver flukes Fasciola spp. The efficacy of TCZ and CLS was investigated on an in vitro culture of E. multilocularis larval tissue. E. multilocularis vesicles were evaluated for their morphology before and after adding TCZ, TCZ sulfoxide (TCZSX) and CLS to the larval tissue culture. TCZ at the concentrations of 20 μg/ml culture solution led to maximum vesicle damage within 12 days and of 25 μg/ml within 13 days, and TCZSX at the concentrations of 20 μg/ml within 20 days and of 25 μg/ml within 14 days. Contrary, CLS added at 5, 10 and 15 μg/ml to culture solution did not lead to any vesicle damage. TCZ is a promising further candidate drug for the treatment of AE.
Similar content being viewed by others
References
Abdi YA, Gustafsson LL, Ericsson O, Hellgren U (1995) Handbook of drugs for tropical parasitic diseases. 2nd ed.; Taylor and Francis London. pp.12-17 and pp. 78–82
Alvarez LI, Mottier ML, Lanusse CE (2004) Comparative assessment of albendazol, febendazol and triclabendazol to Fasciola hepatica: effect of bile in the incubation medium. Parasitology 128(1):73–81
Ammann RW, Fleiner Hoffmann A, Eckert J, und Schweizerische Echinokokkose-Studiengruppe (SESG) (1999) Schweizerische Studie für Chemotherapie der alveolären Echinokokkose–Rückblick auf ein 20jähriges klinisches Forschungsprojekt. Swiss chemotherapy trial for alveolar echinococcosis: review of a 20-year clinical research project. Schweiz Med Wochenschr 129:323–332
Boray JC, Crowfoot PD, Strong MB, Allison JR, Schellenbaum M, Von Orelli M, Sarasin G (1983) Treatment of immature and mature Fasciola hepatica infections in sheep with triclabendazole. Vet Rec 113:315–317
Brunetti E, Kern P, Vuitton DE (2010) Writing panel for the WHO-International Working Group on Echinococcosis. Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop 114:1–16
Bygott JM, Chiodini PL (2009) Praziquantel: neglected drug? ineffective treatment? or therapeutic choice in cystic hydatid disease. Acta Trop 111:95–101
Coles GC, Stafford KA (2001) Activity of oxyclozanide, nitroxynil, clorsulon and albendazole against adult triclabendazole-resistant Fasciola hepatica. Vet Rec 148:723–724
Da Violante G, Zerrouk N, Richard I, Provot G, Chaumeil JC, Arnaud P (2002) Evaluation of the cytotoxicity effect of dimethyl sulfoxide (DMSO) on Caco2/TC7 colon tumor cell cultures. Biol Pharm Bull 12:1600–1603
Eckert J, Deplazes D, Kern P (2011) Alveolar echinococcosis (Echinococcus multilocularis) and neotropical forms of echinococcosis (Echinococcus vogeli and Echinococcus oligarthrus). In SR Palmer Lord Soulsby, PR Torgerson, DWW Brown edts.: Oxford Textbook of Zoonoses. Oxford University Press, pp. 669–699
Elitok B, Elitok OM, Kabu M (2006) Field trial on comparative efficacy of four fasciolicides against natural liver fluke infection in cattle. Vet Parasitol 135:279–285
Fairweather I (2005) Triclabendazole: new skills to unravel an old(ish) enigma. J Helminthol 79:227–234
Fairweather I, Boray JC (1999a) Fasciolicides: efficacy, actions, resistance and its management. Vet J 158:81–112
Fairweather I, Boray JC (1999b) Mechanism of fasciolicide action and drug resistance in Fasciola hepatica. In: Dalton JP (ed) Fascioliasis. CABI publishing, Dublin, Ireland, pp 225–276
Gelmedin V, Caballero-Gamiz R, Brehm K (2008) Characterization and inhibition of a p38-like mitogen and mitogen-activated protein kinase (MAPK) from Echinococcus multilocularis: antiparasitic activities of p38 APK inhibitors. Biochem Pharmacol 76:1068–1081
Heath DD, Christie MJ, Chevis RAF (1975) The lethal effect of mebendazole on secondary Echinococcus granulosus cysticerci and Taenia pisiformis and tetrahydria Mesocestoides corti. Parasitology 70:273–285
Hemphill A, Gottstein B (1995) Immunological and morphological studies on the proliferation of in vitro cultivated Echinococcus multilocularis metacestode. Parasitol Res 851:605–614
Hemphill A, Müller J (2009) Alveolar and cystic echinococcosis: towards novel chemotherapeutical treatment options. J Helminthol 83:99–111
Hemphill A, Stettler M, Walker M, Siles-Lucas M, Fink R, Gottstein B (2003) In vitro culture of Echinococcus multilocularis and Echinococcus vogeli metacestodes: studies on the host-parasite interface. Acta Trop 85:145–155
Hemphill A, Spicher S, Stadelmann B, Mueller J, Naguleswaran A, Gottstein B (2007) Innovative chemotherapeutical treatment options for alveolar and cystic echinococcosis. Parasitology 134:1657–1670
Hutchinson GW, Dawson K, Fitzgibbon CC, Martin PJ (2009) Efficacy of an injectable combination anthelmintic (nitroxynil + clorsulon + ivermectin) against early immature Fasciola hepatica compared to triclabendazole combination flukicides given orally or topically to cattle. Vet Parasitol 162:278–284
Ingold K, Bigler P, Thormann W, Cavaliero T, Gottstein B, Hemphill A (1999) Efficacies of albendazole sulfoxide and alebendazole sulfone against in vitro cultivated Echinococcus multilocularis metacestodes. Antimicrob Agents Chemother 43:1052–1061
Jura H, Bader A, Frosch M (1998) In vitro activities of benimidazoles against Echinococcus multilocularis metacestodes. Antimicrob Agents Chemother 42:1052–1056
Keiser J, Engels D, Büscher G, Utzinger J (2005) Triclabendazole for the treatment of fascioliasis and paragonimiasis. Expert Opinion Invest Drugs 14:1513–1526
Kern P, Reuter S, Manfras B, Merkle M, Härter G (2006) In vitro activities of itraconazol, methiazol and nitazoxanide versus Echinococcus multilocularis larvae. Antimicrobial Agents Chemother 50:2966–2970
Küster T, Stadelmann B, Scholl S, Barna F, Kropf C, Keiser J, Boykin DW, Stephens CE, Hemphill A (2011) In vitro and in vivo efficacies of mefloquine-based treatment against alveolar echinococcosis. Antimicrob Agents Chemother 55:713–721
Lacey E (1990) Mode of action of benzimidazoles. Parasitol Today 6:112–115
Lawton PN, Walchshofer N, Sarciron M (2001) In vitro and in vivo effects of Isoprinosine and a dipeptide methyl ester on Echinococcus multilocularis protoscolices. J Helminthol 75:251–257
Lecaillon JB, Godbillon J, Campestrini J, Naquira C, Miranda L, Pacheco R, Mull R, Poltera AA (1998) Effect of food on the bioavailability of triclabendazole in patients with fascioliasis. Br J Clin Pharmacol 45:601–604
Liance M, Nemati C, Bories C, Couvreur P (1992) Effects of cyclosprin A on the course of murine alveolar echinococcosis and on specific cellular and humoral immune responses against Echinococcus multilocularis. Int J Parasitol 22:23–28
Liance M, Nemati C, Bories C, Couvreur P (1993) Experience with doxorubicine-bound polyisohexylcyanoacrylate nanoparticles on murine alveolar echinococcosis of the liver. Int J Parasitol 23:427–429
Mathis A, Wild P, Boettger C, Kapel CM, Deplazes P (2005) Mitochondrial ribosome as the target for the macrolide antibiotic clarithromycin in the helminth Echinococcus multilocularis. Antimicrob Agents Chemother 49:3251–3255
Millán JC, Mull R, Freise S, Richter J, The Triclabendazole Study Group (2000) Efficacy and tolerability of triclabendazole for the treatment of latent and chronic fascioliasis. Am J Trop Med and Hyg 63:264–269
Miyaji S, Katakura K, Matsufuji S, Murakami Y, Hayashi S, Oku Y, Okamoto M, Kamiya M (1993) Failure of treatment with alpha-difluoromethylornithine against secondary multilocular echinococcosis in mice. Parasitol Res 79:75–76
Mottier L, Virkel G, Solana H, Alvarez L, Salles J, Lanusse C (2004) Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica. Xenobiotica 34:1043–1057
Müller J, Limban C, Stadelmann B, Missir AV, Chirita IC, Chifiriuc MC, Nitulescu GM, Hemphill A (2009) Thioureides of 2-(phenoxymethyl)benzoic acid 4-R substituted. A novel class of antiparasitic compounds. Parasitol Int 58:128–135
Naguleswaran A, Spicher M, Vonlaufen N, Ortega-Mora LM, Torgerson P, Gottstein B, Hemphill A (2006) In vitro metacestocidal activities of genistein and other isoflavones against Echinococcus multilocularis and Echinococcus granulosus. Antimicrob Agents Chemother 50:3770–3778
Peréz-Molina JA, Diaz-Menendez M, Gallego JI, Norman F, Monge-Maillo B, Peréz-Ayala A, López-Vélez R (2011) Evaluation of nitazoxanide for the treatment of disseminated cystic echinococcosis. Report of five cases and literature review. Am J Trop Med H 84:351–356
Reuter S, Kratzer W, Kurz S, Wellinghausen N, Kern P (1998) Chemotherapy of alveolar echinococcosis with benzimidazoles. A prospective long-term study. Med Klin 93:463–467
Reuter S, Jensen B, Buttenschoen K, Kratzer W, Kern P (2000) Benzimidazoles in the treatment of alveolar echinococcosis: a comparative study and review of the literature. J Antimicrob Chemother 46:451–456
Reuter S, Merkle M, Brehm K, Kern P, Manfras B (2003a) Effect of amphotericin b on larval growth of Echinococcus multilocularis. Antimicrob Agents Chemother 47:620–625
Reuter S, Buck A, Grebe O, Nüssle-Kügele K, Kern P, Manfras B (2003b) Salvage treatment with amphotericin B in progressive human alveolar echinococcosis. Antimicrob Agents Chemother 47:3586–3591
Reuter S, Manfras B, Merkle M, Härter G, Kern P (2006) In vitro activities of itraconazole, methiazole, and nitazoxanide versus Echinococcus multilocularis. Antimicrob Agents Chemother 50:2866–2970
Reuter S, Beisler T, Kern P (2010) Combined albendazole and amphotericin B against Echinococcus multilocularis in vitro. Acta Trop 115:270–274
Richter D (2010) In vitro Testung ausgewählter Antihelminthica auf das Larvenstadium von Echinocccus multilocularis. [In vitro testing of selected antihelminthica on the larval stage of Echinocccus multilocularis]. Diploma thesis in Pharmacy. Institute for Pharmacy and Medical Faculty, Ernst-Moritz-Arndt-Universität Greifswald and Department of Internal Medicine III, Section Infectiology and Clinical Immunology, University Hospitals Ulm, Germany
Richter J, Freise S, Mull R, Millán JC, The Triclabendazole Clinical Study Group (1999) Fascioliasis: sonographic abnormalities of the biliary tract and evolution after treatment with triclabendazole. Trop Med Intern Health 4:774–781
Richter J, Knipper M, Göbels K, Häussinger D (2002) Fascioliasis. In Current Treatment Options in Infectious Diseases 4:313–317
Schulman MD, Ostlind DA, Valentino D (1982) Mechanism of action of MK-401 against Fasciola hepatica: inhibition of phosphoglycerate kinase. Mol Biochem Parasitol 5:133–145
Spicher M, Roethlisberger C, Lany C, Stadelmann B, Keiser J, Ortega-Mora LM, Gottstein B, Hemphill A (2008a) In vitro and in vivo treatments of echinococcus protoscoleces and metacestodes with artemisinin and artemisinin derivatives. Antimicrob Agents Chemother 52:3447–3450
Spicher M, Naguleswaran A, Ortega-Mora LM, Müller J, Gottstein B, Hemphill A (2008b) In vitro and in vivo effects of 2-methoxyestradiol, either alone or combined with albendazole, against Echinococcus metacestodes. Exp Parasitol 119:475–482
Stadelmann B, Küster T, Scholl S, Barna F, Kropf C, Keiser J, Boykin DW, Stephens CE, Hemphill A (2011) Efficacy of dicatonic compounds and mefloquine enantiomers against Echinococcus multilocularis metacestodes. Antimicrob Agents Chemother 55:4866–4872
Stettler M, Siles-Lucas M, Sarciron E, Lawton P, Gottstein B, Hemphill A (2003) In vitro parasitocidal effect of nitazoxanide against Echinococcus multilocularis metacestodes. Antimicrob Agents Chemother 47:467–474
Stettler M, Siles-Lucas M, Sarciron E, Lawton P, Gottstein B, Hemphill A (2004) Secondary and primary alveolar echinococcosis: combined albendazole/nitazoxanide chemotherapy exhibits profound anti-parasitic activity. Int J Parasitol 34:615–624
Sundlof SF, Whitlock TW (1992) Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration. J Vet Pharmacol Ther 5:282–291
Torgerson PR, Schweiger A, Deplazes P, Pohar M, Reichen J, Ammann RW, Tarr PE, Halkik N, Mullhaupt B (2008) Alveolar echinococcosis: from a deadly disease to a well-controlled infection. Relative survival and economic analysis in Switzerland over the last 35 years. J Hepatol 49:72–77
World Health Organization (1993) Evaluation of certain veterinary drug residues in food. WHO Tech Rep Ser 832:1–62
World Health Organization (1996) Guidelines for treatment of cystic and alveolar echinococcosis in humans. WHO Informal Working Group on Echinococcosis. Bull WHO 74:231–242
World Health Organization (2007) Report of the WHO Informal Meeting on Use of Triclabendazole in Fascioliasis Control. WHO Headquarters, Geneva, Switzerland: October 17–18, 2006. Available at: www.who.int/neglected_diseases/preventive_chemotherapy/WHO_CDS_NTD_PCT_2007.1.pdf. Accessed June 12, 2012.World Health Organization
Acknowledgments
This work is part of a diploma thesis in Pharmacy by David Richter. We are indebted to Dr. S. Wacker, Dr. F. Oswald, Dr. K. Wahlers, Dr. M. Willmann, Dr. G. Härter, U. Knoll, I. Katz, A. Helfrich and M. Holl for their cooperation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Richter, D., Richter, J., Grüner, B. et al. In vitro efficacy of triclabendazole and clorsulon against the larval stage of Echinococcus multilocularis . Parasitol Res 112, 1655–1660 (2013). https://doi.org/10.1007/s00436-013-3321-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-013-3321-7