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Monepantel: the most studied new anthelmintic drug of recent years

Published online by Cambridge University Press:  09 September 2014

L. LECOVÁ*
Affiliation:
Department of biochemical sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
L. STUCHLÍKOVÁ
Affiliation:
Department of biochemical sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
L. PRCHAL
Affiliation:
Department of biochemical sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
L. SKÁLOVÁ
Affiliation:
Department of biochemical sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
*
*Corresponding author. Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. E-mail: lecoval@faf.cuni.cz

Summary

Monepantel (MOP), a new anthelmintic drug from a group of amino-acetonitrile derivatives, has been intensively studied during last years. Many authors examined this new drug from different perspectives, e.g. efficacy against different species and stages of parasites, mode of action, metabolism, pharmacokinetics, toxicity, resistance, ecotoxicity, etc. MOP is an anthelmintic for livestock (currently only sheep and goats), with molecular mode of action which is different to all other anthelmintics. MOP has a broad-spectrum of activity against gastrointestinal nematodes of sheep, including adults and L4 larvae of the most important species. The key feature of MOP is its full effectiveness against strains of nematodes resistant to benzimidazoles, levamisole, macrocyclic lactones and closantel. After oral administration, MOP is quickly absorbed into the bloodstream and quickly metabolized to MOP sulfone that has a similar efficacy as the parent molecule. Several other MOP metabolites formed in ovine hepatocytes were described. MOP and its metabolites are considered to be non-toxic to environment and its components, such as soil microflora, aquatic organisms, dung organisms, vegetation, etc. The aim of the presented review was not to collect all reported data but to bring an overview of various approaches in the study of MOP and to evaluate their principal results.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2014 

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References

REFERENCES

Abdelsalam, E. B. (1986). The effects of levamisole (L-Tetramisole) in domestic animals. Acta Veterinaria (Beograd) 36, 2330.Google Scholar
Andrews, A. H., Blowey, R. W. and Boyd, H. (2008). Bovine Medicine: Diseases and Husbandry of Cattle, 2nd Edn. Wiley-Blackwell, USA.Google Scholar
Australian Pesticides and Veterinary Medicines Authority (2010). Public Release Summary on the Evaluation of the New Active Monepantel in the Product Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep. APVMA product number 62752, 1–79. ISSN: 1443–1335, Available: http://www.apvma.gov.au/registration/assessment/docs/prs_monepantel.pdf Google Scholar
Bahrami, B. F., Morris, D. L. and Pourgholami, M. H. (2013). Monepantel suppress ovarian cancer cell proliferation by arresting cell cycle at G1 through ERK/p70S6k pathway and down regulating cycline D1 and Cdk 4. Presented at Lowy Cancer Symposium: Discovering Cancer Therapeutics, 15.–17.5.2013, The University of New South Wales, Sydney, Australia, Lowy Cancer Research Centre. Available: http://lowy-cancer-symposium.p.asnevents.com.au/event/abstract/5849 Google Scholar
Besier, R. B. and Love, S. C. J. (2003). Anthelmintic resistance in sheep nematodes in Australia: the need for new approaches. Australian Journal of Experimental Agriculture 43, 13831391.Google Scholar
Beynon, S. A. (2012). Potential environmental consequences of administration of anthelmintics to sheep. Veterinary Parasitology 189, 113124.Google Scholar
Baker, K. E., George, S. D., Stein, P. A., Seewald, W., Rolfe, P. F. and Hosking, B. C. (2012). Efficacy of monepantel and anthelmintic combinations against multiple-resistant Haemonchus contortus in sheep, including characterisation of the nematode isolate. Veterinary Parasitology 186, 513517.CrossRefGoogle ScholarPubMed
Coles, G. C., Jackson, F., Pomroy, W. E., Prichard, R. K., Von Samson-Himmelstjerna, G., Silvestre, A., Taylor, M. A. and Vercruysse, J. (2006). The detection of anthelmintic resistance in nematodes of veterinary importance. Veterinary Parasitology 136, 167185.Google Scholar
Cvilink, V., Lamka, J. and Skálová, L. (2009). Xenobiotic metabolizing enzymes and metabolism of anthelmintics in helminthes. Drug Metabolism Reviews 41, 826.CrossRefGoogle Scholar
Dobson, R. J., Hosking, B. C., Besier, R. B., Love, S., Larsen, J. W. A., Rolfeb, P. F. and Bailey, J. N. (2011). Minimising the development of anthelmintic resistance, and optimising the use of the novel anthelmintic monepantel, for the sustainable control of nematode parasites in Australian sheep grazing system. Australian Veterinary Journal 89, 160166.CrossRefGoogle Scholar
Ducray, P., Gauvry, N., Pautrat, F., Goebel, T., Fruechtel, J., Desaules, Y., Schorderet Weber, S., Bouvier, J., Wagner, T., Froelich, O. and Kaminsky, R. (2008). Discovery of amino-acetonitrile derivatives, a new class of synthetic anthelmintic compound. Bioorganic and Medicinal Chemistry Letters 18, 29352938.Google Scholar
Epe, Ch. and Kaminsky, R. (2013). New advancement in anthelmintic drugs in veterinary medicine. Trends in Parasitology 29, 129134.Google Scholar
Fankhauser, R., Cozzie, L. R., Nare, B., Powell, K., Sluder, A. E. and Hammerland, L. G. (2012). Use of rodent models in the discovery of novel amthelmintics. In Parasitic Helminths – Targets, Screens, Drugs and Vaccines (ed. Caffrey, C. R.), pp. 181199. Wiley-Blackwell, Weinheim, Germany.CrossRefGoogle Scholar
Fleming, S. A., Craig, T., Kaplan, R. M., Miller, J. E., Navarre, Ch. and Rings, M. (2006). Anthelmintic resistance of gastrointestinal parasites in small ruminants. Journal of Veterinary Internal Medicine 20, 435444.CrossRefGoogle ScholarPubMed
Geudern, T., Hoste, H., Jacquiet, P., Traversa, D., Sotikari, S., Frangipane di Regalbono, A., Tzanidakis, N., Kostopoulou, D., Gaillac, C. H., Privat, S., Giangaspero, A., Zanardello, C., Noé, L., Vanimisetti, B. and Bartram, D. (2014). Anthelmintic resistance and multidrug resistance in sheep gastro-intestinal nematodes in France, Greece and Italy. Veterinary Parasitology 201, 5966.Google Scholar
Good, B. (2012). Anthelmintic resistance – a potential challenge for sheep procedures? In Technical Updates on Sheep Production (ed. Diskin, M. G. and McHugh, M. P.), pp. 7275. Teagasc – Agriculture and Food Development Authority, Carlow, Ireland.Google Scholar
Gordon, Ch. P., Hizartzidis, L., Tarleton, M., Sakoff, J. A., Gilbert, J., Campbell, B. E., Gasser, R. B. and McCluskey, A. (2014). Discovery of acrylonitrile-based small molecules active against Haemonchus contortus . Medicinal Chemistry Communications 5, 159164.Google Scholar
Herd, R. P., Sams, R. A. and Ashcraft, S. M. (1996). Persistence of ivermectin in plasma and faeces following treatment of cows with ivermectin sustained-release, pour-on or injectable formulations. International Journal of Parasitology 26, 10871093.Google Scholar
Holčapek, M., Kolářová, L. and Nobilis, M. (2008). High-performance liquid chromatography-tandem mass spectrometry in the identification and determination of phase I and phase II drug metabolites. Analytical and Bioanalytical Chemistry 391, 5978.CrossRefGoogle ScholarPubMed
Holčapek, M., Jirásko, R. and Lísa, M. (2012). Recent developments in liquid chromatography-mass spectrometry and related techniques. Journal of Chromatography A 1259, 315.Google Scholar
Hosking, B. C., Dobson, D. P., Stein, P. A., Kaminsky, R., Bapst, B., Mosimann, D., Mason, P. C., Seewald, W., Strehlau, G. and Sager, H. (2009). Dose confirmation studies for monepantel, an amino-acetonitrile derivative, against fourth stage gastro-intestinal nematode larvae infecting sheep. Veterinary Parasitology 160, 251257.Google Scholar
Hosking, B. C., Kaminsky, R., Sager, H., Rolfe, P. F. and Seewald, W. (2010 a). A pooled analysis of the efficacy of monepantel an amino-acetonitrile derivative against gastrointestinal nematodes of sheep. Parasitology Research 106, 529532.CrossRefGoogle ScholarPubMed
Hosking, B. C., Kaminsky, R., Sager, H., Karadzovska, D., Seewald, W., Giraudel, J. M. and Vercruysse, J. (2010 b). The effect of sheep breed, age, and gender on the pharmacokinetics and efficacy of monepantel, an amino-acetonitrile derivative. Parasitology Research 106, 367375.CrossRefGoogle ScholarPubMed
Hosking, B. C., Stein, P. A., Karadzovska, D., House, J. K., Seewald, W. and Giraudel, J. M. (2010 c). Effect of route of administration on the efficacy and pharmacokinetics of an experimental formulation of the amino-acetonitrile derivative monepantel in sheep. Veterinary Record 166, 490494.Google Scholar
Hsu, W. H. (1980). Toxicity and drug interactions of levamisole. Journal of the American Veterinary Medical Association 176, 11661169.Google ScholarPubMed
Kaminsky, R. and Rufener, L. (2012). Monepantel: from discovery to mode of action. In Parasitic Helminths – Targets, Screens, Drugs and Vaccines (ed. Caffrey, C. R.), pp. 233249. Wiley-Blackwell, Weinheim, Germany.Google Scholar
Kaminsky, R., Ducray, P., Jung, M., Clover, R., Rufener, L., Bouvier, J., Weber, S., Wenger, A., Wieland-Berghausen, S., Goebel, T., Gauvry, N., Pautrat, F., Skripsky, T., Froelich, O., Komoin-Oka, C., Westlund, B., Sluder, A. and Mäser, P. (2008). A new class of anthelmintics effective against drug-resistant nematodes. Nature 452, 176180.CrossRefGoogle ScholarPubMed
Kaminsky, R., Bapst, B., Stein, P. A., Strehlau, G. A., Allan, B. A., Hosking, B. C., Rolfe, P. F. and Sager, H. (2011). Differences in efficacy of monepantel, derquantel and abamectin against multi-resistant nematodes of sheep. Parasitology Research 109, 1923.Google Scholar
Kaminsky, R., Rufener, L., Bouvier, J., Lizundia, R., Weber, S. S. and Sager, H. (2013). Worms – a “license to kill”. Veterinary Parasitology 195, 286291.Google Scholar
Kaplan, R. M. (2004). Drug resistance in nematodes of veterinary importance: a status report. Trends in Parasitology 20, 477481.CrossRefGoogle ScholarPubMed
Karadzovska, D., Seewald, W., Browning, A., Smal, M., Bouvier, J. and Giraudel, J. M. (2009). Pharmacokinetics of monepantel and its sulfone metabolite, monepantel sulfone, after intravenous and oral administration in sheep. Journal of Veterinary Pharmacology and Therapeutics 32, 359367.CrossRefGoogle ScholarPubMed
Kinsella, B., Byrne, P., Cantwell, H., McCormack, M., Furey, A. and Danaher, M. (2011). Determination of the new anthelmintic monepantel and its sulfone metabolite in milk and muscle using a UHPLC-MS/MS and QuEChERS method. Journal of Chromatography B 879, 37073713.Google Scholar
Lanusse, C. E., Alvarez, L. I., Sallovitz, J. M., Mottier, M. L. and Sanchez Bruni, S. F. (2009). Antinematodal drugs. In Veterinary Pharmacology and Therapeutics (ed. Riviere, J. E. and Papich, M. G.), pp. 10531093. John Wiley & Sons, USA.Google Scholar
Leathwick, D. M. (2013). Managing anthelmintic resistance – parasite fitness, drug use strategy and the potential for reversion towards susceptibility. Veterinary Parasitology 198, 145153.Google Scholar
Leathwick, D. M. and Besier, R. B. (2014). The management of anthelmintic resistance in grazing ruminants in Australasia—strategies and experiences. Veterinary Parasitology 204, 4454.CrossRefGoogle ScholarPubMed
Lecová, L., Stuchlíková, L., Lamka, J., Špulák, M., Várady, M. and Skálová, L. (2013). Efficacy of monepantel against lower developmental stages of a multi-resistant and susceptible Haemonchus contortus isolates: an in vitro study. Helminthologia 50, 9195.CrossRefGoogle Scholar
Lin, J. H. and Lu, A. Y. H. (1997). Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacological Reviews 49, 403449.Google ScholarPubMed
Losey, J. E. and Vaughan, M. (2006). The economic value of ecological services provided by insects. Bioscience 56, 311323.CrossRefGoogle Scholar
Love, S. (2014). First confirmed case of resistance to new drench in Australia—what does it mean? WormBoss. Retrieved 29 July 2014 from http://www.wormboss.com.au/news/articles/drench-resistance/first-confirmed-case-of-resistance-to-new-drench-in-australiawhat-does-it-mean.php.Google Scholar
Lumaret, J. P. and Errouissi, F. (2002). Use of anthelmintics in herbivores and evaluation of risks for the non-target fauna of pastures. Veterinary Research 33, 547562.Google Scholar
Olliaro, P., Seiler, J., Kuesel, A., Horton, J., Clark, J. N., Don, R. and Keiser, J. (2011). Potential drug development candidates for human soil transmitted helminthiases. PLoS Neglected Tropical Diseases 5, e1138.CrossRefGoogle ScholarPubMed
Martin, R. J., Verma, S., Levandoski, M., Clark, C. L., Qian, H., Stewart, M., and Robertson, A. P. (2005). Drug resistance and neurotransmitter receptors of nematodes: recent studies on the mode of action of levamisole. Parasitology 131, 7184.Google Scholar
McKellar, Q. A. (1997). Ecotoxicology and residues of anthelmintic compounds. Veterinary Parasitology 72, 413435.Google Scholar
Morris, D. L., inventor; (2013). Newsouth Innovations Pty Limited, assignee. Kinase inhibitors for the treatment of cancer. Patent WO2013/138863 A1. September 26, 2013.Google Scholar
Parkinson, J., Mitreva, M., Whitton, C., Thomson, M., Daub, J., Martin, J., Schmid, R., Hall, N., Barrell, B., Waterston, R. H., McCarter, J. P. and Blaxter, M. L. (2004). A transcriptomic analysis of the phylum Nematoda. Nature Genetics 36, 12591267.Google Scholar
Ramage, C., Bartley, D. J., Jackson, F., Cody, R. and Hosking, B. C. (2012). The efficacy of monepantel against naturally acquired inhibited and developing fourth-stage larvae of Teladorsagia cicumcinta in sheep in the United Kingdom. Veterinary Parasitology 186, 528531.Google Scholar
Robertson, A. P., Buxton, S. K., Puttachary, S., Williamson, S. M., Wolstenhome, A. J., Neveu, C., Cabaret, J., Chavret, C. L. and Martin, R. J. (2012). Antinematodal drugs – modes of action and resistance: and worms will not come to thee (Shakespeare: Cymbeline: IV, ii). In Parasitic Helminths – Targets, Screens, Drugs and Vaccines (ed. Caffrey, C. R.), pp. 233249. Wiley-Blackwell, Weinheim, Germany.Google Scholar
Rufener, L., Mäser, P., Roditi, I. and Kaminsky, R. (2009). Haemonchus contortus acetylcholine receptors of the DEG-3 subfamily and their role in sensitivity to monepantel. PLoS Pathogens 5, e1000380.CrossRefGoogle ScholarPubMed
Rufener, L., Keiser, J., Kaminsky, R., Mäser, P. and Nilsson, D. (2010 a). Phylogenomics of ligand-gated ion channels predicts monepantel effect. PLoS Pathogens 6, e1001091.Google Scholar
Rufener, L., Baur, R., Kaminsky, R., Mäser, P. and Sigel, E. (2010 b). Monepantel allosterically activates DEG-3/DEG-2 channels of the gastrointestinal nematode. Haemonchus contortus . Molecular Pharmacology 78, 895902.Google Scholar
Sager, H., Hosking, B. C., Bapst, B., Stein, P., Vanhoff, K. and Kaminsky, R. (2009). Efficacy of the amino-acetonitrile derivative, monepantel, against experimental and natural adult stage gastro-intestinal nematode infection in sheep. Veterinary Parasitology 159, 4954.CrossRefGoogle ScholarPubMed
Sager, H., Bapst, B., Strehlau, G. A. and Kaminsky, R. (2012). Efficacy of monepantel, derquantel and abamectin against adult stages of a multi-resistant Haemonchus contortus isolate. Parasitology Research 111, 22052207.Google Scholar
Sangster, N. C. and Gill, J. (1999). Pharmacology of anthelmintic resistance. Parasitology Today 15, 141146.CrossRefGoogle ScholarPubMed
Scott, I., Pomroy, W. E., Kenyon, P. R., Smith, G., Adlington, B. and Moss, A. (2013). Lack of efficacy of monepantel against Teladorsagia circumcincta and Trichostrongylus colubriformis . Veterinary Parasitology 198, 166171.Google Scholar
Shalaby, H. A. (2013). Anthelmintics resistance; how to overcome it? Iranian Journal of Parasitology 8, 1832.Google Scholar
Skripsky, T. and Hoffmann, S. (2010). Assessment of risk of monepantel faecal residues to dung fauna. Australian Veterinary Journal 88, 490496.Google Scholar
Stein, P. A., Rolfe, P. F. and Hosking, B. C. (2010). The control of inhibited fourth-stage larvae of Haemonchus contortus and Teladorsagia spp. in sheep in Australia with monepantel. Veterinary Parasitology 169, 358361.Google Scholar
Stein, P. A., George, S. D., Rolfe, P. F. and Hosking, B. C. (2012). Safety and efficacy against fourth-stage gastrointestinal nematode larvae, of monepantel in 6-week old lambs. Veterinary Parasitology 185, 339342.CrossRefGoogle ScholarPubMed
Stuchlíková, L., Jirásko, R., Vokřál, I., Lamka, J., Špulák, M., Holčapek, M., Szotáková, B., Bártíková, H., Pour, M. and Skálová, L. (2013). Investigation of the metabolism of monepantel in ovine hepatocytes by UHPLC/MS/MS. Analytical and Bioanalytical Chemistry 405, 17051712.CrossRefGoogle Scholar
Stuchlíková, L., Jirásko, J., Vokřál, I., Valát, M., Lamka, J., Szotáková, B., Holčapek, M. and Skálová, L. (2014). Metabolic pathways of anthelmintic drug monepantel in sheep and in its parasite (Haemonchus contortus). Drug Testing and Analysis. doi: 10.1002/dta.1630.CrossRefGoogle ScholarPubMed
Suarez, V. H., Lifschitz, A. L., Sallovitz, J. M. and Lanusse, C. E. (2003). Effects of ivermectin and doramectin faecal residues on the invertebrate colonization of cattle dung. Journal of Applied Entomology 127, 481488.Google Scholar
Sutton, G., Bennett, J. and Bateman, M. (2014). Effects of ivermectin residues on dung invertebrate communities in a UK farmland habitat. Insect Conservation and Diversity 7, 6472.CrossRefGoogle Scholar
Taylor, M. A., Hunt, K. R. and Goodyear, K. L. (2002). Anthelmintic resistance detection methods. Veterinary Parasitology 103, 183194.Google Scholar
Tritten, L., Silbereisen, A. and Keiser, J. (2011). In vitro and in vivo efficacy of monepantel (AAD 1566) against laboratory models of human intestinal nematode infections. PLoS Neglected Tropical Disease 5, 1457.Google Scholar
Van Wyk, J. A. (2001). Refugia – overlooked as perhaps the most potent factor concerning the development of anthelmintic resistance. Onderstepoort Journal of Veterinary Research 68, 5567.Google ScholarPubMed
Vokřál, I., Jirásko, R., Jedličková, V., Bártíková, H., Skálová, L., Lamka, J., Holčapek, M. and Szotáková, B. (2012 a). The inability of tapeworm Hymenolepis diminuta and fluke Dicrocoelium dendriticum to metabolize praziquantel. Veterinary Parasitology 185, 168174.Google Scholar
Vokřál, I., Bartíková, H., Prchal, L., Stuchlíková, L., Skálová, L., Szotáková, B., Lamka, J., Várady, M. and Kubíček, V. (2012 b). The metabolism of flubendazole and the activities of selected biotransformation enzymes in Haemonchus contortus strains susceptible and resistant to anthelmintics. Parasitology 139, 13091316.CrossRefGoogle Scholar
Vokřál, I., Jedličková, V., Jirásko, R., Stuchlíková, L., Bártíková, H., Skálová, L., Lamka, J., Holčapek, M. and Szotáková, B. (2013 a). Metabolic fate of ivermectin in host (Ovis aries) and parasite (Haemonchus contortus). Parasitology 140, 361367.Google Scholar
Vokřál, I., Jirásko, R., Stuchlíková, L., Bártíková, H., Szotáková, B., Lamka, J., Várady, M. and Skálová, L. (2013 b). Biotransformation of albendazole and activities of selected detoxification enzymes in Haemonchus contortus strains susceptible and resistant to anthelmintics. Veterinary Parasitology 196, 373381.CrossRefGoogle ScholarPubMed
Wall, R. and Beynon, S. (2012). Area-wide impact of macrocyclic lactone parasiticides in cattle dung. Medical and Veterinary Entomology 26, 18.Google Scholar
Waller, P. J. (1997). Anthelmintic resistance. Veterinary Parasitology 72, 391412.CrossRefGoogle ScholarPubMed
Wolstenholme, A. J., Fairweather, I., Prichard, R., Samson-Himmelstjerna, G. and Sangster, N. C. (2004). Drug resistance in veterinary helminths. Trends in Parasitology 20, 469476.Google Scholar
Wrigley, J., McArthur, M., McKenna, P. B. and Mariadass, B. (2006). Resistance to a triple combination of broad-spectrum anthelmintics in naturally acquired Ostertagia circumcincta infections in sheep. New Zealand Veterinary Journal 54, 4749.CrossRefGoogle ScholarPubMed