A Review of FDA-Approved Antiparasitic Drugs in USA for Sheep and Goats: Their Synthesis and Pharmaceutical Use

Document Type : Review Article


1 National Institute of Chemistry, Hajdrihova ulica 19, 1000, Ljubljana.

2 Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000, Ljubljana.



This review describes the Food and Drug Administration (FDA)-approved antiparasitic drugs for sheep and goats in the USA updated to 2021. The emerging drug resistance is posing a significant burden for the treatment of parasitic infections in these small ruminants and the need for novel antiparasitic drugs is urgent. Sheep and goats are producing every year important resources such as milk and wool, among others. This work incorporates the OneHealth approach which focuses not only on human health, but also on animal health and the environment in an interdependent modus operandi. The dynamic equilibrium among these three sectors plays a fundamental role in general healthcare. Drug discovery (e.g., a novel benzimidazole recently identified) and drug delivery (incorporation of the antiparasitic agent into the proper carrier to increase effectiveness) have provided some promising results in recent time. This should go hand-in-hand with the scientific awareness. Education is key in spreading the word about the responsible use of antiparasitic drugs. The synthesis of the currently approved drugs will be provided including synthetic procedures which date from 1961 to 2021. More synthetic pathways, when available, will be described. Their mechanism of action and ecotoxicological data will be presented as well.


Davide Benedetto Tiz (Google Scholar)

Črtomir Podlipnik (Google Scholar)


1.    Rao TV, Bandyopadhyay SK. A comprehensive review of goat pox and sheep pox and their diagnosis. Anim Health Res Rev. 2000 Dec;1(2):127-36. doi: 10.1017/s1466252300000116. PMID: 11708598.
2.    Newcomer BW, Cebra C, Chamorro MF, Reppert E, Cebra M, Edmondson MA. Diseases of the hematologic, immunologic, and lymphatic systems (multisystem diseases). Sheep, Goat, and Cervid Medicine. 2021:405–38. doi: 10.1016/B978-0-323-62463-3.00025-6. Epub 2020 Apr 17. PMCID: PMC7169350.
3.    New Antiparasitic Drugs Needed for Sheep and Goats. Available online:  https://www.fda.gov/animal-veterinary/safety-health/new-antiparasitic-drugs-needed-sheep-and-goats (accessed on 25 October 2023).
4.    Baron S, editor. Medical Microbiology. 4th ed. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. PMID: 21413252.
5.    Bishop SC. Possibilities to breed for resistance to nematode parasite infections in small ruminants in tropical production systems. Animal. 2012 May;6(5):741-7. doi: 10.1017/S1751731111000681. PMID: 22558922.
6.    Sheep and Goats. Available online:  https://www.nass.usda.gov/Surveys/Guide_to_NASS_Surveys/Sheep_and_Goat_Inventory/index.php (accessed on 25 October 2023). 
7.    Kornele ML, McLean MJ, O'Brien AE, Phillippi-Taylor AM. Antiparasitic resistance and grazing livestock in the United States. J Am Vet Med Assoc. 2014 May 1;244(9):1020-2. doi: 10.2460/javma.244.9.1020. PMID: 24739108.
8.    Field HE. Bats and emerging zoonoses: henipaviruses and SARS. Zoonoses Public Health. 2009 Aug;56(6-7):278-84. doi: 10.1111/j.1863-2378.2008.01218.x. PMID: 19497090.
9.    Mintezol (Thiabendazole). Avail‌able online: https://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/cps-_monographs/CPS-_(General_Monographs-_M)/MINTEZOL.html (accessed on 25 October 2023).
10.    Hebden SP. The Aathelmintic Activity of Thiabendazole (M.K.360). Aust Vet J. 1961 Jul;37(7):264–9. doi: 10.1111/j.1751-0813.1961.tb03921.x. Epub 2008 Mar 10. PMCID: PMC7159646.
11.    Andersen, Ferron L., Keith H. Hoopes, and J. Carl Fox. “THE EFFICACY OF HALOXON AND THIABENDAZOLE AS ANTHELMINTICS AGAINST GASTRO-INTESTINAL NEMATODES IN SHEEP.” The Great Basin Naturalist 29, no. 1 (1969): 35–41. http://www.jstor.org/stable/41711212.
12.    THIBENZOLE SHEEP & GOAT WORMER. Available online: https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/013-022 (accessed on 25 January 2023).
13.    McCarthy JS. Moore TA. Drugs for Helminths. In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases; Elsevier, 2015; pp. 519-527.e3 ISBN 978-1-4557-4801-3.
14.    Thiabendazole. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/5430 (accessed on 25 January 2023).
15.    Meyer S, Gaines WA, Grenda VJ. Chemical Processes for Preparing Nu-Substituted Amidines. US3299081A, 17 January 1967.
16.    Brown HD, Matzuk AR, Ilves IR, Peterson LH, Harris SA, Sarett LH, et al. Antiparasitic drugs. IV. 2-(4’-thiazolyl)-benzimidazole, a new anthelmintic. J Am Chem Soc. 1961:83;1764-5. doi: 10.1021/ja01468a052.
17.    Kim Y, Kumar MR, Park N, Heo Y, Lee S. Copper-Catalyzed, One-Pot, Three-Component Synthesis of Benzimidazoles by Condensation and C–N Bond Formation. J Org Chem. 2011:76;9577-83. doi:10.1021/jo2019416.
18.    Albanese G, Venturi C. Albendazole: a new drug for human parasitoses. Dermatol Clin. 2003 Apr;21(2):283-90. doi: 10.1016/s0733-8635(02)00085-2. PMID: 12757251.
19.    J. G. Hardman, L. E. Limbird, and A. G. Gilman., K.S. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th Edition Edited by J. G. Hardman, L. E. Limbird, and A. G. Gilman. McGraw Hill, New York. 2001. ISBN 0-07-1354469-7.; 2002; Vol. 45.
20.    Valbazen-Albendazole Suspension Available online: https://fda.report/DailyMed/94cf5818-f27d-4374-87ad-54a2d9ce6ef1 (accessed on 25 January 2023).
21.    Cretu, C.-M. Treatment. In Trichinella and Trichinellosis; Elsevier, 2021; pp. 417–429 ISBN 978-0-12-821209-7.
22.    Albendazole. Available online: https://go.drugbank.com/drugs/DB00518 (accessed on 25 January 2023).
23.    ChemDraw-PerkinElmer Informatics. Available online: https://perkinelmerinformatics.com/products/research/chemdraw (accessed on 25 January 2023).
24.    Gyurik, R.J.; Theodorides, V.J. Methods and Compositions for Producing Polyphasic Parasiticide Activity Using Methyl 5-Propylthio-2-Benzimidazolecarbamate. US3956499A, 11 May 1976.
25.    Rane, R.A.; Naithani, S.; Natikar, R.D.; Verma, S.; Arulmoli, T. Process for Preparation of Albendazole. US20130303782A1, 14 November 2013.
26.    Fenbendazole. Available online: https://www.drugs.com/international/fenbendazole.html (accessed on 25 January 2023).
27.    Villar D, Cray C, Zaias J, Altman NH. Biologic effects of fenbendazole in rats and mice: a review. J Am Assoc Lab Anim Sci. 2007 Nov;46(6):8-15. PMID: 17994667.
28.    Fenbendazole. Available online: https://go.drugbank.com/drugs/DB11410 (accessed on 25 January 2023).
29.    Spagnuolo PA, Hu J, Hurren R, Wang X, Gronda M, Sukhai MA, et al. The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma. Blood. 2010 Jun 10;115(23):4824-33. doi: 10.1182/blood-2009-09-243055. Epub 2010 Mar 26. PMID: 20348394.
30.    Duan Q, Liu Y, Rockwell S. Fenbendazole as a potential anticancer drug. Anticancer Res. 2013 Feb;33(2):355-62. PMID: 23393324; PMCID: PMC3580766.
31.    Averkin EA, Beard CC, Dvorak CA, Edwards JA, Fried JH, Kilian JG, et al. Methyl 5(6)-phenylsulfinyl-2-benzimidazolecarbamate, a new, potent anthelmintic. J Med Chem. 1975 Nov;18(11):1164-6. doi: 10.1021/jm00245a029. PMID: 1177265.
32.    Gonczi, C.; Korbonits, D.; Kiss, P.; Palosi, E.; Heja, G.; Kanzel, I.S. nee; Kun, J.C. nee; Wundele, M.S. nee; Kormoczi, G.; Kelemen, A. Sulfur-Containing Benzimidazole Derivatives. US4259344A, 31 March 1981.
33.    Zhang P, Liu C, Yu L, Hou H, Sun W, Ke F. Synthesis of Benzimidazole by Mortar–Pestle Grinding Method. Green Chem Lett Rev. 2021;14:612-9. doi:10.1080/17518253.2021.1991483.
34.    Martin RJ. Modes of action of anthelmintic drugs. Vet J. 1997 Jul;154(1):11-34. doi: 10.1016/s1090-0233(05)80005-x. PMID: 9265850.
35.    Courtot E, Charvet CL, Beech RN, Harmache A, Wolstenholme AJ, Holden-Dye L, et al. Functional Characterization of a Novel Class of Morantel-Sensitive Acetylcholine Receptors in Nematodes. PLoS Pathog. 2015 Dec 1;11(12):e1005267. doi: 10.1371/journal.ppat.1005267. PMID: 26625142; PMCID: PMC4666645.
36.    Wu TY, Smith CM, Sine SM, Levandoski MM. Morantel allosterically enhances channel gating of neuronal nicotinic acetylcholine alpha 3 beta 2 receptors. Mol Pharmacol. 2008 Aug;74(2):466-75. doi: 10.1124/mol.107.044388. Epub 2008 May 5. PMID: 18458055; PMCID: PMC2587017.
37.    Sharma, S.; Anand, N. Tetrahydropyrimidines. In Pharmacochemistry Library; Elsevier, 1997; Vol. 25, pp. 171–180 ISBN 978-0-444-89476-2.
38.    Sheehan, D.J.; Sheehan, S.M.; Marchiondo, A.A. Discovery and Chemistry of Pyrantel, Morantel and Oxantel. In Pyrantel Parasiticide Therapy in Humans and Domestic Animals; Elsevier, 2016; pp. 1–19 ISBN 978-0-12-801449-3.
39.    Austin, W.C.; Conover, L.H.; Mcfarland, J.W. Thiophen Derivatives. GB1120587A, 17 July 1968.
40. Levamisole. Available online: https://go.drugbank.com/drugs/DB00848 (accessed on 25 January 2023).
41.    Al- Fatlawi, M.; Mansour, K.; Neama, A. Dynamics of Some Anthelmintic on Internal Parasites in Camels: Review. Al-Qadis J Vet Med Sci. 2019;18:33-38. 
42.    Raeymaekers AH, Roevens LF, Janssen PA. The absolute configurations of the optical isomers of the broad spectrum anthelmintic tetramisole. Tetrahedron Lett. 1967 Apr;16:1467-70. doi: 10.1016/s0040-4039(00)90983-3. PMID: 6042549.
43.    Bullock MW, Hand JJ, Waletzky E. Resolution and Racemization of di-Tetramisole, di-6-Phenyl-2,3,5,6-tetrahydroimidazo- [2,l-b]thiazole. J Med Chem. 1968 Jan;11(1):169-171. doi: 10.1021/jm00307a601. PMID: 28128946.
44.    Vardanyan, R.S.; Hruby, V.J. Immunopharmacological Drugs. In Synthesis of Essential Drugs; Elsevier, 2006; pp. 419–424 ISBN 978-0-444-52166-8.
45.    Choudhary MK, Tak R, Kureshy RI, Ansari A, Khan NH, Abdi SHR, et al. Enantioselective Aza-Henry Reaction for the Synthesis of (S)-Levamisole Using Efficient Recyclable Chiral Cu(II)–Amino Alcohol Derived Complexes. J Mol Catal A Chem. 2015;409:85-93. doi:10.1016/j.molcata.2015.08.009.
46.    Ivermectin (Systemic). Available online: https://www.drugs.com/monograph/ivermectin-systemic.html (accessed on 25 January 2023).
47.    Omura S, Crump A. Ivermectin: panacea for resource-poor communities? Trends Parasitol. 2014 Sep;30(9):445-55. doi: 10.1016/j.pt.2014.07.005. Epub 2014 Aug 12. PMID: 25130507.
48.    Campbell WC, Fisher MH, Stapley EO, Albers-Schönberg G, Jacob TA. Ivermectin: a potent new antiparasitic agent. Science. 1983 Aug 26;221(4613):823-8. doi: 10.1126/science.6308762. PMID: 6308762.
49.    Wang CC, Pong SS. Actions of avermectin B1a on GABA nerves. Prog Clin Biol Res. 1982;97:373-95. PMID: 6296881.
50.    Miller TW, Chaiet L, Cole DJ, Cole LJ, Flor JE, Goegelman RT, et al. Avermectins, new family of potent anthelmintic agents: isolation and chromatographic properties. Antimicrob Agents Chemother. 1979 Mar;15(3):368-71. doi: 10.1128/AAC.15.3.368. PMID: 464562; PMCID: PMC352667.
51.    Discovery of Ivermectin. Available online: https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/ivermectin-mectizan.html (accessed on 25 January 2023).
52.    Yamashita S, Hayashi D, Nakano A, Hayashi Y, Hirama M. Total synthesis of avermectin B1a revisited. J Antibiot (Tokyo). 2016 Jan;69(1):31-50. doi: 10.1038/ja.2015.47. Epub 2015 Sep 9. PMID: 26350782.
53.    Popp M, Stegemann M, Metzendorf MI, Gould S, Kranke P, Meybohm P, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev. 2021 Jul 28;7(7):CD015017. doi: 10.1002/14651858.CD015017.pub2. Update in: Cochrane Database Syst Rev. 2022 Jun 21;6:CD015017. PMID: 34318930; PMCID: PMC8406455.
54.    WHO Advises That Ivermectin Only Be Used to Treat COVID-19 within Clinical Trials. Available online: https://www.who.int/news-room/feature-stories/detail/who-advises-that-ivermectin-only-be-used-to-treat-covid-19-within-clinical-trials (accessed on 25 January 2023).
55.    Moxidectin. Available online: https://go.drugbank.com/drugs/DB11431 (accessed on 25 January 2023).
56.    Forrester SG, Prichard RK, Beech RN. A glutamate-gated chloride channel subunit from Haemonchus contortus: expression in a mammalian cell line, ligand binding, and modulation of anthelmintic binding by glutamate. Biochem Pharmacol. 2002 Mar 15;63(6):1061-8. doi: 10.1016/s0006-2952(02)00852-3. PMID: 11931838.
57.    Wu YJ, Yang SB, Zhang ZY, Chen SX. Improvement of Nemadectin Production by Overexpressing the Regulatory Gene NemR and Nemadectin Biosynthetic Gene Cluster in Streptomyces Cyaneogriseus. Pharma Fronts. 2020;02:151-9, doi:10.1055/s-0040-1722746.
58.    Cohen, D.H.; Patel, J.; O’neill, M.J.; Cullen, T.G. Process, AU2006203349A1, 31 January 2008.
59.    Lianou DT, Petinaki E, Michael CK, Skoulakis A, Cripps PJ, Katsarou EI, et al. Zoonotic Problems Reported by Sheep and Goat Farmers and Factors Potentially Contributing to the Occurrence of Brucellosis among Them. Int J Environ Res Public Health. 2022 Aug 20;19(16):10372. doi: 10.3390/ijerph191610372. PMID: 36012008; PMCID: PMC9408422.
60.    One Health Basics. Available online: https://www.cdc.gov/onehealth/basics/index.html (accessed on 25 January 2023).
61.    Yoshimura H, Endoh YS. Acute toxicity to freshwater organisms of antiparasitic drugs for veterinary use. Environ Toxicol. 2005 Feb;20(1):60-6. doi: 10.1002/tox.20078. PMID: 15712325.
62.    McKellar QA. Ecotoxicology and Residues of Anthelmintic Compounds. Vet Parasitol. 1997;72:413-35. doi:10.1016/S0304-4017(97)00108-8.
63.    Stone OJ, Mullins JF, Willis CJ. Comparison of Thiabendazole and 5-Hydroxythiabendazole (for Anthelmintic Effect). J Invest Dermatol. 1965 Aug;45:132-3. doi: 10.1038/jid.1965.107. PMID: 14332641. 
64.    5-Hydroxythiabendazole. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/108227 (accessed on 25 January 2023).
65.    Marriner SE, Bogan JA. Pharmacokinetics of fenbendazole in sheep. Am J Vet Res. 1981 Jul;42(7):1146-8. PMID: 7271033.
66.    Goudah A. Aspects of the pharmacokinetics of albendazole sulphoxide in sheep. Vet Res Commun. 2003 Oct;27(7):555-66. doi: 10.1023/a:1026008010899. PMID: 14609267.
67.    Düwel, D. Fenbendazole. II. Biological Properties and Activity. Pestic. Sci. 1977, 8, 550–555, doi:10.1002/ps.2780080520.
68.    Bogan JA, Marriner SE, Galbraith EA. Pharmacokinetics of levamisole in sheep. Res Vet Sci. 1982 Jan;32(1):124-6. PMID: 7089376.
69.    Mesa LM, Lindt I, Negro L, Gutierrez MF, Mayora G, Montalto L, Ballent M, Lifschitz A. Aquatic toxicity of ivermectin in cattle dung assessed using microcosms. Ecotoxicol Environ Saf. 2017 Oct;144:422-429. doi: 10.1016/j.ecoenv.2017.06.016. Epub 2017 Jun 24. PMID: 28654874.
70.    Tipthara P, Kobylinski KC, Godejohann M, Hanboonkunupakarn B, Roth A, Adams JH, et al. Identification of the metabolites of ivermectin in humans. Pharmacol Res Perspect. 2021 Feb;9(1):e00712. doi: 10.1002/prp2.712. PMID: 33497030; PMCID: PMC7836931.
71.    Steel JW. Pharmacokinetics and Metabolism of Avermectins in Livestock. Vet Parasitol. 1993;48:45-57. doi:10.1016/0304-4017(93)90143-B.
72.    Mesa LM, Hörler J, Lindt I, Gutiérrez MF, Negro L, Mayora G, et al. Effects of the Antiparasitic Drug Moxidectin in Cattle Dung on Zooplankton and Benthic Invertebrates and its Accumulation in a Water-Sediment System. Arch Environ Contam Toxicol. 2018 Aug;75(2):316-326. doi: 10.1007/s00244-018-0539-5. Epub 2018 May 30. PMID: 29846763.
73.    Valderas-García E, Escala N, Álvarez-Bardón M, Castilla-Gómez de Agüero V, Cambra-Pellejà M, González del Palacio L, et al. Novel Compound Shows in Vivo Anthelmintic Activity in Gerbils and Sheep Infected by Haemonchus Contortus. Sci Rep. 2022;12:13004. doi:10.1038/s41598-022-17112-3.
74.    Carvalheiro M, Esteves MA, Santos-Mateus D, Lopes RM, Rodrigues MA, Eleutério CV, et al. Hemisynthetic trifluralin analogues incorporated in liposomes for the treatment of leishmanial infections. Eur J Pharm Biopharm. 2015 Jun;93:346-52. doi: 10.1016/j.ejpb.2015.04.018. Epub 2015 May 1. PMID: 25936854.
75.    Sifaoui I, Díaz-Rodríguez P, Rodríguez-Expósito RL, Reyes-Batlle M, López-Arencibia A, Salazar Villatoro L, et al. Pitavastatin loaded nanoparticles: A suitable ophthalmic treatment for Acanthamoeba Keratitis inducing cell death and autophagy in Acanthamoeba polyphaga. Eur J Pharm Biopharm. 2022 Nov;180:11-22. doi: 10.1016/j.ejpb.2022.09.020. Epub 2022 Sep 23. PMID: 36162636.
76.    Animal Antibiotics and Parasite Management Webinar. Available online: https://www.ag.ndsu.edu:8000/agriculture/ag-hub/events/animal-antibiotics-and-parasite-management-webinar (accessed on 27 January 2023).