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Monepantel

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Monepantel
Names
IUPAC name
N-[(2S)-2-cyano-1-[5-cyano-2-(trifluoromethyl)phenoxy]propan-2-yl]-4-(trifluoromethylsulfanyl)benzamide
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
EC Number
  • 639-775-0
UNII
  • InChI=1S/C20H13F6N3O2S/c1-18(10-28,11-31-16-8-12(9-27)2-7-15(16)19(21,22)23)29-17(30)13-3-5-14(6-4-13)32-20(24,25)26/h2-8H,11H2,1H3,(H,29,30)/t18-/m0/s1
    Key: WTERNLDOAPYGJD-SFHVURJKSA-N
  • C[C@@](COC1=C(C=CC(=C1)C#N)C(F)(F)F)(C#N)NC(=O)C2=CC=C(C=C2)SC(F)(F)F
Properties
C20H13F6N3O2S
Molar mass 473.39 g·mol−1
Pharmacology
QP52AX09 (WHO)
Legal status
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Monepantel is an anthelmintic approved for use in sheep and cattle to control gastrointestinal nematodes. It belongs to a new class of anthelmintics called aminoacetonitrile derivatives (AAD).[2][3][4] It is marketed by Elanco as Zolvix (United Kingdom) as a single active, or Zolvix Plus (New Zealand, Australia) in combination with the macrocyclic lactone abamectin.

History

[edit]

Aminoacetonitrile derivatives were originally discovered by scientists working at Novartis to have high potency against in vitro parasite models.[2] Compounds were further validated in rodent parasite models following oral and subcutaneous administration. A lead compound AAD 1566 was isolated that eliminated pathogenic nematodes at doses of 2.5 mg/kg in sheep and 5.0 mg/kg in cattle and was named monepantel.[4] The structure and anthelmintic activity of monepantel was first described in patent WO2005/44784.[5]

It was first registered in 2009 for use in sheep in New Zealand to control adult and immature L4 stages of all major GI nematodes.

Mechanism of action

[edit]

Studies using a molecular genetic approach in C. elegans indicated that AADs worked via ligand-gated ion channels.[2] Further research identified the DEG-3 subfamily of nicotinic acetylcholine receptors as the likely putative target of monepantel.[6] Rufener et al published in 2009 that MPTL-1 was the likely binding site of monepantel in Haemonchus contortus.[7] The DEG-3 subfamily is absent in mammals and this might explain the minimal toxicity of monepantel. It has been shown the AADs and monepantel in particular potentiate DEG-3/Des-2 receptors of H. contortus acting as an agonist of the nicotinic acetylcholine receptor producing spastic paralysis and death of the nematode.[7] Interestingly, only the S-enantiomer is found to be active against gastrointestinal nematodes.[4]

Pharmacology

[edit]

After administration to either sheep or cattle monepantel is rapidly converted to its major metabolite monepantel sulphone which also has similar levels of efficacy against gastrointestinal nematodes compared to the parent compound.[3][8]

Sheep

[edit]

Data on the pharmacokinetics of monepantel in sheep following intravenous and oral dosing have been published.[3] The sulphone metabolite was rapidly formed and predominated after four hours regardless of the route of administration. Following oral dosing of sheep with 3 mg/kg of monepantel the Tmax, Cmax and AUC of monepantel were 16 h, 17.9 ng/mL and 671 ng.h/mL while for the sulphone metabolite they were 24 h, 94.3 ng/mL and 11125 ng.h/mL.

Cattle

[edit]

After oral treatment of dairy cattle monepantel and monepantel sulphone are found in the plasma and milk.[8] Monepantel is rapidly converted to the major metabolite monepantel sulphone which is then found in much higher concentration and lasts much longer in tissues than the parent compound. One study in calves dosed orally with 2.5 mg/kg of monepantel the Tmax was 8 hours, Cmax 21.5 ng/mL and AUC 2174 ng.h/mL while the major metabolite monepantel sulphone had a Tmax of 41.3 hours, Cmax of 96.8 ng/mL and AUC of 10242 ng.h.mL.[9] In dairy cows given monepantel orally the major metabolite observed in plasma and milk was monepantel sulphone.[8] Monepantel was detected for up to 33 hours in milk and the sulphone metabolite up to 177 hours. The milk concentrations of the sulphone metabolite were substantially higher than the plasma with the AUC being nearly 7 fold higher in milk than plasma. There was no significant change in the pharmacokinetics with the addition of oxfendazole.

Efficacy

[edit]

As an oral drench dosed at 2.5 mg/kg in sheep it has claimed efficacy against adult and immature L4 stages of all major GI nematodes, namely: Haemonchus contortus, Teladorsagia circumcincta, Teladorsagia trifurcata, Trichostrongylus axei, Trichostrongylus colubriformis, Trichostrongylus rugatus, Trichostrongylus vitrinus, Nematodirus, battus, Nematodirus filicollis, Nematodirus spathiger (adult stage only), Nematodirus abnormalis (only adult stage tested), Cooperia curticei, Cooperia oncophora, Oesophagostomum venulosum (L4 stageonly) Chabertia ovina[10]

Safety

[edit]

In sheep monepantel is considered to have a good safety profile. Weaned lambs treated with 1x, 3x and 5x doses every 21 days for 8 occasions were found to be unaffected with no adverse events noted.[11] Between control lambs and treated lambs there were no significant differences in body weight, organ weight, blood chemistry and haematology and coagulation detected.

Anthelmintic resistance

[edit]

Due to having a different mode of action and molecular target than other anthelmintics monepantel will generally kill nematodes resistant to the other major classes of anthelmintics. However, within a few years of monepantel's release on the market anthelmintic resistance was reported in several countries including Australia,[12] New Zealand,[13] Uruguay,[14] Brazil,[15] the Netherlands[16] and the United Kingdom.[17] These reports have shown a number of species were resistant to monepantel including Haemonchus contortus, Teladorsagia circumcincta, Trichostrongylus colubriformis, and Oesophagostomum species.

References

[edit]
  1. ^ "Zolvix EPAR". European Medicines Agency. 10 November 2009. Retrieved 26 June 2024.
  2. ^ a b c Kaminsky, Ronald; Ducray, Pierre; Jung, Martin; Clover, Ralph; Rufener, Lucien; Bouvier, Jacques; Weber, Sandra Schorderet; Wenger, Andre; Wieland-Berghausen, Susanne; Goebel, Thomas; Gauvry, Noelle; Pautrat, François; Skripsky, Thomas; Froelich, Olivier; Komoin-Oka, Clarisse (March 2008). "A new class of anthelmintics effective against drug-resistant nematodes". Nature. 452 (7184): 176–180. Bibcode:2008Natur.452..176K. doi:10.1038/nature06722. ISSN 0028-0836. PMID 18337814. S2CID 4428834.
  3. ^ a b c Karadzovska, D.; Seewald, W.; Browning, A.; Smal, M.; Bouvier, J.; Giraudel, J. M. (August 2009). "Pharmacokinetics of monepantel and its sulfone metabolite, monepantel sulfone, after intravenous and oral administration in sheep". Journal of Veterinary Pharmacology and Therapeutics. 32 (4): 359–367. doi:10.1111/j.1365-2885.2008.01052.x. PMID 19614841.
  4. ^ a b c Kaminsky, R.; Gauvry, N.; Schorderet Weber, S.; Skripsky, T.; Bouvier, J.; Wenger, A.; Schroeder, F.; Desaules, Y.; Hotz, R.; Goebel, T.; Hosking, B. C.; Pautrat, F.; Wieland-Berghausen, S.; Ducray, P. (September 2008). "Identification of the amino-acetonitrile derivative monepantel (AAD 1566) as a new anthelmintic drug development candidate". Parasitology Research. 103 (4): 931–939. doi:10.1007/s00436-008-1080-7. ISSN 0932-0113. PMC 2491438. PMID 18594861.
  5. ^ WO2005044784A1, GAUVRY, Noëlle; Goebel, Thomas & Ducray, Pierre et al., "Amidoacetonitrile derivatives", issued 2005-05-19 
  6. ^ Rufener, Lucien; Baur, Roland; Kaminsky, Ronald; Mäser, Pascal; Sigel, Erwin (November 2010). "Monepantel Allosterically Activates DEG-3/DES-2 Channels of the Gastrointestinal Nematode Haemonchus contortus". Molecular Pharmacology. 78 (5): 895–902. doi:10.1124/mol.110.066498. ISSN 0026-895X. PMID 20679419. S2CID 85780.
  7. ^ a b Rufener, Lucien; Mäser, Pascal; Roditi, Isabel; Kaminsky, Ronald (2009-04-10). Wynn, Thomas A. (ed.). "Haemonchus contortus Acetylcholine Receptors of the DEG-3 Subfamily and Their Role in Sensitivity to Monepantel". PLOS Pathogens. 5 (4): e1000380. doi:10.1371/journal.ppat.1000380. ISSN 1553-7374. PMC 2662886. PMID 19360096.
  8. ^ a b c Ballent, M.; Viviani, P.; Imperiale, F.; Dominguez, P.; Halwachs, S.; Mahnke, H.; Honscha, W.; Lanusse, C.; Virkel, G.; Lifschitz, A. (April 2018). "Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows". Journal of Veterinary Pharmacology and Therapeutics. 41 (2): 292–300. doi:10.1111/jvp.12466. hdl:11336/58399. PMID 29139145. S2CID 3603929.
  9. ^ Canton, Candela; Canton, Lucila; Lifschitz, Adrian; Domínguez, María Paula; Torres, Juan; Lanusse, Carlos; Alvarez, Luis; Ceballos, Laura; Ballent, Mariana (April 2021). "Monepantel pharmaco-therapeutic evaluation in cattle: Pattern of efficacy against multidrug resistant nematodes". International Journal for Parasitology: Drugs and Drug Resistance. 15: 162–167. doi:10.1016/j.ijpddr.2021.03.003. PMC 8044591. PMID 33799058.
  10. ^ Epe, Christian; Kaminsky, Ronald (March 2013). "New advancement in anthelmintic drugs in veterinary medicine". Trends in Parasitology. 29 (3): 129–134. doi:10.1016/j.pt.2013.01.001. PMID 23376212.
  11. ^ Malikides, N; Helbig, R; Roth, Dr; Alexander, A; Hosking, Bc; Strehlau, Ga (February 2009). "Safety of an amino-acetonitrile derivative (AAD), monepantel, in weaned lambs following repeated oral administration". New Zealand Veterinary Journal. 57 (1): 10–15. doi:10.1080/00480169.2009.36862. ISSN 0048-0169. PMID 19252537. S2CID 205460366.
  12. ^ Sales, Narelle; Love, Stephen (2016-09-15). "Resistance of Haemonchus sp. to monepantel and reduced efficacy of a derquantel / abamectin combination confirmed in sheep in NSW, Australia". Veterinary Parasitology. 228: 193–196. doi:10.1016/j.vetpar.2016.08.016. ISSN 1873-2550. PMID 27692326.
  13. ^ Scott, I.; Pomroy, W. E.; Kenyon, P. R.; Smith, G.; Adlington, B.; Moss, A. (2013-11-15). "Lack of efficacy of monepantel against Teladorsagia circumcincta and Trichostrongylus colubriformis". Veterinary Parasitology. 198 (1–2): 166–171. doi:10.1016/j.vetpar.2013.07.037. ISSN 1873-2550. PMID 23953148.
  14. ^ Mederos, América E.; Ramos, Zully; Banchero, Georgget E. (2014-12-17). "First report of monepantel Haemonchus contortus resistance on sheep farms in Uruguay". Parasites & Vectors. 7: 598. doi:10.1186/s13071-014-0598-z. ISSN 1756-3305. PMC 4305228. PMID 25515711.
  15. ^ Cintra, M. C. R.; Teixeira, V. N.; Nascimento, L. V.; Sotomaior, C. S. (2016-01-30). "Lack of efficacy of monepantel against Trichostrongylus colubriformis in sheep in Brazil". Veterinary Parasitology. 216: 4–6. doi:10.1016/j.vetpar.2015.11.013. ISSN 1873-2550. PMID 26801587.
  16. ^ Van den Brom, R.; Moll, L.; Kappert, C.; Vellema, P. (2015-04-30). "Haemonchus contortus resistance to monepantel in sheep". Veterinary Parasitology. 209 (3–4): 278–280. doi:10.1016/j.vetpar.2015.02.026. ISSN 1873-2550. PMID 25770852.
  17. ^ Hamer, Kim; Bartley, Dave; Jennings, Amy; Morrison, Alison; Sargison, Neil (2018-06-15). "Lack of efficacy of monepantel against trichostrongyle nematodes in a UK sheep flock". Veterinary Parasitology. 257: 48–53. doi:10.1016/j.vetpar.2018.05.013. hdl:20.500.11820/cb389572-0665-461d-889d-d266898c5f5a. ISSN 1873-2550. PMID 29907192. S2CID 49243133.
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