FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Int J Parasitol Drugs Drug Resist / P-glycoproteins play a role in ivermectin resistance in cyat...
International journal for parasitology. Drugs and drug resistance2017; 7(3); 388-398; doi: 10.1016/j.ijpddr.2017.10.006

P-glycoproteins play a role in ivermectin resistance in cyathostomins.

Abstract: Anthelmintic resistance is a global problem that threatens sustainable control of the equine gastrointestinal cyathostomins (Phylum Nematoda; Superfamily Strongyloidea). Of the three novel anthelmintic classes that have reached the veterinary market in the last decade, none are currently licenced in horses, hence current control regimens focus on prolonging the useful lifespan of licenced anthelmintics. This approach would be facilitated by knowledge of the resistance mechanisms to the most widely used anthelmintics, the macrocyclic lactones (ML). There are no data regarding resistance mechanisms to MLs in cyathostomins, although in other parasitic nematodes, the ABC transporters, P-glycoproteins (P-gps), have been implicated in playing an important role. Here, we tested the hypothesis that P-gps are, at least in part, responsible for reduced sensitivity to the ML ivermectin (IVM) in cyathostomins; first, by measuring transcript levels of pgp-9 in IVM resistant versus IVM sensitive third stage larvae (L3) pre-and post-IVM exposure in vitro. We then tested the effect of a range of P-gp inhibitors on the effect of IVM against the same populations of L3 using the in vitro larval development test (LDT) and larval migration inhibition test (LMIT). We demonstrated that, not only was pgp-9 transcription significantly increased in IVM resistant compared to IVM sensitive L3 after anthelmintic exposure (p < 0.001), but inhibition of P-gp activity significantly increased sensitivity of the larvae to IVM in vitro, an effect only observed in the IVM resistant larvae in the LMIT. These data strongly implicate a role for P-gps in IVM resistance in cyathostomins. Importantly, this raises the possibility that P-gp inhibitor-IVM combination treatments might be used in vivo to increase the effectiveness of IVM against cyathostomins in Equidae.
Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Get Full Text
Publication Date: 2017-10-25 PubMed ID: 29121562PubMed Central: PMC5681340DOI: 10.1016/j.ijpddr.2017.10.006Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research investigates the way P-glycoproteins are involved in ivermectin resistance in cyathostomins, parasites that commonly affect horses, suggesting a new treatment intervention that could enhance ivermectin’s effectiveness.

Objective and Problem

  • The study addresses a significant global issue, anthelmintic resistance, particularly in the control of equine gastrointestinal parasites known as cyathostomins. This kind of resistance is a severe challenge because no new anthelmintic (anti-parasitic) drugs have been licensed for horses in the last decade.
  • The research primarily focuses on the role of P-glycoproteins (P-gps) in causing resistance to the drug ivermectin (IVM), a widely used anthelmintic treatment under the macrocyclic lactones (ML) class, in cyathostomins.

Method and Analysis

  • The researchers hypothesized that P-gps plays a central role in reducing cyathostomins’ sensitivity to IVM. They tested this by comparing the transcript levels of a particular P-gp, pgp-9, in both IVM-resistant and IVM-sensitive cyathostomin larvae before and after IVM exposure in a laboratory setting.
  • The team also examined the impact of various P-gp inhibitors on the effectiveness of IVM against these two kinds of cyathostomin larvae populations.
  • The in vitro tests carried out during the study were the larval development test (LDT) and the larval migration inhibition test (LMIT).

Findings

  • The study found a significant increase in the transcription of pgp-9 in IVM-resistant cyathostomin larvae compared to the IVM-sensitive ones after they were exposed to the anthelmintic treatment.
  • Notably, using P-gp inhibitors considerably improved the cyathostomin larvae’s sensitivity to IVM in the lab environment, a phenomenon that was only witnessed in the IVM-resistant larvae in the LMIT.
  • These findings point to a substantial contribution by P-gps to IVM resistance in cyathostomins.

Impact and Future Research

  • The implications of this research are critical to the future of equine health, suggesting that using a combination of P-gp inhibitors and IVM could potentially heighten the drug’s effectiveness against cyathostomins in horses.
  • This gives rise to an opportunity for more detailed exploration on the use of P-gp inhibitor-IVM blend treatments in active equine environments.

Cite This Article

APA
Peachey LE, Pinchbeck GL, Matthews JB, Burden FA, Lespine A, von Samson-Himmelstjerna G, Krücken J, Hodgkinson JE. (2017). P-glycoproteins play a role in ivermectin resistance in cyathostomins. Int J Parasitol Drugs Drug Resist, 7(3), 388-398. https://doi.org/10.1016/j.ijpddr.2017.10.006

Publication

International journal for parasitology. Drugs and drug resistance
ISSN: 2211-3207
NlmUniqueID: 101576715
Country: Netherlands
Language: English
Volume: 7
Issue: 3
Pages: 388-398

Researcher Affiliations

Peachey, L E
  • Institute of Infection and Global Health, University of Liverpool, Liverpool Science Park IC2, Brownlow Hill, Liverpool, United Kingdom. Electronic address: peachey14@hotmail.com.
Pinchbeck, G L
  • Institute of Infection and Global Health, University of Liverpool, Liverpool Science Park IC2, Brownlow Hill, Liverpool, United Kingdom.
Matthews, J B
  • Moredun Research Institute, Pentlands Science Park, Bush Loan, Midlothian, Scotland, United Kingdom.
Burden, F A
  • The Donkey Sanctuary, Sidmouth, Devon, United Kingdom.
Lespine, A
  • Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
von Samson-Himmelstjerna, G
  • Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
Krücken, J
  • Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
Hodgkinson, J E
  • Institute of Infection and Global Health, University of Liverpool, Liverpool Science Park IC2, Brownlow Hill, Liverpool, United Kingdom.

MeSH Terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / drug effects
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Animals
  • Anthelmintics / pharmacology
  • Drug Resistance / genetics
  • Horses / parasitology
  • Ivermectin / pharmacology
  • Lactones / pharmacology
  • Larva / drug effects
  • Larva / genetics
  • Larva / growth & development
  • Levamisole / pharmacology
  • Strongyloidea / drug effects
  • Strongyloidea / genetics

References

This article includes 91 references
  1. AlGusbi S, Krucken J, Ramunke S, von Samson-Himmelstjerna G, Demeler J. Analysis of putative inhibitors of anthelmintic resistance mechanisms in cattle gastrointestinal nematodes.. Int. J. Parasitol. 2014;44:647–658.
    pubmed: 24907555
  2. Ardelli B.F.. Transport proteins of the ABC systems superfamily and their role in drug action and resistance in nematodes.. Parasitol. Int. 2013;62:639–646.
    pubmed: 23474412
  3. Ardelli B.F., Guerriero S.B., Prichard R.K.. Genomic organization and effects of ivermectin selection on Onchocerca volvulus P-glycoprotein.. Mol. Biochem. Parasitol. 2005;143:58–66.
    pubmed: 15993957
  4. Ardelli B.F., Prichard R.K.. Reduced genetic variation of an Onchocerca volvulus ABC transporter gene following treatment with ivermectin.. Trans. R. Soc. Trop. Med. Hyg. 2007;101:1223–1232.
    pubmed: 17904599
  5. Ardelli B.F., Prichard R.K.. Inhibition of P-glycoprotein enhances sensitivity of Caenorhabditis elegans to ivermectin.. Vet. Parasitol. 2013;191:264–275.
    pubmed: 23062691
  6. Areskog M., Engström A., Tallkvist J., von Samson-Himmelstjerna G., Höglund J.. PGP expression in Cooperia oncophora before and after ivermectin selection.. Parasitol. Res. 2013;112:3005–3012.
    pmc: PMC3724988pubmed: 23771718
  7. Ballent M., Lifschitz A., Virkel G., Sallovitz J., Lanusse C.. Modulation of the P-glycoprotein-mediated intestinal secretion of ivermectin: in vitro and in vivo assessments.. Drug Metab. Dispos. 2006;34:457–463.
    pubmed: 16381664
  8. Bartley D.J., McAllister H., Bartley Y., Dupuy J., Menez C., Alvinerie M., Jackson F., Lespine A.. P-glycoprotein interfering agents potentiate ivermectin susceptibility in ivermectin sensitive and resistant isolates of Teladorsagia circumcincta and Haemonchus contortus.. Parasitology 2009;136:1081–1088.
    pubmed: 19549355
  9. Bartley D.J., Morrison A.A., Dupuy J., Bartley Y., Sutra J.F., Menez C., Alvinerie M., Jackson F., Devin L., Lespine A.. Influence of Pluronic 85 and ketoconazole on disposition and efficacy of ivermectin in sheep infected with a multiple resistant Haemonchus contortus isolate.. Vet. Parasitol. 2012;187:464–472.
    pubmed: 22429700
  10. Batrakova E.V., Kabanov A.V.. Pluronic block copolymers: evolution of drug delivery concept from inert nanocarriers to biological response modifiers.. J. Control. Release. 2008;130:98–106.
    pmc: PMC2678942pubmed: 18534704
  11. Blackhall W.J., Prichard R.K., Beech R.N.. P-glycoprotein selection in strains of Haemonchus contortus resistant to benzimidazoles.. Vet. Parasitol. 2008;152:101–107.
    pubmed: 18241994
  12. Bourguinat C., Keller K., Blagburn B., Schenker R., Geary T.G., Prichard R.K.. Correlation between loss of efficacy of macrocyclic lactone heartworm anthelmintics and P-glycoprotein genotype.. Vet. Parasitol. 2011;176:374–381.
    pubmed: 21300438
  13. Bucknell D.G., Gasser R.B., Beveridge I.. The prevalence and epidemiology of gastrointestinal parasites of horses in Victoria, Australia.. Int. J. Parasitol. 1995;25:711–724.
    pubmed: 7657457
  14. Canever R.J., Braga P.R., Boeckh A., Grycajuck M., Bier D., Molento M.B.. Lack of Cyathostomin sp. reduction after anthelmintic treatment in horses in Brazil.. Vet. Parasitol. 2013;194:35–39.
    pubmed: 23318166
  15. Choi Y.J., Bisset S.A., Doyle S.R., Hallsworth-Pepin K., Martin J., Grant W.N., Mitreva M.. Genomic introgression mapping of field-derived multiple-anthelmintic resistance in Teladorsagia circumcinta.. PLoS Genet. 2017;13:e1006857.
    pmc: PMC5507320pubmed: 28644839
  16. Coles G.C., Bauer C., Borgsteede F.H., Geerts S., Klei T.R., Taylor M.A., Waller P.J.. World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.) methods for the detection of anthelmintic resistance in nematodes of veterinary importance.. Vet. Parasitol. 1992;44:35–44.
    pubmed: 1441190
  17. Dassa E.. Phylogenetic and functional classification of ABC (ATP-binding cassette) systems.. In: Holland I.B., Cole S.P.C., Kuchler K., Higgins C., editors. ABC Proteins: from Bacteria to Man. Academic Press; London: 2003. pp. 3–35.
  18. David M.A., Orlowski S., Prichard R.K., Hashem S., André F., Lespine A.. In silico analysis of the binding of anthelmintics to Caenorhabditis elegans P-glycoprotein 1.. Int. J. Parasitol. Drugs Drug Resist. 2016;6:299–313.
    pmc: PMC5196494pubmed: 27746191
  19. De Graef J., Demeler J., Skuce P., Mitreva M., Von Samson-Himmelstjerna G., Vercruysse J., Claerebout E., Geldhof P.. Gene expression analysis of ABC transporters in a resistant Cooperia oncophora isolate following in vivo and in vitro exposure to macrocyclic lactones.. Parasitology 2013;140:499–508.
    pmc: PMC3690601pubmed: 23279803
  20. Demeler J., Krucken J., AlGusbi S., Ramunke S., De Graef J., Kerboeuf D., Geldhof P., Pomroy W.E., von Samson-Himmelstjerna G.. Potential contribution of P-glycoproteins to macrocyclic lactone resistance in the cattle parasitic nematode Cooperia oncophora.. Mol. Biochem. Parasitol. 2013;188:10–19.
    pubmed: 23384738
  21. Demeler J., Kuttler U., El-Abdellati A., Stafford K., Rydzik A., Varady M., Kenyon F., Coles G., Hoglund J., Jackson F., Vercruysse J., von Samson-Himmelstjerna G.. Standardization of the larval migration inhibition test for the detection of resistance to ivermectin in gastro intestinal nematodes of ruminants.. Vet. Parasitol. 2010;174:58–64.
    pubmed: 20850930
  22. Demeler J., Kuttler U., von Samson-Himmelstjerna G.. Adaptation and evaluation of three different in vitro tests for the detection of resistance to anthelmintics in gastro intestinal nematodes of cattle.. Vet. Parasitol. 2010;170:61–70.
    pubmed: 20189310
  23. Dicker A.J., Nisbet A.J., Skuce P.J.. Gene expression changes in a P-glycoprotein (Tci-pgp-9) putatively associated with ivermectin resistance in Teladorsagia circumcincta.. Int. J. Parasitol. 2011;41:935–942.
    pubmed: 21683705
  24. Dolinska M., Konigova A., Letkova V., Molnar L., Varady M.. Detection of ivermectin resistance by a larval development test–back to the past or a step forward?. Vet. Parasitol. 2013;198:154–158.
    pubmed: 23993637
  25. Drogemuller M., Schnieder T., von Samson-Himmelstjerna G.. Evidence of p-glycoprotein sequence diversity in cyathostomins.. J. Parasitol. 2004;90:998–1003.
    pubmed: 15562598
  26. Dupuy J., Alvinerie M., Menez C., Lespine A.. Interaction of anthelmintic drugs with P-glycoprotein in recombinant LLC-PK1-mdr1a cells.. Chem. Biol. Interact. 2010;186:280–286.
    pubmed: 20513441
  27. Dupuy J., Lespine A., Sutra J.F., Alvinerie M.. The interaction between moxidectin and MDR transporters in primary cultures of rat hepatocytes.. J. Vet. Pharmacol. Ther. 2006;29:107–111.
    pubmed: 16515664
  28. El-Abdellati A., De Graef J., Van Zeveren A., Donnan A., Skuce P., Walsh T., Wolstenholme A., Tait A., Vercruysse J., Claerebout E., Geldhof P.. Altered avr-14B gene transcription patterns in ivermectin-resistant isolates of the cattle parasites, Cooperia oncophora and Ostertagia ostertagi.. Int. J. Parasitol. 2011;41:951–957.
    pubmed: 21683704
  29. Eysker M., Pandey V.S.. Small strongyle infections in donkeys from the highveld in Zimbabwe.. Vet. Parasitol. 1989;30:345–349.
    pubmed: 2728325
  30. Gawor J.J.. The prevalence and abundance of internal parasites in working horses autopsied in Poland.. Vet. Parasitol. 1995;58:99–108.
    pubmed: 7676606
  31. Geary T.G., Bourguinat C., Prichard R.K.. Evidence for macrocyclic lactone anthelmintic resistance in Dirofilaria immitis.. Top. Companion Anim. Med. 2011;26:186–192.
    pubmed: 22152606
  32. Getachew M., Trawford A., Feseha G., Reid S.W.. Gastrointestinal parasites of working donkeys of Ethiopia.. Trop. Anim. Health Prod. 2010;42:27–33.
    pubmed: 19548106
  33. Godoy P., Che H., Beech R.N., Prichard R.K.. Characterisation of P-glycoprotein-9.1 in Haemonchus contortus.. Parasit. Vectors. 2016;9:52.
    pmc: PMC4730751pubmed: 26822677
  34. Hodgkinson J.E., Clark H.J., Kaplan R.M., Lake S.L., Matthews J.B.. The role of polymorphisms at beta tubulin isotype 1 codons 167 and 200 in benzimidazole resistance in cyathostomins.. Int. J. Parasitol. 2008;38:1149–1160.
    pubmed: 18367189
  35. Hugnet C., Lespine A., Alvinerie M.. Multiple oral dosing of ketoconazole increases dog exposure to ivermectin.. J. Pharm. Pharm. Sci. 2007;10:311–318.
    pubmed: 17727794
  36. James C.E., Davey M.W.. Increased expression of ABC transport proteins is associated with ivermectin resistance in the model nematode Caenorhabditis elegans.. Int. J. Parasitol. 2009;39:213–220.
    pubmed: 18708066
  37. Janssen I.J., Krucken J., Demeler J., Basiaga M., Kornas S., von Samson-Himmelstjerna G.. Genetic variants and increased expression of Parascaris equorum P-glycoprotein-11 in populations with decreased ivermectin susceptibility.. PLoS One. 2013;8:e61635.
    pmc: PMC3634834pubmed: 23637871
  38. Janssen I.J., Krucken J., Demeler J., von Samson-Himmelstjerna G.. Caenorhabditis elegans: modest increase of susceptibility to ivermectin in individual P-glycoprotein loss-of-function strains.. Exp. Parasitol. 2013;134 171–1.
    pubmed: 23518455
  39. Janssen I.J., Krucken J., Demeler J., von Samson-Himmelstjerna G.. Transgenically expressed Parascaris P-glycoprotein-11 can modulate ivermectin susceptibility in Caenorhabditis elegans.. Int. J. Parasitol. Drugs Drug Resist. 2015;5:44–47.
    pmc: PMC4401813pubmed: 25905032
  40. Kageyama M., Namiki H., Fukushima H., Ito Y., Shibata N., Takada K.. In vivo effects of cyclosporin A and ketoconazole on the pharmacokinetics of representative substrates for P-glycoprotein and cytochrome P450 (CYP) 3A in rats.. Biol. Pharm. Bull. 2005;28:316–322.
    pubmed: 15684491
  41. Kaplan R.M., Vidyashankar A.N.. An inconvenient truth: global worming and anthelmintic resistance.. Vet. Parasitol. 2012;186:70–78.
    pubmed: 22154968
  42. Kaschny M., Demeler J., Janssen I.J., Kuzmina T.A., Besognet B., Kanellos T., Kerboeuf D., von Samson-Himmelstjerna G., Krucken J.. Macrocyclic lactones differ in interaction with recombinant P-glycoprotein 9 of the parasitic nematode Cylicocylus elongatus and ketoconazole in a yeast growth assay.. PLoS Pathog. 2015;11:e1004781.
    pmc: PMC4388562pubmed: 25849454
  43. Kharchenko V., Kuzmina T., Trawford A., Getachew M., Feseha G.. Morphology and diagnosis of some fourth-stage larvae of cyathostomines (Nematoda: Strongyloidea) in donkeys Equus asinus L. from Ethiopia.. Syst. Parasitol. 2009;72:1–13.
    pubmed: 19048404
  44. Kiki-Mvouaka S., Menez C., Borin C., Lyazrhi F., Foucaud-Vignault M., Dupuy J., Collet X., Alvinerie M., Lespine A.. Role of P-glycoprotein in the disposition of macrocyclic lactones: a comparison between ivermectin, eprinomectin, and moxidectin in mice.. Drug Metab. Dispos. 2010;38:573–580.
    pubmed: 20089736
  45. Krecek R.C., Reinecke R.K., Kriek N.J., Horak I.G., Malan F.S.. Helminth parasites of cape mountain zebras from cape providence, South Africa.. J. Wildl. Dis. 1994;30:277–280.
    pubmed: 8028118
  46. Laffont C.M., Toutain P.L., Alvinerie M., Bousquet-Melou A.. Intestinal secretion is a major route for parent ivermectin elimination in the rat.. Drug Metab. Dispos. 2002;30:626–630.
    pubmed: 12019186
  47. Lespine A., Dupuy J., Alvinerie M., Comera C., Nagy T., Krajcsi P., Orlowski S.. Interaction of macrocyclic lactones with the multidrug transporters: the bases of the pharmacokinetics of lipid-like drugs.. Curr. Drug Metab. 2009;10:272–288.
    pubmed: 19442089
  48. Lespine A., Dupuy J., Orlowski S., Nagy T., Glavinas H., Krajcsi P., Alvinerie M.. Interaction of ivermectin with multidrug resistance proteins (MRP1, 2 and 3). Chem. Biol. Interact. 2006;159:169–179.
    pubmed: 16384552
  49. Lespine A., Martin S., Dupuy J., Roulet A., Pineau T., Orlowski S., Alvinerie M.. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship.. Euro. J. Pharm. Sci. 2007;30:84–94.
    pubmed: 17134887
  50. Lespine A., Prichard R., Menez C.. US20140256619 A1: Use of Avermectin Derivative for Increasing Bioavailability and Efficacy of Macrocylic Lactones (Google Patents). 2013.
  51. Lichtenfels J.R., Kharchenko V.A., Krecek R.C., Gibbons L.M.. An annotated checklist by genus and species of 93 species level names for 51 recognized species of small strongyles (Nematoda: Strongyloidea: Cyathostominea) of horses, asses and zebras of the world.. Vet. Parasitol. 1998;79:65–79.
    pubmed: 9777726
  52. Lifschitz A., Entrocasso C., Alvarez L., Lloberas M., Ballent M., Manazza G., Virkel G., Borda B., Lanusse C.. Interference with P-glycoprotein improves ivermectin activity against adult resistant nematodes in sheep.. Vet. Parasitol. 2010;172:291–298.
    pubmed: 20605686
  53. Lifschitz A., Suarez V.H., Sallovitz J., Cristel S.L., Imperiale F., Ahoussou S., Schiavi C., Lanusse C.. Cattle nematodes resistant to macrocyclic lactones: comparative effects of P-glycoprotein modulation on the efficacy and disposition kinetics of ivermectin and moxidectin.. Exp. Parasitol. 2010;125:172–178.
    pubmed: 20109455
  54. Lifschitz A., Virkel G., Sallovitz J., Imperiale F., Pis A., Lanusse C.. Loperamide-induced enhancement of moxidectin availability in cattle.. J. Vet. Pharm. Ther. 2002;25:111–120.
    pubmed: 12000531
  55. Lind E.O., Uggla A., Waller P., Hoglund J.. Larval development assay for detection of anthelmintic resistance in cyathostomins of Swedish horses.. Vet. Parasitol. 2005;128:261–269.
    pubmed: 15740863
  56. Love S., Duncan J.L.. The development of naturally acquired cyathostome infection in ponies.. Vet. Parasitol. 1992;44:127–142.
    pubmed: 1441184
  57. Love S., Murphy D., Mellor D.. Pathogenicity of cyathostome infection.. Vet. Parasitol. 1999;85:113–121.
    pubmed: 10485358
  58. Lyons E.T., Drudge J.H., Tolliver S.C.. Larval cyathostomiasis.. Vet. Clin. N. Am. Equine. 2000;16:501–513.
    pubmed: 11219346
  59. Matthews J.B.. Anthelmintic resistance in equine nematodes.. Int. J. Parasitol. Drugs Drug Resist. 2014;4:310–315.
    pmc: PMC4266799pubmed: 25516842
  60. Maurice M., Pichard L., Daujat M., Fabre I., Joyeux H., Domergue J., Maurel P.. Effects of imidazole derivatives on cytochromes P450 from human hepatocytes in primary culture.. FASEB J. 1992;6:752–758.
    pubmed: 1371482
  61. McArthur C.L., Handel I.G., Robinson A., Hodgkinson J.E., Bronsvoort B.M., Burden F., Kaplan R.M., Matthews J.B.. Development of the larval migration inhibition test for comparative analysis of ivermectin sensitivity in cyathostomin populations.. Vet. Parasitol. 2015;212:292–298.
    pubmed: 26120037
  62. Ménez C., Alberich M., Kansoh D., Blanchard A., Lespine A.. Aquired tolerance to ivermectin and moxidectin after drug selection pressure in the nematode Caenorhabditis elegans.. Antimicrob. Agents Chemother. 2016;60:4809–4819.
    pmc: PMC4958191pubmed: 27246778
  63. Milillo P., Boeckh A., Cobb R., Otranto D., Lia R.P., Perrucci S., di Regalbono A.F., Beraldo P., von Samson-Himmelstjerna G., Demeler J., Bartolini R., Traversa D.. Faecal Cyathostomin Egg Count distribution and efficacy of anthelmintics against cyathostomins in Italy: a matter of geography?. Parasit. Vectors. 2009;2(Suppl. 2):S4.
    pmc: PMC2751840pubmed: 19778465
  64. Molento M.B., Antunes J., Bentes R.N., Coles G.C.. Anthelmintic resistant nematodes in Brazilian horses.. Vet. Rec. 2008;162:384–385.
    pubmed: 18359933
  65. Murphy D., Love S.. The pathogenic effects of experimental cyathostome infections in ponies.. Vet. Parasitol. 1997;70:99–110.
    pubmed: 9195714
  66. Nappert G., Van Dyck T., Papich M., Chirino-Trejo M.. Successful treatment of a fever associated with consistent pulmonary isolation of Scopulariopsis sp. in a mare.. Equine Vet. J. 1996;28:421–424.
    pubmed: 8894543
  67. Nareaho A., Vainio K., Oksanen A.. Impaired efficacy of ivermectin against Parascaris equorum, and both ivermectin and pyrantel against strongyle infections in trotter foals in Finland.. Vet. Parasitol. 2011;182:372–377.
    pubmed: 21689886
  68. Nielsen M.K., Reinemeyer C.R., Donecker J.M., Leathwick D.M., Marchiondo A.A., Kaplan R.M.. Anthelmintic resistance in equine parasites–current evidence and knowledge gaps.. Vet. Parasitol. 2014;204:55–63.
    pubmed: 24433852
  69. Ogbourne C.P.. The prevalence, relative abundance and site distribution of nematodes of the subfamily Cyathostominae in horses killed in Britain.. J. Helminthol. 1976;50:203–214.
    pubmed: 993579
  70. Peregrine A.S., McEwen B., Bienzle D., Koch T.G., Weese J.S.. Larval cyathostominosis in horses in Ontario: an emerging disease?. Can. Vet. J. 2006;47:80–82.
    pmc: PMC1316126pubmed: 16536234
  71. Peregrine A.S., Molento M.B., Kaplan R.M., Nielsen M.K.. Anthelmintic resistance in important parasites of horses: does it really matter?. Vet. Parasitol. 2014;201:1–8.
    pubmed: 24485565
  72. R Core Team. R: a Language and Environment for Statistical Computing (Vienna, Austria, R Foundation for Statistical Computing). 2014.
  73. Raza A., Kopp S.R., Jabbar A., Kotze A.C.. Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro.. Vet. Parasitol. 2015;211:80–88.
    pubmed: 25986327
  74. Reinemeyer C.R., Smith S.A., Gabel A.A., Herd R.P.. The prevalence and intensity of internal parasites of horses in the USA.. Vet. Parasitol. 1984;15:75–83.
    pubmed: 6237483
  75. Relf V.E., Lester H.E., Morgan E.R., Hodgkinson J.E., Matthews J.B.. Anthelmintic efficacy on UK Thoroughbred stud farms.. Int. J. Parasitol. 2014;44:507–514.
    pubmed: 24746779
  76. Sanchez L.C.. Clinical application of gastrointestinal therapeutics.. In: Cole C., Bentz B., Maxwell L., editors. Equine Pharmacology. Wiley Blackwell; 2014. p. 185.
  77. Schinkel A.H., Smit J.J., van Tellingen O., Beijnen J.H., Wagenaar E., van Deemter L., Mol C.A., van der Valk M.A., Robanus-Maandag E.C., te Riele H.P.. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs.. Cell. 1994;77:491–502.
    pubmed: 7910522
  78. Shaik N., Pan G., Elmquist W.F.. Interactions of pluronic block co-polymers on P-gp efflux activity: experience with HIV-1 protease inhibitors.. J. Pharm. Sci. 2008;97:5412–5433.
    pmc: PMC5096432pubmed: 18393290
  79. Smith J.M., Prichard R.K.. Localization of p-glycoprotein mRNA in the tissues of Haemonchus contortus adult worms and its relative abundance in drug-selected and susceptible strains.. J. Parasitol. 2002;88:612–620.
    pubmed: 12099436
  80. Tandon R., Kaplan R.M.. Evaluation of a larval development assay (DrenchRite) for the detection of anthelmintic resistance in cyathostomin nematodes of horses.. Vet. Parasitol. 2004;121:125–142.
    pubmed: 15110410
  81. Thienpont D., Rochette F., Vanparijs O.F.J.. Diagnosing Helminthiasis by Coprological Examination.. second ed. Janssen Research Foundation; Beerse, Belgium: 1986. Coprological Examination; p. 205.
  82. Traversa D., Milillo P., Barnes H., von Samson-Himmelstjerna G., Schurmann S., Demeler J., Otranto D., Lia R.P., Perrucci S., di Regalbono A.F., Beraldo P., Boeckh A., Amodie D., Rohn K., Cobb R., Boeckh A.. Distribution and species-specific occurrence of cyathostomins (Nematoda, Strongylida) in naturally infected horses from Italy, United Kingdom and Germany.. Vet. Parasitol. 2010;168:84–92.
    pubmed: 19906489
  83. Traversa D., von Samson-Himmelstjerna G., Demeler J., Milillo P., Schurmann S., Barnes H., Otranto D., Perrucci S., di Regalbono A.F., Beraldo P., Boeckh A., Cobb R.. Anthelmintic resistance in cyathostomin populations from horse yards in Italy, United Kingdom and Germany.. Parasit. Vectors. 2009;2(Suppl. 2):S2.
    pmc: PMC2751838pubmed: 19778463
  84. Trawford A.F., Burden F.A., Hodgkinson J.E.. Suspected moxidectin resistance in cyathostomes in two donkey herds at the Donkey Sanctuary, UK. 20th International Conference of the World Assosciation for the Advancement of Veterinary Parasitology. 2005; p. 196. Christchurch, New Zealand.
  85. Trawford A.F., Burden F.. Ivermectin resistance in cyathostomes in four donkeys herds at the Donkey Sanctuary, UK.. Worldwide Association for the Advancement of Veterinary Parasitology. 2009. Calgary.
  86. Tyden E., Skarin M., Hoglund J.. Gene expression of ABC transporters in Cooperia oncophora after field and laboratory selection with macrocyclic lactones.. Mol. Biochem. Parasitol. 2014;198:66–70.
    pubmed: 25619799
  87. Tzelos T., Barbeito J.S.G., Nielsen M.K., Morgan E.R., Hodgkinson J.E., Matthews J.B.. Strongyle egg reappearance period after moxidectin treatment and its relationship with management factors in UK equine populations.. Vet. Parasitol. 2017;237:70–76.
    pubmed: 28249767
  88. Uhlinger C.A.. Equine small strongyles - epidemiology, pathology, and control.. Comp. Cont. Educ. Pract. 1991;13:863–869.
  89. Ward K.W., Stelman G.J., Morgan J.A., Zeigler K.S., Azzarano L.M., Kehler J.R., McSurdy-Freed J.E., Proksch J.W., Smith B.R.. Development of an in vivo preclinical screen model to estimate absorption and first-pass hepatic extraction of xenobiotics. II. Use of ketoconazole to identify P-glycoprotein/CYP3A-limited bioavailability in the monkey.. Drug Metab. Dispos. 2004;32:172–177.
    pubmed: 14744938
  90. Williamson S.M., Storey B., Howell S., Harper K.M., Kaplan R.M., Wolstenholme A.J.. Candidate anthelmintic resistance-associated gene expression and sequence polymorphisms in a triple-resistant field isolate of Haemonchus contortus.. Mol. Biochem. Parasitol. 2011;180:99–105.
    pubmed: 21945142
  91. Xu M., Molento M., Blackhall W., Ribeiro P., Beech R., Prichard R.. Ivermectin resistance in nematodes may be caused by alteration of P-glycoprotein homolog.. Mol. Biochem. Parasitol. 1998;91:327–335.
    pubmed: 9566525
Subscribe to our newsletter
Join 99,359 horse owners like you who receive our email updates on horse health and nutrition.