title: P-gp modulating drugs greatly potentiate the in vitro effect of ivermectin against resistant larvae of Haemonchus placei.
abstract: Since its production in the 1980s, ivermectin (IVM) has been used indiscriminately and the selection pressure to which bovine gastrointestinal nematodes have been exposed has been intense, resulting in considerable economic losses due to parasitic resistance. One possibility for the control of resistant parasites is the use of P-glycoprotein (P-gp) modulators, because one of the main biochemical changes in ivermectin-resistant parasites is the increased activity of membrane proteins responsible for the efflux of drugs and xenobiotics. This study aimed to evaluate the in vitro effect of eight P-gp modulating drugs to potentiate IVM efficacy against an IVM-resistant field isolate of Haemonchus placei (Nematoda: Trichostrongylidae). The association of IVM with cyclosporin-A, ceftriaxone, dexamethasone, diminazene aceturate, quercetin, trifluoperazine, verapamil, or vinblastine resulted in increased IVM (10(-4)M) efficacy of 5.1%, 49.06%, 76.42%, 3.31%, 28.85%, 13.74%, 45.64% and 43.61%, respectively, and reduced the IVM half maximal effective concentration (EC50) from 4.381 × 10(-6)M to 9.877 × 10(-8), 2.739 × 10(-7), 1.240 × 10(-6), 1.651 × 10(-6), 2.710 × 10(-7), 1.159 × 10(-7), 1.026 × 10(-6) and 7.136 × 10(-7)M, respectively. Only diminazene aceturate did not significantly reduce the number of migrating larvae when associated with IVM (P > 0.05). The effect of P-gp modulating drugs depended on IVM concentration, with greater potentiating effect at lower IVM concentrations. The in vitro application of trifluoperazine, dexamethasone, quercetin, verapamil, cyclosporin A, vinblastine, and ceftriaxone potentiated IVM efficacy against an IVM-resistant field isolate of H. placei, resulting in higher efficacy and lower IVM EC50.
authors.affiliation: Federal University of Mato Grosso do Sul, UFMS, Campo Grande, MS 79070-900, Brazil.
authors.forename: R P
authors.initials: RP
authors.lastname: Heckler
authors.affiliation: Federal University of Mato Grosso do Sul, UFMS, Campo Grande, MS 79070-900, Brazil.
authors.forename: G D
authors.initials: GD
authors.lastname: Almeida
authors.affiliation: Federal University of Mato Grosso do Sul, UFMS, Campo Grande, MS 79070-900, Brazil.
authors.forename: L B
authors.initials: LB
authors.lastname: Santos
authors.affiliation: Federal University of Mato Grosso do Sul, UFMS, Campo Grande, MS 79070-900, Brazil.
authors.forename: D G L
authors.initials: DG
authors.lastname: Borges
authors.affiliation: Federal University of Mato Grosso do Sul, UFMS, Campo Grande, MS 79070-900, Brazil.
authors.forename: J P L
authors.initials: JP
authors.lastname: Neves
authors.affiliation: Federal University of Mato Grosso do Sul, UFMS, Campo Grande, MS 79070-900, Brazil.
authors.forename: M K V
authors.initials: MK
authors.lastname: Onizuka
authors.affiliation: Federal University of Mato Grosso do Sul, UFMS, Campo Grande, MS 79070-900, Brazil. Electronic address: fernando.borges@ufms.br.
authors.forename: F A
authors.initials: FA
authors.lastname: Borges
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002417:Cattle; D004357:Drug Synergism; D005243:Feces / Q000469:parasitology; D005260:Female; D006188:Haemonchiasis / Q000188:drug therapy / Q000469:parasitology / Q000662:veterinary*; D006189:Haemonchus / Q000187:drug effects*; D007559:Ivermectin / Q000494:pharmacology* / Q000627:therapeutic use; D007814:Larva; D010270:Parasite Egg Count
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000977:Antiparasitic Agents; D007559:Ivermectin
keywords: Cattle; Chemical reversal; Macrocyclic lactones; Nematodes; P-gp; Resistance