Effect of Ivermectin on the Expression of P-Glycoprotein in Third-Stage Larvae of Haemonchus contortus Isolated from China
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Haemonchus contortus poses a severe hazard to the healthy development of the sheep industry and threatens the welfare of sheep. Ivermectin is the primary anthelmintic used for the prevention and treatment of H. contortus parasitism. However, the widespread and uncontrolled application of ivermectin has resulted in the development and spread of resistant strains of H. contortus. P-glycoprotein (P-gp) plays important roles in the pharmacology and toxicology of ivermectin, and changes in P-gp expression levels can be used to analyze the resistance of H. contortus to ivermectin. This study aimed to analyze the effects of ivermectin on P-gp expression in H. contortus L3 larvae isolated from China and to evaluate whether changes in P-gp expression levels can be used to analyze resistant H. contortus strains. In the absence of drug treatment, the ivermectin-resistant strains isolated in China showed increased expression of P-gp11 (p < 0.01) compared with sensitive strains from elsewhere, whereas the expressions of P-gp2 and P-gp9.1 were downregulated (p < 0.01). When the same strain was compared before and after drug treatment, obvious differences in expression were observed between the different strains. Ivermectin-induced P-gp expression was found to be very complex among the L3 larvae of different strains. In addition, it was confirmed that using P-gp to determine ivermectin resistance in H. contortus strains from different geographic environments can yield different results.Cite
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Two groups of 33 helminth-naive lambs were infected with 5,000 L3 of an ivermectin-resistant or -susceptible strain of Haemonchus contortus (groups R and S). On days 6, 10, 16, and 21 postinfection, 5 animals from each group were chosen at random and orally treated with 0.2 mg/kg of ivermectin. On each occasion, 2 randomly selected lambs from each group were also killed to determine the number and stage of development of the worms present at the time of treatment. These necropsies revealed that by day 6 early and late fourth-stage larvae were present, whereas on day 10 the early fifth stage had been reached; by days 16 and 21 all worms had reached the adult stage. Necropsies on day 28 postinfection revealed that although animals treated at day 6 had 26.3% fewer worms than the controls, there was no significant difference (P greater than 0.05) between worm burdens from any of the animals infected with the R strain and treated at different times after infection when compared with the untreated controls. With ivermectin significant reductions were obtained in the worm burdens of the animals infected with the susceptible strain; these were reduced by 96% when treatment was given on day 6 against fourth-stage larvae and 98.9% when the drug was given on day 21 against adult stages. From these results it is clear that resistance to ivermectin in this strain of H. contortus is present as early as the fourth larval stage.
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Albendazole
Eggs per gram
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Haemonchus contortus poses a severe hazard to the healthy development of the sheep industry and threatens the welfare of sheep. Ivermectin is the primary anthelmintic used for the prevention and treatment of H. contortus parasitism. However, the widespread and uncontrolled application of ivermectin has resulted in the development and spread of resistant strains of H. contortus. P-glycoprotein (P-gp) plays important roles in the pharmacology and toxicology of ivermectin, and changes in P-gp expression levels can be used to analyze the resistance of H. contortus to ivermectin. This study aimed to analyze the effects of ivermectin on P-gp expression in H. contortus L3 larvae isolated from China and to evaluate whether changes in P-gp expression levels can be used to analyze resistant H. contortus strains. In the absence of drug treatment, the ivermectin-resistant strains isolated in China showed increased expression of P-gp11 (p < 0.01) compared with sensitive strains from elsewhere, whereas the expressions of P-gp2 and P-gp9.1 were downregulated (p < 0.01). When the same strain was compared before and after drug treatment, obvious differences in expression were observed between the different strains. Ivermectin-induced P-gp expression was found to be very complex among the L3 larvae of different strains. In addition, it was confirmed that using P-gp to determine ivermectin resistance in H. contortus strains from different geographic environments can yield different results.
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The study was conducted at Department of Veterinary Clinical Medicine, Ethics and Jurisprudence.The polyherbal tablet comprising Artimisia maritima, Butea frondosa, Vernonia anthelmintica and Holarrhena antidysentrica was prepared and its anthelmintic efficacy and effect on body weight was studied on goats naturally infected with Haemonchus contortus.Total 140 goats were selected which were naturally infected with Haemonchus contortus.Out of 140 goats, 100 goats were selected as Group I (Polyherbal Treatment), 20 goats were selected as Group II (Positive control) and 20 goats were selected as Group III (Negative control), respectively.For the positive control albendazole (10 mg/kg BW) was given to the control group goats and in negative control goats maintained untreated.Group I animals were given polyherbal polymer complex anthelmintic and Group II animals were given albendazole.The faecal samples were examined on 0 th day before and 3 rd , 7 th , 15 th and 30 th day post treatment.Body weights of goats under treatment were recorded on day 0 i.e. before treatment and on 15 th and 30 th day post treatment.There was significant reduction in Egg per Gram (EPG) count seen in Group I and Group II, whereas, the EPG count increased significantly in Group III.Increase in body weight was observed significantly in Group I and Group II whereas, there was decrease in body weight observed in Group III.Further it was concluded that the polyherbal anthelmintic tablet was effective in elimination of Haemonchus contortus which could be the reason for increase in body weight during the trial.
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A subcutaneous injection of 2,6-diiodo-4-nitrophenol (Disophenol) at 10 mg/kg sheep leaves a residue bound to serum albumin which is lethal to Haemonchus contortus for 3 months after treatment. In the larval anthelmintic test, susceptible worm free sheep are dosed so that either third stage larvae (L3), or fourth stage larvae (L4) or 5th and adult stages are present on the day of treatment but slaughter is delayed to allow these larval stages to develop to adults because the larger worms are more easily seen, identified and counted. The larval anthelmintic test in sheep had to be altered and sheep killed within a few days of treatment, because the residues may be more effective against subsequent stages of development. Disophenol was greater than 60% effective against L3 of Oesophagostomum columbianum and L4 of H. contortus in greater than 60% of sheep (Class B). It rose to greater than 80% effective against adult H. contortus in greater than 80% of sheep (Class A). Against H. contortus it maintained Class A for 32 days, fell to Class B from 45--76 days and Class C (greater than 50% effective in greater than 50% of sheep) at 91 days after treatment respectively. In the RSA a treatment in December followed by another in March would protect sheep adequately against H. contortus for the entire season.
Ancylostoma caninum
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Membranes from both ivermectin-sensitive and -resistant Haemonchus contortus L3 larvae were examined for the presence of high affinity [3H]ivermectin binding sites. Both tissue preparations displayed high affinity drug binding sites (Kd = 0.13 nM). Receptor density (Bmax = 0.4 pmol/mg) was the same in both the sensitive and resistant nematodes suggesting that target site modification was not involved in the development of drug resistance in this particular strain of H. contortus. The H. contortus ivermectin binding site appeared to be similar to the well characterized Caenorhabditis elegans ivermectin binding site with respect to affinity for ivermectin and receptor density.
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