P-glycoproteins play a role in ivermectin resistance in cyathostomins
Laura PeacheyGina PinchbeckJonathan C. F. MatthewsFaith BurdenAnne LespineGeorg von Samson‐HimmelstjernaJürgen KrückenJane E. Hodgkinson
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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.Keywords:
Parasitology
Strongyloidiasis
Albendazole
Antiparasitic agent
Avermectin
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Levamisole
Albendazole
Pyrantel
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Efficacy of three commonly used anthelmintics (ivermectin, levamisole and albendazole) was evaluated against naturally occurring gastrointestinal (GI) nematodosis in Garole sheep under field conditions. After qualitative and quantitative screening of faeces of 150 sheep, sixty sheep having eggs per gram of faeces (EPG) 150 were randomly selected and divided into four equal groups. Ivermectin @ 200μg kg−1 body weight and levamisole @ 7.5 μg kg−1 body weight, injected subcutaneously, in two different groups, were 98.56 and 99.52 per cent effective, respectively. Whereas, albendazole suspension @ 10mg kg−1 body weight, orally was 99.04 per cent effective and the fourth group was kept as untreated control with natural exposure to gastrointestinal nematodes. Blood and serum samples were collected once prior to treatment and on 10th day post-treatment for estimation of haemato-biochemical changes due to anthelmintic treatment. Further, the body weight changes due to anthelmintic treatment were also taken into consideration for the assessment of anthelmintic efficacy.
Levamisole
Albendazole
Eggs per gram
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The persistent anthelmintic effect of subcutaneously and orally administered ivermectin given at a dose rate of 0.2 mg/kg was evaluated against experimentally induced infections of Haemonchus contortus, Ostertagia spp., Trichostrongylus spp. and Cooperia curticei in sheep. While both ivermectin treatments apparently resulted in some reduction in the establishment of most of the parasite species examined, only for C. curticei were these reductions statistically significant. For C. curticei, statistically significant antiparasitic activity was evident in animals five and ten days after treatment with ivermectin given by injection and five days after treatment with ivermectin given orally. The possible relevance of these results to parasite control and the potential for selecting for anthelmintic resistance are briefly discussed.
Antiparasitic
Ostertagia
Persistence (discontinuity)
Avermectin
Ostertagia ostertagi
Antiparasitic agent
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Twenty-four Collies sensitive to the toxic effects of ivermectin, when administered at high dosages, were studied to evaluate the effects of repeated monthly treatment with an ivermectin beef-based formulation at amounts up to 10 times the dosage recommended for heartworm prevention in dogs. Collies were treated 3 times at 30-day intervals at rates of 12, 36, or 60 micrograms of ivermectin/kg of body weight, or with vehicle. Complete physical and neurologic examinations were performed on all dogs prior to the first treatment and after the final treatment. Clinical observations and ivermectin reaction scores were recorded daily for each dog throughout the study. Clinical or neurologic signs characteristic of ivermectin toxicosis were not observed for any dog during the study. Single episodes of vomiting were recorded for 2 vehicle-treated dogs and 2 dogs treated with ivermectin at 12 micrograms/kg from 6 to 21 days after treatment. At the end of the study, all dogs were challenge-exposed with ivermectin at 120 micrograms/kg to reconfirm their sensitivity to this class of compounds. All dogs developed signs typical of ivermectin toxicosis during the subsequent 48- to 72-hour period. Results of this study demonstrated that ivermectin can be administered repeatedly without adverse effects at rates up to 60 micrograms/kg (10 times the recommended use level) to Collies known to be sensitive to this drug.
Dose
Avermectin
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Ivermectin is increasingly being used to treat scabies, especially crusted (Norwegian) scabies. However, treatment failures, recrudescence, and reinfection can occur, even after multiple doses. Ivermectin resistance has been documented for some intestinal helminths in animals with intensive ivermectin exposure. Ivermectin resistance has also been induced in arthropods in laboratory experiments but, to date, has not been documented among arthropods in nature. We report clinical and in vitro evidence of ivermectin resistance in 2 patients with multiple recurrences of crusted scabies who had previously received 30 and 58 doses of ivermectin over 4 and 4.5 years, respectively. As predicted, ivermectin resistance in scabies mites can develop after intensive ivermectin use.
Sarcoptes scabiei
Antiparasitic agent
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Summary Twenty-four Collies sensitive to the toxic effects of ivermectin, when administered at high dosages, were studied to evaluate the effects of repeated monthly treatment with an ivermectin beef-based formulation at amounts up to 10 times the dosage recommended for heartworm prevention in dogs. Collies were treated 3 times at 30-day intervals at rates of 12, 36, or 60 μg of ivermectin/kg of body weight, or with vehicle. Complete physical and neurologic examinations were performed on all dogs prior to the first treatment and after the final treatment. Clinical observations and ivermectin reaction scores were recorded daily for each dog throughout the study. Clinical or neurologic signs characteristic of ivermectin toxicosis were not observed for any dog during the study. Single episodes of vomiting were recorded for 2 vehicle-treated dogs and 2 dogs treated with ivermectin at 12 μg/kg from 6 to 21 days after treatment. At the end of the study, all dogs were challenge-exposed with ivermectin at 120 μg/kg to reconfirm their sensitivity to this class of compounds. All dogs developed signs typical of ivermectin toxicosis during the subsequent 48- to 72-hour period. Results of this study demonstrated that ivermectin can be administered repeatedly without adverse effects at rates up to 60 μg/kg (10 times the recommended use level) to Collies known to be sensitive to this drug.
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Antiparasitic agent
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In this paper the problems that may arise when ivermectin is used in small animal medicine are discussed. A case-report is presented concerning a Canadian-American White Shepherd showing symptoms of fatal ivermectin poisoning following a normal dosage of ivermectin (220 micrograms per kilogramme of body weight). The treatment of dogs with ivermectin poisoning is described and some guide lines concerning the use of ivermectin are given.
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Gastrointestinal nematodes infection is one of the most important diseases of small ruminants in Malaysia, particularly goats. Control of gastrointestinal helminthiasis in small ruminants relies almost exclusively on the use of anthelmintic drugs but the effective control is limited by the development of anthelmintic resistance. This study evaluated the efficacy of albendazole and ivermectin that are currently used as preventive medicine in herd health programme of small ruminants as well as to detect the presence of anthelmintic resistance to both anthelmintics. Faecal examination was done by the McMaster technique to determine the number of eggs/g faeces. Efficacy of albendazole and ivermectin were calculated based on arithmetic means of pre-treatment and post-treatment eggs/g (e.p.g). While detection of anthelmintic resistance was done by faecal egg count reduction test (FECRT) in which arithmetic means of post-treatment e.p.g. for treated and control group were used. In this study, albendazole was moderately effective with percentage efficacy of 86% and ivermectin was ineffective with percentage efficacy of 16%. Anthelmintic resistance was detected to both drugs used in this study in which albendazole with 87% of reduction on faecal egg counts (FEC) associated with 61% lower 95% confidence limit and ivermectin with 13% reduction of FEC associated with -91% lower 95% confidence limit. In this study the resistance of gastrointestinal nematodes to albendazole and ivermectin in treated goats was detected. There was also evidence of reduction in FEC in both treated groups but not to a desirable level.
Albendazole
Eggs per gram
Abamectin
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Abstract Five sheep farms located in different geo-climatic regions were surveyed for resistance in gastrointestinal nematodes to albendazole, levamisole and ivermectin. Resistance to albendazole and levamisole was evident on all the farms. Albendazole reduced faecal egg counts by 0–73% and levamisole by 0–61%. No eggs were detected after treatment with ivermectin.
Albendazole
Levamisole
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