The efficacy of monepantel against naturally acquired inhibited and developing fourth-stage larvae of Teladorsagia circumcincta in sheep in the United Kingdom

The inhibition of Teladorsagia and other nematode genera at the early fourth-stage is a biological process that allows the parasites to survive in their host in a dormant state when prevailing conditions may otherwise kill them or prevent their progeny from surviving in the external environment. A study was conducted in Scotland to evaluate the efficacy of monepantel, an amino-acetonitrile derivative, against natural infections of inhibited fourth-stage Teladorsagia spp. larvae. At necropsy it was determined that the untreated control sheep were additionally infected with developing fourth-stage Teladorsagia spp. larvae and this is the first published evidence on the efficacy of monepantel against natural infections of this parasite and stage. The study sheep, which had grazed on naturally contaminated pastures since birth, were transferred to indoor housing after a subset of animals was examined to confirm the presence of inhibited larvae within the study population prior to the experiment. After 14 days of housing, monepantel was orally administered at 2.5 mg/kg to half of the animals. The sheep were necropsied seven days later and their parasite burdens recovered for the determination of efficacy, which was 99.7% for the inhibited stages and 99.3% for the developing fourth-stages. In conclusion, monepantel dosed orally at 2.5 mg/kg is a highly effective treatment against naturally acquired infections of inhibited and developing fourth-stage larvae of Teladorsagia spp.     

The comparative efficacy of abamectin, monepantel and an abamectin/derquantel combination against fourth-stage larvae of a macrocyclic lactone-resistant Teladorsagia spp. isolate infecting sheep

Anthelmintic resistance by gastrointestinal nematodes of sheep continues to be an issue of global interest. While the recent introduction in some countries of one or two new anthelmintic classes (amino-acetonitrile derivatives [AAD] and spiroindoles [SI]) has been welcomed, it is important that there is no relaxation in parasite control and the management of drug resistance. Monepantel (an AAD) was the first new anthelmintic to be approved for use (New Zealand, 2009) and was followed a year later in the same country by a combination of derquantel (a SI) and abamectin. The present study determined the efficacy of the new anthelmintic products and abamectin against fourth-stage larvae of macrocyclic lactone-resistant Teladorsagia spp. in lambs. Efficacies were calculated by comparing post-mortem nematode burdens of treated animals with those of untreated control sheep, and were 98.5, 86.3 and 34.0% for monepantel, abamectin/derquantel and abamectin, respectively. The nematode burdens of monepantel- and abamectin/derquantel-treated sheep were significantly lower than those sheep treated with abamectin and the untreated controls. Similarly, the burden of the monepantel group was significantly lower than that of the abamectin/derquantel group. These findings provide an opportunity to reinforce the recommendation that farmers and animal health advisors need to know the resistance status of nematode populations on subject farms to ensure effective control programs are designed and implemented. Such control programs should include an appropriate choice of anthelmintic(s), monitoring parasite burdens for correct timing of treatments, and pasture management to reduce larval challenge balanced with the maintenance of drug-susceptible populations in refugia.     

Therapeutic efficacy of eprinomectin extended-release injection against induced infections of developing (fourth-stage larvae) and adult nematode parasites of cattle

The therapeutic efficacy of eprinomectin in an extended-release injection (ERI) formulation was evaluated against induced infections of developing fourth-stage larval or adult gastrointestinal and pulmonary nematodes of cattle in a series of six studies under two identical protocols (three each for developing fourth-stage larvae or adults) conducted in the USA, Germany or the UK (two studies at each location, one per stage).     

Dose determination studies for monepantel, an amino-acetonitrile derivative, against fourth stage gastro-intestinal nematode larvae infecting sheep

Monepantel is the first compound from the recently discovered amino-acetonitrile derivative (AAD) class of anthelmintics to be developed for use in sheep. Three dose determination studies were conducted in Australia and Switzerland to identify the minimum therapeutic dose of monepantel when formulated for the oral treatment of sheep to control fourth stage (L4) gastro-intestinal nematode larvae. In each study, sheep infected with the target nematodes (selected from Haemonchus contortus, Teladorsagia (Ostertagia) circumcincta, Teladorsagia trifurcata, Trichostrongylus axei, Trichostrongylus colubriformis, Trichostrongylus vitrinus, Cooperia curticei, Cooperia oncophora, Nematodirus battus, Nematodirus filicollis, Nematodirus spathiger, Chabertia ovina and Oesophagostomum venulosum) were treated with either 1.25, 2.5 or 5.0mg monepantel/kg liveweight. Following euthanasia and worm counting, efficacy was calculated against worm counts from untreated control groups. Monepantel proved highly effective at 2.5 and 5.0mg/kg, but was only moderately effective against some nematode species (L4 stage) at 1.25mg/kg. The results also confirmed that monepantel will effectively control L4 stages of nematodes resistant to at least some of the currently available broad-spectrum anthelmintic classes (macrocyclic lactone resistant strains were not included in the studies). It was concluded that 2.5mg/kg would be a suitable minimum dose rate for a commercial product. No adverse events related to treatment with monepantel were detected.     

Dose confirmation studies for monepantel, an amino-acetonitrile derivative, against fourth stage gastro-intestinal nematode larvae infecting sheep

Monepantel is the first compound from the recently discovered amino-acetonitrile derivative (AAD) class of anthelmintics to be developed for use in sheep. Nine dose confirmation studies were conducted in Australia, New Zealand and Switzerland to confirm the minimum therapeutic oral dose of monepantel to control fourth stage (L4) gastro-intestinal nematode larvae in sheep (target species were Haemonchus contortus, Teladorsagia (Ostertagia) circumcincta, Teladorsagia trifurcata, Trichostrongylus axei, Trichostrongylus colubriformis, Trichostrongylus vitrinus, Cooperia curticei, Cooperia oncophora, Nematodirus battus, Nematodirus filicollis, Nematodirus spathiger, Chabertia ovina and Oesophagostomum venulosum). In each study, sheep infected with a defined selection of the target nematodes were treated with 2.5 mg monepantel/kg liveweight. Following euthanasia and worm counting, efficacy was calculated against worm counts from untreated control groups. The results demonstrate high (95 < 100%) efficacy of monepantel when administered orally to sheep at 2.5 mg/kg for most species tested. Efficacy levels against N. spathiger and O. venulosum were variable and failed to meet the required regulatory standard (≥90%) in some studies. Efficacy was demonstrated against L4 stages of nematodes known to be resistant to either benzimidazole and/or levamisole anthelmintics (macrocyclic lactone resistant isolates were not available for testing). The broad-spectrum activity of monepantel against L4 larvae of common gastro-intestinal nematodes in sheep and its favorable safety profile represents a significant advance in the treatment of parasitic gastro-enteritis in this animal species. No adverse effects related to treatment with monepantel were observed.     

The efficacy of eprinomectin extended-release injection against naturally acquired nematode parasites of cattle,with special regard to inhibited fourth-stage Ostertagia larvae

The efficacy of eprinomectin in an extended-release injection (ERI) formulation in the treatment of cattle harboring naturally acquired nematode populations (including inhibited nematodes) was evaluated. Five studies were conducted under a similar protocol in the USA, the UK, and in Germany. All study animals were infected by grazing naturally contaminated pastures. The adequacy of pasture infectivity was confirmed by examining tracer calves prior to allocation and treatment of the study animals. The cattle were of various breeds or crosses, weighing 79–491 kg, and aged approximately 6–15 months. In each study, 20 animals were infected by grazing, and then removed from pasture and housed in a manner to preclude further nematode infections for 8–16 days until treatment. Animals were blocked based on descending pre-treatment body weight and randomly allocated to one of two treatments: ERI vehicle (control) at 1 mL/50 kg body weight or eprinomectin 5% (w/v) ERI at 1 mL/50 kg body weight (1.0 mg eprinomectin/kg). Treatments were administered once on Day 0 by subcutaneous injection in front of the shoulder. For parasite recovery and count, all study animals were humanely euthanized 14/15 days after treatment. Cattle treated with eprinomectin ERI had significantly (p < 0.05) fewer of the following nematodes than the controls with overall reduction of parasite counts of ≥94%: adult Dictyocaulus viviparus, Capillaria spp., Cooperia oncophora, Cooperia pectinata, Cooperia punctata, Cooperia surnabada, Haemonchus placei, Nematodirus helvetianus, Oesophagostomum radiatum, Ostertagia lyrata, Ostertagia ostertagi, Trichostrongylus axei, Trichostrongylus colubriformis, Trichuris discolor, Trichuris skrjabini, and Trichuris spp.; developing fourth-stage larvae of Ostertagia spp. and Trichostrongylus spp.; and inhibited fourth-stage larvae of Cooperia spp., Haemonchus spp., Nematodirus spp., Oesophagostomum spp., Ostertagia spp., and Trichostrongylus spp.     

Prophylactic efficacy of an ivermectin sustained-release bolus against challenge exposure with gastrointestinal and pulmonary nematode infective larvae in calves

Twelve Holstein calves were used to determine the prophylactic efficacy of ivermectin against challenge exposure with gastrointestinal and pulmonary nematodes. Two groups of 6 calves (mean body weight, 205 kg) each were formed by restricted randomization according to body weight. Group-1 calves served as nonmedicated controls. Each calf of group 2 was orally given one prototype sustained-release bolus designed to deliver ivermectin at a continuous daily dose of 8 mg. Third-stage nematode infective larvae were given to the calves on posttreatment days 28 and 42. The calves were euthanatized 77 or 78 days after treatment. Ivermectin was 100% effective (P less than 0.05) in preventing the establishment of infection by Haemonchus placei, Ostertagia ostertagi, Cooperia spp (C punctata, C oncophora, C surnabada), Nematodirus helvetianus, Oesophagostomum radiatum, and Dictyocaulus viviparus and was greater than 99% effective against Trichostrongylus axei. Incidental infection by Trichuris spp was reduced by 94% (P = 0.08).     

Activity of fenbendazole against inhibited early fourth-stage larvae of Ostertagia ostertagi

The efficacy of fenbendazole (Panacur, Hoechst-Roussel) against inhibited early fourth-stage larvae of Ostertagia ostertagi and other nematodes of the abomasum and intestinal tract was investigated in naturally infected, yearling cattle in April 1978. The time when peak levels of inhibited larvae occurred was determined by epizootiologic study which began in November 1977. All animals were removed from pasture and maintained free from further helminth infection until slaughter (19 to 21 days). The fenbendazole liquid suspension was administered as an oral drench at dose level of 10 mg/kg to 10 animals and then at dose level of 15 mg/kg to an additional 10 animals at 10 days after removal from pasture. Eleven animals were maintained as untreated controls. In cattle given the dose of 10 mg/kg, the following reductions were observed: O ostertagi adults--100%, developing stages--80%, and inhibited larvae--97%; other worm genera in the abomasum and nematodes of the intestinal tract--100%. In the cattle given the larger dose, the following reductions were observed: O ostertagi adults--100%, developing stages--98%, and inhibited larvae--99%; other worm genera in the abomasum and nematodes of the intestinal tract--100%.     

Efficacy of the amino-acetonitrile derivative,monepantel, against experimental and natural adult stage gastro-intestinal nematode infections in sheep

Multiple drug resistance by nematodes, against anthelmintics has become an important economic problem in sheep farming worldwide. Here we describe the efficacy of monepantel, a developmental molecule from the recently discovered anthelmintic class, the amino-acetonitrile derivatives (AADs). Efficacy was tested against adult stage gastro-intestinal nematodes (GINs) in experimentally and naturally infected sheep at a dose of 2.5 mg/kg body weight when administered as an oral solution. Some of the isolates used in experimental infection studies were known to be resistant to the benzimidazoles or levamisole anthelmintics; strains resistant to the macrocyclic lactones were not available for these tests. Worm count-based efficacies of >98% were determined in these studies. As an exception, Oesophagostomum venulosum was only reduced by 88% in one study, albeit with a low worm burden in the untreated controls (geometric mean 15.4 worms). Similar efficacies for monepantel were also confirmed in naturally infected sheep. While the efficacy against most species was >99%, the least susceptible species was identified as Nematodirus spathiger, and although efficacy was 92.4% in one study it was generally >99%. Several animals were infected with Trichuris ovis, which was not eliminated after the treatment. Monepantel demonstrated high activity against a broad range of the important GINs of sheep, which makes this molecule an interesting candidate for use in this species, particularly in regions with problems of anthelmintic resistance. Monepantel was well tolerated by the treated sheep, with no treatment related adverse events documented.     

The anthelmintic efficacy of five plant products against gastrointestinal trichostrongylids in artificially infected lambs

Forty-eight helminth-free lambs were divided into eight groups (A-H) of six animals. Groups A-G were infected artificially with 10,000 third stage larvae of Haemonchus contortus and 20,000 third stage larvae of Trichostrongylus colubriformis, whereas group H remained uninfected. Thirty days post-infection the lambs were treated orally with a single dosage of one of the following products: group A with 3 mg/kg body weight (BW) of an aqueous ethanol extract (70%, v/v) of the seeds of Azadirachta indica A. Juss syn. Melia azedarach L. (Meliaceae); group B with 1 g/kg BW of a raw powder of the leaves of Ananas comosus (L.) Merr. (Bromeliaceae); group C with 0.3 mg/kg BW of an aqueous ethanol extract of a 1:1 mixture (g/g) of Vernonia anthelmintica (L.) Willd. (Asteraceae) seeds and Embelia ribes Burm (Myrsinaceae) fruits; group D with 183 mg/kg BW of an aqueous ethanol extract of the whole plants of Fumaria parviflora Lam. (Fumariaceae); group E with 28 mg/kg BW of an aqueous ethanol extract of the seeds of Caesalpinia crista L. (Caesalpiniaceae); group F with 25 mg/kg BW of pyrantel tartrate and group G with 50% ethanol. Group H remained untreated. Only the ethanol extract of F. parviflora caused a strong reduction of the faecal egg counts (100%) and a 78.2 and 88.8% reduction of adult H. contortus and T. colubriformis on day 13 post-treatment. The extract was as effective as the reference compound pyrantel tartrate. Therefore, the ethanol extract itself or single constituents of F. parviflora could be a promising alternative source of anthelmintic for the treatment of gastrointestinal trichostrongylids in small ruminants.     

The efficacy of an albendazole intraruminal controlled-release device against gastrointestinal parasitism in lambs.

The effectiveness of albendazole in a controlled-release bolus in controlling gastrointestinal nematodes in lambs was assessed during the summer of 1986. Faecal egg counts were almost entirely negative throughout in the treated group and larval challenge remained low at below 2000 larvae kg-1. Untreated control lambs showed a characteristic pattern of auto-infection, culminating in a peak pasture larval count of over 70,000 larvae kg-1 and an outbreak of parasitic gastroenteritis in September associated with a serum pepsinogen concentration of 1.183 IU tyrosine and a mean worm burden of 91,165 nematodes at necropsy, including Ostertagia, Trichostrongylus and Nematodirus species. Subject to the restrictions imposed by the size of the bolus, this was considered to be a highly effective method of seasonal parasite control.     

Efficacy of monepantel and anthelmintic combinations against multiple-resistant Haemonchus contortus in sheep, including characterisation of the nematode isolate

Three experiments defined the resistance profile of a population of Haemonchus contortus, which was shown to express multiple resistances to the benzimidazole, levamisole, macrocyclic lactone and salicylanilide anthelmintic classes when given as a registered combination. Study 1 was a faecal egg count reduction (FECR) test and the efficacies for the anthelmintics were monepantel, 100%; abamectin+levamisole+oxfendazole, 40.0%; and abamectin+levamisole+oxfendazole+naphthalophos, 100%. No larvae were recovered from the post-treatment cultures for monepantel or the 4-way treatment, and for the 3-way treatment the culture was 100% Haemonchus spp. Efficacies in Study 2 were calculated from mean post-mortem nematode burdens of H. contortus and were levamisole+oxfendazole, 3.1%; abamectin+levamisole+oxfendazole, 5.0%; ivermectin, 0.4%; moxidectin, 28.4% and closantel, 70.2%. Study 3 was also a FECR test that resulted in efficacies of 100% for monepantel and 83.0% for a formulated 4-way combination of abamectin+levamisole+albendazole+closantel. Larvae recovered from the post-treatment culture for the combination-treated sheep were all Haemonchus spp. Multi-resistant parasites such as examined in these studies are a continuing challenge to be managed by farmers and their advisors. Control programs must be planned and well-managed, and should include on-farm testing for anthelmintic resistance, monitoring of nematode burdens (by FEC and larval culture) to determine appropriate treatment times and the management of pastures to reduce the overall parasite challenge. This should be in balance with the generation, use and maintenance of drug-susceptible nematode populations in refugia.     

Clinical field study to evaluate the efficacy and safety of the amino-acetonitrile derivative, monepantel, compared with registered anthelmintics against gastrointestinal nematodes of sheep in Australia

Objective   To determine the efficacy of monepantel, a developmental compound from the amino-acetonitrile derivative class of anthelmintics, against field infections of gastrointestinal nematodes in sheep.
Procedures   Comparisons of efficacy (using standard faecal worm egg count reduction tests) and safety (on the basis of visual observations) were made in a large-scale field study in Australia, between groups of sheep treated with either an oral solution of monepantel or a registered anthelmintic. The sheep were naturally infected with the major gastrointestinal nematode genera present in Australia.
Results   The post-treatment efficacy results for monepantel were: at 7 days (±1 day) efficacy was >98%; at 14 days (±1 day) it was generally close to or >99%; and at 21 days (±1 day) efficacy was consistently >99%. A high proportion of the targeted nematode populations were confirmed as being resistant to one or more of the currently available anthelmintic classes.
Conclusions   Monepantel when used under field conditions at a minimum dose rate of 2.5 mg/kg was highly effective against mixed-genus natural field infections of the major gastrointestinal nematode genera including Haemonchus , Teladorsagia ( Ostertagia ), Trichostrongylus , Nematodirus , Chabertia and Oesophagostomum . This result included efficacy against some populations resistant to the currently available broad-spectrum anthelmintics. Few Cooperia spp. were present to allow confirmation of efficacy against this genus. On no occasion after treatment did any commercial anthelmintic-treated groups have significantly lower faecal egg counts than the monepantel-treated groups. Monepantel was safe for the target animals and human operators when used in a field situation.     

Efficacy of milbemycin oxime against fourth-stage larvae and adults of Ancylostoma tubaeforme in experimentally infected cats

The efficacy of milbemycin oxime against fourth-stage (L4) larvae and adults of Ancylostoma tubaeforme was investigated in a trial involving 24 young domestic shorthair cats. The animals were inoculated with approximately 300 infective stage three (L3) larvae and divided into three groups. After 12 days, eight cats (group 1) were treated with medicated tablets containing 4 mg milbemycin and 10 mg praziquantel to test the efficacy against L4 larvae; eight cats in group 2 were treated with the same tablets after 33 days to test the efficacy against adult worms; and eight cats in group 3 were treated with a placebo tablet. Faecal egg counts were determined periodically in each cat and after 40 or 41 days the number of worms in each animal was determined postmortem. The egg count reduction was determined by comparing the geometric mean numbers of eggs per gram of faeces in the placebo and medicated groups, and the worm reduction by comparing the geometric mean numbers of worms. The egg count reduction was more than 99 per cent in both treated groups, while the number of worms in groups 1 and 2 were reduced by 94.7 per cent and 99.2 per cent, respectively.     

胃肠道线虫的黏膜免疫

从机体抗胃肠道线虫的黏膜免疫、胃肠道黏膜的抗原加工与递呈、胃肠道黏膜抵御寄生虫的效应机制等几方面论述了胃肠道线虫的免疫机理和免疫学研究的进展，旨在进一步阐明用免疫介入方法防治胃肠道线虫的理论基础，以解决胃肠道线虫治疗过程中的药物残留以及寄生虫的抗药性问题。     

Immunization with irradiated larvae against Dictyocaulus filaria in young lambs

In the lungworm-endemic areas of Kashmir, 6-10 week old lambs of Karnah and Kashmir Merino breeds were vaccinated with two doses of 50 kR gamma-irradiated larvae of Dictyocaulus filaria, given a month apart. Assessed on the basis of reduced prevalence and significantly lower faecal larval output over an eight-month observation period, vaccinated lambs showed a high degree of resistance to naturally acquired D. filaria infection. The results also show that vaccination against D. filaria provided some degree of protection against infection with other lungworm species.     

Epidemiological observations and heterosis analysis of gastrointestinal nematode parasitism in Suffolk, Gulf Coast Native, and crossbred lambs.

A crossbreeding program was conducted to evaluate the resistant status to gastrointestinal nematode parasite infection in crossbred (F1) lambs and their Suffolk and Gulf Coast Native (Native) breed counterparts. A total of 253 lambs were included in the study over 2 years. Fecal egg count (FEC) and blood packed cell volume (PCV) of 18-20 monitor lambs of each breed group in each year were collected every other week from birth to 24-30 weeks of age. The FEC and PCV of all lambs were determined at weaning (11-12 weeks of age) and at three subsequent times when anthelmintic treatment was administered. Nematode counts of wether lambs were obtained at 30 weeks of age in the first year. The epidemiological patterns of FEC and PCV of each breed group were similar in both years. The Suffolk group consistently showed the highest FEC and the lowest PCV. Conversely, the Native group had the lowest FEC and highest PCV. For the most part, all parameters for the F1 group fell intermediate to the Native and Suffolk groups. Nematode count followed the same pattern. Heterosis analysis showed that FEC, PCV, nematode count and weight gain of the F1 group favored the Native group. These results suggested that crossbreeding Suffolk to Native sheep may be a suitable way to produce lambs with improved resistance to gastrointestinal nematode infection, but production may be compromised.     

Pilot project to investigate over-wintering of free-living gastrointestinal nematode larvae of sheep in Ontario,Canada

This study investigated the overwintering survival and infectivity of free-living gastrointestinal nematode (GIN) stages on pasture. The presence of GIN larvae was assessed on 3 sheep farms in Ontario with a reported history of clinical haemonchosis, by collecting monthly pasture samples over the winter months of 2009/2010. The infectivity of GIN larvae on spring pastures was evaluated using 16 tracer lambs. Air and soil temperature and moisture were recorded hourly. Free-living stages of Trichostrongylus spp. and Nematodirus spp. were isolated from herbage samples. Gastrointestinal nematodes were recovered from all tracer lambs on all farms; Teladorsagia sp. was the predominant species. Very low levels of Haemonchus contortus were recovered from 1 animal on 1 farm. The results suggest that Haemonchus larvae do not survive well on pasture, while Teladorsagia sp., Trichostrongylus spp. and Nematodirus spp. are able to overwinter on pasture in Ontario and are still infective for sheep in the spring.