B.C. Hosking

Determination of the effective dose rate for monepantel (AAD 1566) against adult gastro-intestinal nematodes in sheep.

Monepantel (AAD 1566) 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 Europe to identify the therapeutic dose of monepantel, when formulated for the oral treatment of sheep, to control adult gastro-intestinal nematodes. In each study, sheep infected with various nematode species were treated with either 1.25, 2.5 or 5.0mg monepantel/kg bodyweight. Following euthanasia and worm counting, their worm burdens were compared with those from untreated control groups. At a dose rate of 1.25mg/kg, monepantel showed efficacy above 91.9% against all major nematode species, with the exception of Chabertia ovina and Oesophagostomum venulosum. Efficacy against these two species was 93.6% and 94.0%, respectively, at a dose of 2.5mg/kg. At this dose, efficacy was above 99.2% against nine other nematode species including Haemonchus contortus, Teladorsagia circumcincta, Trichostrongylus spp. and Nematodirus spp. It was concluded that 2.5mg/kg would be a suitable dose rate for a commercial product.

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, Nematodirusbattus, Nematodirusfilicollis, Nematodirus spathiger, Chabertia ovina and Oesophagostomum venulosum). In each study, sheep infected with a defined selection of the target nematodes were treated with 2.5mg 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 2.5mg/kg for most species tested. Efficacy levels against N. spathiger and O. venulosum were variable and failed to meet the required regulatory standard (> or =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.

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 2.5mg/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.

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.

Quarantine treatment of sheep with monepantel - rapidity of fecal egg count reduction.

In the presence of multiple anthelmintic resistance, effective quarantine treatment of sheep entering a farm has become a crucial tool in nematode management. In the present work, the use of the amino-acetonitrile derivative, monepantel as a quarantine treatment was investigated. Of special interest was the rapidity of decrease in fecal egg counts (FEC) compared to other anthelmintics used in sheep. In three different studies, sheep were either infected with Haemonchus contortus of known resistance status or with a panel of susceptible and multi-resistant gastro-intestinal nematodes. Fecal egg counts were determined from several hours up to 14 days after treatment with monepantel, benzimidazoles, levamisole, macrocyclic lactones or combinations of the latter three classes. The treatment of susceptible isolates with effective anthelmintics, either as single or combined applications caused a reduction of FEC to 0 within 3-4 days. The status of the resistant nematodes could be confirmed, as treatment with the affected classical anthelmintics never resulted in complete absence of parasite eggs in all samples analyzed. In the case of multi-resistant isolates, only monepantel was able to stop egg excretion, while all other treatments resulted in only a partial reduction of FEC. The resistance status of the nematodes did not influence the rapid decline of egg counts after treatment with monepantel.

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.

A telephone survey of internal parasite control practices on sheep farms in Spain

A telephone survey of farmers was conducted to determine current internal parasite control practices on sheep farms in Spain; the farmers were interviewed by their veterinarians. Anthelmintic choice was largely on veterinary advice and dominated by benzimidazoles and macrocyclic lactones. Anthelmintic rotation was separated into: no rotation (42% of farms); annual rotation (36%); rotate within year (20%); and rotate every second year (2%). The mean annual number of treatments varied subtly by region; ewes and rams 1.6-2.1, replacement lambs 1.7-2.1. Anthelmintics are administered primarily during spring and early summer (47% of treatments), and autumn (41%). Thirty-two percent of farmers introduced sheep to their properties and more than half did not quarantine drench the arrivals.

The control of inhibited fourth-stage larvae of Haemonchus contortus and Teladorsagia spp. in sheep in Australia with monepantel

Monepantel is the first molecule from the amino-acetonitrile derivatives to be developed for controlling gastro-intestinal nematodes in sheep. Two studies were undertaken to examine the drugs efficacy against inhibited fourth-stage larvae of Haemonchus contortus and Teladorsagia spp. in sheep when administered as an oral solution at 2.5mg/kg bodyweight. In study 1, efficacy was 99.7% against H. contortus (p<0.0001) and in study 2, 99.8% against Teladorsagia spp. (p<0.0001). This population consisted of 93% T. circumcincta and 7% T. trifurcata. In conclusion, monepantel is a highly effective treatment against inhibited fourth-stage larvae of H. contortus and Teladorsagia spp. and the studies reported here provide the first published evidence of efficacy of this new anthelmintic against these parasites.

Safety and efficacy against fourth-stage gastrointestinal nematode larvae, of monepantel in 6-week old lambs

A controlled, blinded study was undertaken in 6-week old, pre-weaned lambs to demonstrate the safety and efficacy against fourth-stage gastrointestinal nematode larvae, of monepantel administered per os at 2.5mg/kg body weight. Worm burdens of 10 monepantel-treated lambs were compared to those from 10 untreated control lambs. Geometric mean derived efficacies of 100, 100, 96.4 and 99.9% were demonstrated against Haemonchus contortus, Teladorsagia spp., Cooperia curticei and Trichostrongylus colubriformis, respectively. These results, considered in the light of an earlier series of studies demonstrating the efficacy of monepantel in older animals, and an absence of any adverse events, provides strong support for the use of monepantel as a safe and effective anthelmintic in lambs from six weeks of age.

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.