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The aim of this study was to evaluate the effect of two nutritional statuses on the productive performance of Dorper lambs naturally infected with gastrointestinal nematodes. Thirty-two lambs, grazing together on the same pasture, were allocated into four experimental groups: (G1) infected-supplemented diet, (G2) control-supplemented diet, (G3) infected-basal diet, and (G4) control-basal diet. Control animals received suppressive treatment with monepantel every two weeks, while precautionary anthelmintic treatments were given to all lambs of the infected groups with packed cell volume (PCV) <23%. There was reduction in the PCV means of all groups, which was more pronounced in the infected lambs that also presented reduction in total plasma protein values in comparison with the controls. Weight gain was affected by diet and infection status (P < 0.05). Daily body weight gain was 0.170 kg in the G1, 0.205 kg in the G2, 0.085 kg in the G3, and 0.116 kg in the G4. The cold carcass weight was 4.1% and 13.7% higher in controls in comparison with infected lambs, respectively, in the supplemented and basal diets. The infected groups, despite receiving precautionary anthelmintic treatments to prevent deaths due to haemonchosis, presented reduction in the production parameters in comparison with the controls.

Background: Endoparasites are considered a major health problem of South American camelids as shown in a recent survey among German and Austrian camelid owners. Although prophylactic and therapeutic measures such as application of anthelmintics are commonly used, treatment efficacy is usually not assessed. Owners have expressed significant concerns regarding the effect of antiparasitic therapy, so this study aimed to evaluate the outcome of anthelmintic treatment in German alpaca herds with different drugs., Results: Overall, 617 samples from 538 clinically healthy alpacas > 1 year-old from 27 farms (n = 11-157 animals/herd) were examined. The most common parasites detected by flotation were Eimeria spp. (75.1%) followed by strongylids (55.0%), Nematodirus spp. (19.3%), cestodes (3.1%) and Trichuris (2.7%). After initial coproscopical examination by flotation and strongylid egg quantification by the McMaster technique, positive animals excreting at least 150 eggs per gram of faeces were included in a faecal egg count reduction test (FECRT) using fenbendazole (n = 71 samples), moxidectin (n = 71) or monepantel (n = 66). Pre-treatment larval cultures (n = 23 positive pooled farm samples) revealed Haemonchus (87% of the farms), Cooperia (43.5%), Trichostrongylus (21.7%), Ostertagia (13.0%), Nematodirus and Oesophagostomum (4.3% each). Fenbendazole treatment reduced egg excretion by 45%, moxidectin by 91% and monepantel by 96%. On the farm level, 13/18 farms that used fenbendazole, 6/6 farms that used moxidectin and 2/5 farms that used monepantel had individual FECR values < 90% (fenbendazole) or < 95% (moxidectin, monepantel). Haemonchus and Cooperia were overrepresented on the farms with reduced treatment efficacy., Conclusions: Gastrointestinal strongylids are common in German alpacas and fenbendazole in particular was not sufficiently effective to reduce strongylid egg excretion. Although the FECRT could not unambiguously determine anthelmintic resistance in the present study, the finding that small ruminant strongylids, especially Haemonchus, are common in alpacas indicates that determination of effective anthelmintic doses, monitoring of efficacy and adapted (selective) treatment regimens must be implemented as part of sustainable deworming practices in this species in accordance with recommendations for ruminants.

Gastrointestinal nematodes significantly affect the ovine industry, and Haemonchus contortus is considered the most pathogenic parasite in tropical regions. This situation is aggravated when the main strategy to control worms fails because of the genetic resistance that parasites acquire against anthelmintics. Aiming to anticipate the events involved in anthelmintic resistance, we induced monepantel resistance in H. contortus by in vivo subdosing of sheep hosts. Four successive passages of a monepantel-susceptible H. contortus isolate in Santa Ines or Ile de France sheep hosts resulted in three monepantel-resistant (efficacy varying from 0 to 58.5%) H. contortus isolates. Sheep hosts were treated from 0.075 mg/kg to the therapeutic dose of 2.5 mg/kg of monepantel in 19-26 rounds of selection for 112-133 weeks. Success in inducing H. contortus resistance to monepantel may have been affected by worm burden and by host-parasite interactions, including a possible effect of the breed of sheep hosts. We conclude that subdosing of sheep, although time-consuming, is an efficient in vivo strategy for the induction of monepantel resistance in H. contortus. The resistant parasites can be used in further studies to elucidate the genetic and biochemical events involved in the acquisition of anthelmintic resistance.

Monepantel (MNP) is a novel anthelmintic compound launched into the veterinary pharmaceutical market. MNP is not licenced for use in dairy animals due to the prolonged elimination of its metabolite monepantel sulphone (MNPSO 2 ) into milk. The goal of this study was to evaluate the presence of potential in vivo drug-drug interactions affecting the pattern of milk excretion after the coadministration of the anthelmintics MNP and oxfendazole (OFZ) to lactating dairy cows. The concentrations of both parent drugs and their metabolites were measured in plasma and milk samples by HPLC. MNPSO 2 was the main metabolite recovered from plasma and milk after oral administration of MNP. A high distribution of MNPSO 2 into milk was observed. The milk-to-plasma ratio (M/P ratio) for this metabolite was equal to 6.75. Conversely, the M/P ratio of OFZ was 1.26. Plasma concentration profiles of MNP and MNPSO 2 were not modified in the presence of OFZ. The pattern of MNPSO 2 excretion into milk was also unchanged in animals receiving MNP plus OFZ. The percentage of the total administered dose recovered from milk was 0.09 ± 0.04% (MNP) and 2.79 ± 1.54% (MNPSO 2 ) after the administration of MNP alone and 0.06 ± 0.04% (MNP) and 2.34 ± 1.38% (MNPSO 2 ) after the combined treatment. The presence of MNP did not alter the plasma and milk disposition kinetics of OFZ. The concentrations of the metabolite fenbendazole sulphone tended to be slightly higher in the coadministered group. Although from a pharmacodynamic point of view the coadministration of MNP and OFZ may be a useful tool, the presence of OFZ did not modify the in vivo pharmacokinetic behaviour of MNP and therefore did not result in reduced milk concentrations of MNPSO 2 ., (© 2017 John Wiley & Sons Ltd.)

Gastrointestinal nematodes (GINs) cause considerable economic losses in grazing goat herds. At present, GIN control cannot rely on conventional anthelmintic (AH) drugs because parasites have developed resistance against such drugs. Thus, alternative control methods are being sought to reduce the dependence on AH. Many tannin-rich plants exhibit AH activity and may be used as alternatives for GIN control. Mimosa caesalpiniifolia is a tannin-rich shrub consumed by small ruminants in Brazil. This study evaluated the in vivo AH effect of M. caesalpiniifolia leaf powder supplementation on GIN egg fecal excretion and worm burden in goats. Plant leaves were harvested, dried and ground to obtain a powder. Twenty-four castrated male goats, aged six to eight months, with a mean body weight of 15.0 ± 2.5 kg were used in the experiment. Animals were infected orally with 16,000 larvae comprising 50% Haemonchus spp., 41% Trichostrongylus spp. and 9% Oesophagostomum spp. Once the infection was patent, the goats were distributed into four groups of six animals. The control group received concentrate without condensed tannins (CTs) and did not receive any drench against GINs. The monepantel group received concentrate without CTs and were drenched once with monepantel. The other two groups received the M. caesalpiniifolia leaf powder in two periods of seven consecutive days (days 1-7 and 14-21), with one of the groups also receiving 10 g of polyethyleneglycol (PEG)/day. The animals were weighed weekly, and individual fecal eggs counts (FECs) were performed daily. After 28 days, the animals were humanly slaughtered, and the worm burden was estimated. Although live weight gain and FECs did not differ among the groups (P > 0.05), post-mortem worm counts showed a reduction in Haemonchus contortus adult worm burden (57.7%) in goats of the CT group compared to control goats (P < 0.05). The addition of PEG did not diminish AH activity in the CT + PEG group (66.9% reduction compared to the control). No AH effect against other GIN species was found. The result for the addition of PEG suggested that the observed AH activity was associated with plant secondary compounds, as opposed to CTs. As expected, no AH effect against Oesophagostomum columbianum was found for the monepantel group showed. Thus, feeding dry leaves of M. caesalpiniifolia represent a promising alternative for the control of GIN infections in goats., (Copyright © 2018 Elsevier B.V. All rights reserved.)

There is an increasing interest in the use of combination anthelmintic products for the control of intestinal nematode parasites of livestock. These products are seen as attractive options for parasite control in the face of increasing levels of resistance to the different anthelmintic drug classes, as well as a means to slow the rate at which resistance develops to the individual components of the combination. With the recent introduction of an anthelmintic combination product containing abamectin and monepantel (at 1:12.5), we were interested in measuring the response of drug-susceptible and drug-resistant isolates of Haemonchus contortus to these two drugs alone and in combination, using larval development assays. The GWBII isolate showed resistance to abamectin (12-fold) alongside susceptibility to monepantel. The resistance ratio was reduced from 12- to 3.2-fold when the two drugs were combined. The MPL-R isolate was resistant to both drugs, with resistance factors of 6-fold towards abamectin, and 10.6- and 1008-fold towards monepantel in two sub-populations present in the isolate. This isolate showed 6.4-fold resistance to the drug combination. Hence, for both GWBII and MPL-R, the level of resistance towards the combination was reduced compared to the resistance towards abamectin or monepantel alone, respectively, but was not abolished. However, for GWBII, this in vitro resistance to the drug combination would be expected to have no impact on the in vivo efficacy of the combination drench product as the isolate is resistant to only the abamectin component of the drench, with monepantel remaining effective. On the other hand, the observed in vitro resistance to the combination shown by the MPL-R isolate is derived from significant levels of resistance towards both components separately, and hence may impact on in vivo efficacy of the combination. Isobologram analysis did not find any evidence for a synergistic interaction between the two drugs in larval development assays. We examined the predicted effects of varying the abamectin:monepantel ratio in drug combinations, assuming that the two drugs acted in an additive fashion. For GWBII, resistance to the drug combination was reduced to almost zero as the abamectin:monepantel ratio increased from 1:12.5 to 1:100, reflecting its resistance to only the abamectin component of the combination. For MPL-R, on the other hand, the resistance increased as the relative proportion of monepantel in the combination was increased, reflecting the extreme level of in vitro resistance shown by this isolate to monepantel., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Drug resistance in gastrointestinal nematodes is a severe problem for sheep farmers. With the recent introduction of monepantel (Zolvix®) and of derquantel plus abamectin (Startect®) in New Zealand, two new anthelmintic classes will be available to control gastrointestinal nematodes. While monepantel covers a broad spectrum of nematodes, the efficacy of derquantel is mid-spectrum and limited to a smaller number of species and stages. The combination of derquantel and abamectin allows to enlarge the spectrum and to cover most parasitic nematodes in sheep. However, the question remained open, if the efficacy of the new anthelmintics can be maintained in the presence of severe anthelmintic resistance. The present study investigated the efficacy against adult stages of a multi-resistant Haemonchus contortus isolate. While monepantel resulted in 100 % elimination, derquantel in combination with abamectin resulted in efficacies <95 % (faecal egg counts and worm counts).

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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Few effective drugs are available for soil-transmitted helminthiases and drug resistance is of concern. In the present work, we tested the efficacy of the veterinary drug monepantel, a potential drug development candidate compared to standard drugs in vitro and in parasite-rodent models of relevance to human soil-transmitted helminthiases., Methodology: A motility assay was used to assess the efficacy of monepantel, albendazole, levamisole, and pyrantel pamoate in vitro on third-stage larvae (L3) and adult worms of Ancylostoma ceylanicum, Necator americanus and Trichuris muris. Ancylostoma ceylanicum- or N. americanus-infected hamsters, T. muris- or Ascaris suum-infected mice, and Strongyloides ratti-infected rats were treated with single oral doses of monepantel or with one of the reference drugs., Principal Findings: Monepantel showed excellent activity on A. ceylanicum adults (IC(50) = 1.7 µg/ml), a moderate effect on T. muris L3 (IC(50) = 78.7 µg/ml), whereas no effect was observed on A. ceylanicum L3, T. muris adults, and both stages of N. americanus. Of the standard drugs, levamisole showed the highest potency in vitro (IC(50) = 1.6 and 33.1 µg/ml on A. ceylanicum and T. muris L3, respectively). Complete elimination of worms was observed with monepantel (10 mg/kg) and albendazole (2.5 mg/kg) in A. ceylanicum-infected hamsters. In the N. americanus hamster model single 10 mg/kg oral doses of monepantel and albendazole resulted in worm burden reductions of 58.3% and 100%, respectively. Trichuris muris, S. ratti and A. suum were not affected by treatment with monepantel in vivo (following doses of 600 mg/kg, 32 mg/kg and 600 mg/kg, respectively). In contrast, worm burden reductions of 95.9% and 76.6% were observed following treatment of T. muris- and A. suum infected mice with levamisole (200 mg/kg) and albendazole (600 mg/kg), respectively., Conclusions/significance: Monepantel reveals low or no activities against N. americanus, T. muris, S. ratti and A. suum in vivo, hence does not qualify as drug development candidate for human soil-transmitted helminthiases.

Drug resistance has become a global phenomenon in gastrointestinal nematodes of sheep, particularly resistance to macrocyclic lactones. New anthelmintics are urgently needed for both the control of infections with multi-resistant nematodes in areas where classical anthelmintics are no longer effective, and the prevention of the spread of resistance in areas where the problem is not as severe. Recently, two new active ingredients became commercially available for the treatment of nematode infections in sheep, monepantel (Zolvix®) and derquantel, the latter used only in a formulated combination with the macrocyclic lactone, abamectin (Startect®). In order to assess the potential of the new actives for the control and prevention of spread of anthelmintic resistance, two characterized multi-resistant field isolates from Australia were used in a GLP (good laboratory practice) conducted efficacy study in sheep. Eight infected sheep in each group were treated orally according to the product labels with 2.5 mg/kg body weight monepantel, 0.2 mg/kg abamectin, or with the combination of 2.0 mg/kg derquantel and 0.2 mg/kg abamectin. The results demonstrate that monepantel was fully effective against multi-resistant species, Trichostrongylus colubriformis and Haemonchus contortus (99.9%). In contrast, the combination of derquantel and abamectin was effective against T. colubriformis (99.9%), but was not effective against larval stages of the barber's pole worm H. contortus (18.3%).

The effect of the route of administration (oral, intraruminal and intra-abomasal) on the efficacy and pharmacokinetics of the new anthelmintic monepantel in sheep was investigated. The target nematodes were fourth-stage Haemonchus contortus, Teladorsagia circumcincta, Trichostrongylus colubriformis and Cooperia curticei. A clear difference in efficacy was identified between the routes of administration, although the difference did not consistently reach statistical significance; oral treatment was most effective, followed by intraruminal and then intra-abomasal administration. The same pattern was observed in the pharmacokinetic analysis, with lambs treated orally having more favourable exposure to monepantel and its sulfone metabolite (albeit in all but one instance not significantly different) than the lambs treated by the other routes of administration, which were very similar for most parameters.

Monepantel is the first compound from the amino-acetonitrile derivative class of anthelmintics to be developed for the control of gastrointestinal nematodes of sheep. An analysis of pooled data from a series of controlled studies is reported providing a single point of efficacy (+/- 95% confidence interval) for each gastrointestinal nematode tested at the fourth larval and/or adult stages. For most nematode species, the pooled efficacy was greater than 99%, and for the remaining few species, efficacy was greater than 90%. These data are well supported by field studies conducted across five countries, where the pooled efficacy (on the basis of fecal worm egg count reduction) was in most cases, greater than 99% (depending on the calculation used). Monepantel is highly effective when administered to sheep at 2.5 mg/kg, and its introduction as a new anthelmintic for sheep is timely, given the problems with anthelmintic resistance that the world's sheep farmers are now experiencing.

Aim: To demonstrate the clinical and reproductive safety in ewes and their offspring of repetitive oral doses of monepantel, an amino-acetonitrile derivative (AAD), when administered at three times the proposed maximum recommended dose (MRD) over an entire reproductive cycle., Methods: A randomised controlled blinded study design was used. One hundred and twelve primi- or multi-parous ewes and 28 rams were randomly allocated into control and treated groups (n=56 for groups of ewes, n=14 for groups of rams). Two control ewes and two treated ewes were randomly selected to form 28 subgroups. A control or treated ram was then randomly allocated to each subgroup, to form control ram/treated ewe, control ram/control ewe, treated ram/treated ewe, and treated ram/control ewe 'treatment/mating' units. Control animals were treated with saline, and treated animals given three times the MRD (11.25 mg/kg) of monepantel. Treatments were administered orally every 5 days during an entire reproductive cycle, including oestrus and mating, gestation, and post-lambing to weaning. Detailed recording at multiple time points were made of veterinary examinations; observations for adverse events; bodyweight measurements; faecal scores; and haematology, clinical chemistry and coagulation variables. Reproductive indices determined included percent pregnant, number of failed embryos, abortion percentage, number of lambs with teratogenic defects, length of gestation, percentage of stillbirths, number of ewes experiencing reproductive problems, lambing percentage, and pre-weaning mortality. Post-mortem examination, including measurement of organ weights, was performed on randomly selected ewes (n=40) and lambs (n=40) at the completion of the study., Results: All ewes treated with monepantel and those in the control group thrived and behaved normally to the end of the study. No treatment-related, toxicologically relevant adverse events, clinical observations or gross post-mortem changes were observed. Furthermore, there were no significant differences in bodyweight or organ weights, and haematological, clinical chemistry or coagulation variables between ewes treated with monepantel and control ewes. No significant differences were observed in any of the reproductive indices measured. No significant clinical differences were noted between lambs born from treated ewes and those from controls., Conclusions and Clinical Relevance: Repeated oral administration of monepantel at three times the MRD every 5 days over an entire reproductive cycle was not associated with any treatment-related adverse effects on the reproductive performance of ewes nor on the viability of their offspring, and was systemically very well tolerated. This study demonstrated that this population of ewes could tolerate accidental overdoses of up to three times the MRD of monepantel or prolonged repetitive administration of overdoses. Thus, those so treated entering a breeding programme would have normal reproductive indices, mating behaviour, and health, and their lambs would suffer no ill effects.

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.

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 5.0 mg 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 5.0 mg/kg, but was only moderately effective against some nematode species (L4 stage) at 1.25 mg/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 2.5 mg/kg would be a suitable minimum dose rate for a commercial product. No adverse events related to treatment with monepantel were detected.