Efficacy of thiabendazole, mebendazole, levamisole and ivermectin against gullet worm, Gongylonema pulchrum: in vitro and in vivo studies

In vitro and in vivo studies were conducted to evaluate the effects of thiabendazole, mebendazole, levamisole and ivermectin against Gongylonema pulchrum. For in vitro assays, third-stage larvae (L3) incubated with the drugs were administered orally to mice and the ability of larvae to invade the gastric mucosa of the animals was examined. After incubation, only those larvae treated with high concentrations of levamisole (1 and 10 microg/ml) were tightly coiled with intestines exhibiting morphological abnormalities. Good dose-response data for the drugs tested was observed at the time of worm recovery from mice, with no worms recovered at the two highest concentrations of levamisole. In vivo efficacy of the drugs against adult worms was evaluated in six groups of three rabbits, each of which was infected with 30 L3 of G. pulchrum and treated with thiabendazole at 100 mg/kg for 3 days, mebendazole at 70 mg/kg for 3 days, levamisole as a single dose of 8 mg/kg, and subcutaneously injected ivermectin as a single dose of 0.2 mg/kg or vehicles of the drugs (control) at 4 months post-infection. Necropsy 14 days after treatment revealed that levamisole, mebendazole and ivermectin reduced worm burdens by 63.2%, 22.8% and 25.8%, respectively, with no reductions in worms observed with thiabendazole. The surviving worms were principally found in the esophagus with the remainder distributed among the buccal mucosa, the tongue, and/or pharyngeal mucosa in all groups. A number of morphologically abnormal eggs were observed within the uterus and ovijector in female worms recovered from the thiabendazole-treated group. These findings suggest that levamisole exhibits in vivo efficacy against G. pulchrum infection and that the larval invasion tests using mice could be used to screen for anthelmintic susceptibility of nematodes.     

Phase I biotransformation of albendazole in lancet fluke (Dicrocoelium dendriticum)

Dicroceliosis, a lancet fluke infection, is a frequent parasitosis of small ruminants and the anthelmintic drug albendazole (ABZ) is effective in control of this parasitosis. The aim of our project was to study the metabolism of ABZ and ABZ sulphoxide (ABZ.SO) in lancet fluke. Both invitro (subcellular fractions of fluke homogenates) and exvivo experiments (adult flukes cultivated in medium) were performed for this purpose. ABZ was metabolised invitro by lancet fluke NADPH-dependent enzymes by two oxidative steps (sulphoxidation and sulphonation). The apparent kinetic parameters of these reactions have been determined. In the exvivo experiments, only ABZ sulphoxidation was observed. The stereospecificity in ABZ sulphoxidation invitro was slight, with preferential formation of (+)-ABZ.SO enantiomer. In contrast (−)-ABZ.SO formation predominated in exvivo experiments. Sulphoreduction of ABZ.SO occurred neither invivo nor exvivo. The detection of ABZ oxidative metabolites indicates the presence of drug metabolising oxidases in lancet fluke.     

Nematode control in suckler beef cattle over their first two grazing seasons using a targeted selective treatment approach

Background

With concerns over the development of anthelmintic resistance in cattle nematode populations, we must re-examine our approach to nematode control in cattle. Targeted selective treatments (TST), whereby individual animals are treated instead of entire groups, are being investigated as an alternative. The study objective was to determine if anthelmintic usage could be reduced using a TST-based approach to nematode control in spring-born suckler beef cattle over their first and second grazing seasons (SGS) without affecting performance. In the first grazing season (FGS), 99 calves with an initial mean (s.d.) calf age and live weight on day 0 (June 28^th 2012) of 107 (23.1) days and 160 (32.5) kg, respectively, were used. The study commenced on day 0 when calves were randomised and allocated to one of two treatments; 1), standard treatment (control) and 2), TST. Control calves were treated subcutaneously with ivermectin on days 0, 41 and 82 in the FGS. All calves were treated with ivermectin on day 124 and housed on day 133. In the SGS, only heifer calves from the FGS were used and control heifers were treated with ivermectin on day 393. Animals were weighed, blood and faecal sampled every three weeks. The TST animals were treated with ivermectin if thresholds based on a combination of plasma pepsinogen concentrations, faecal egg count and/or the presence of Dictyocaulus viviparus larvae in faeces (FGS only) were reached.

Results

No TST calves reached the treatment threshold criteria in the FGS. The FGS average daily live weight gain (ADG ± s.e.m.) for control and TST group calves was 0.89 ± 0.02 kg and 0.94 ± 0.02 kg day⁻¹, respectively (P = 0.17). In the SGS, all heifers were treated with ivermectin on day 431 due to clinical signs of respiratory disease. The ADG for control and TST heifers from turnout on day 321 to day 431 was 0.90 ± 0.04 and 0.80 ± 0.04 kg day⁻¹, respectively (P = 0.03).

Conclusions

Spring-born FGS suckler beef calves require minimal anthelmintic treatment to maintain performance. In contrast, clinical parasitic disease may develop in the SGS unless appropriate anthelmintic treatment is provided.     

Evaluation of the persistent activity of moxidectin (10%) long-acting (LA) injectable formulation against Dictyocaulus viviparus, Haemonchus placei, Trichostrongylus axei and Oesophagostomum radiatum infections in cattle

Two controlled studies were conducted to evaluate the persistent efficacy of moxidectin (10%) long-acting (LA) injectable formulation against Dictyocaulus viviparus, Haemonchus placei, Trichostrongylus axei and Oesophagostomum radiatum in cattle. The moxidectin LA injectable formulation was administered as a single subcutaneous injection into the proximal third of the ear at a dose rate of 0.01 ml/kg BW to provide 1.0 mg moxidectin/kg BW. The product had persistent efficacy of >90% against D. viviparus, H. placei and Oe. radiatum for at least 150 days post-treatment and against T. axei for at least 90 days post-treatment.     

Evaluation of the efficacy of anthelmintics sold on Ethiopian markets against <Emphasis Type="Italic">Haemonchus contortus</Emphasis> in experimentally infected Sheep

A total of 54 lambs, aged between 6–8 months were experimentally infected with Haemonchus contortus to evaluate the efficacy of different anthelmintic brands sold on Ethiopian markets using the faecal egg count reduction test (FECRT) and controlled anthelmintic efficacy trial. Accordingly four different albendazole (Alzole®, Analgon-300®, Albenjung_s® and Ahshialben-300®), two tetramisole (Tetsole® and Ashitetra 600) and two tetramisole-oxyclozanide (Tetraclozan sheep® and Tetraclozash 900®) brands were evaluated at the dosage rates recommended by the manufacturers. Animals were allocated into nine groups of six animals each, and balanced for faecal egg counts (FEC), based on their pre-treatment FEC and treatments were randomized among the groups. One group was kept untreated as a control. Faecal egg count was conducted on day 30 post-infection (day of treatment) and on the 10th day post-treatment. Evaluation of anthelmintics based on FECRT revealed high efficacy (99.55–100% reduction in FEC) for all anthelmintic brands tested against H. contortus. The worm count reduction test using controlled anthelmintic efficacy trial also supported the above finding with 99–100% efficacy of the tested anthelmintics. Therefore, the suspicion on the anthelmintic products as being substandard in quality is not credible, at least, for the brands investigated in this study and it might rather be attributed to under dosing. The need for a good extension system for livestock producers with regard to good anthelmintic usage practices, in light of the inevitable development of anthelminitic resistance, is emphasized. Regular surveillance and laboratory quality evaluation of the anthelmintic products in Ethiopia is indicated.     

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.     

Factors affecting pharmacokinetics of benzimidazole anthelmintics in food-producing animals: the consequences and potential risks

Benzimidazoles are frequently and widely used veterinary anthelmintics. Unfortunately, an administration of these anthelmintics does not always result in the expected therapeutic success. Many host-related factors modify pharmacokinetic behavior and efficacy of a chosen anthelmintic. Pharmacokinetics of anthelmintics varies among animals of different species, sex and age. Also diseases, medication, feed and environmental conditions can significantly affect behavior of anthelmintics and resultant drug efficacy in animals. The presented review gathers information, gained in last 20 years, on factors which bring about the variability in performance of benzimidazole anthelmintics in food-producing animals. It is focused particularly on differences in absorption and metabolism of these anthelmintics as these stages of the pharmacokinetic process seem to be the most important for the overall anthelmintic efficacy. The consequences of abnormalities and alterations in pharmacokinetics of benzimidazole anthelmintics are summarized and discussed.     

Effect of dose escalation on multiple dose pharmacokinetics of orally administered praziquantel in kingfish Seriola lalandi

Oral praziquantel (PZQ) preparations, administered using multiple dosing regimens, have recently been investigated for the treatment of monogenean parasites of Seriola species cultured in sea-cages. To evaluate existing dosing regimens, the pharmacokinetics of two oral PZQ doses, 50 mg kg^− 1 body weight (BW) and 150 mg kg^− 1 BW, administered every 24 h for 8 days and 3 days respectively were compared in the plasma and skin of kingfish Seriola lalandi using HPLC. In the skin of kingfish, significantly higher maximum tissue PZQ concentrations (C_max) were achieved with a 150 mg kg^− 1 PZQ dose, but no difference in plasma C_max occurred between the two doses. The higher dose resulted in, on average, 2.4 fold higher PZQ concentrations in skin than the lower dose. Although no difference was found between the residual PZQ concentrations (C_min) of either dose measured prior to dosing each day, there were significant differences in this parameter between days of drug administration. Praziquantel C_min varied significantly in kingfish skin regardless of dose, but similar differences were only found at the lower dose in plasma. A non-linear relationship between tissue drug concentration and dosage indicated potential saturation of active absorption mechanisms; a 3-fold increase in the administered dose only led to an average 1.5 fold increase in plasma and 2.4 fold increase in skin PZQ concentrations over the three days the doses could be compared. Concentrations of the drug in the skin of kingfish were found to be 40-50% of that in plasma and the drug appeared not to accumulate significantly in either tissue over the administration period. These initial studies indicate that under existing oral dosing regimens, using a fixed 24 h dosing interval, parasites will be exposed to similar and highly variable anthelmintic concentrations on a daily basis, which may be sub-optimal for the treatment of monogeneans in this finfish species.