Comparison of ivermectin, oxfendazole and levamisole for use as anthelmintics during the periparturient period in sheep

Ewes synchronised with progestin impregnated sponges to reduce the spread of lambing were treated during the periparturient period with anthelmintic. The suppression of nematode egg output in faeces was measured in ewes given ivermectin either by subcutaneous injection or orally, or oxfendazole or levamisole orally. Ivermectin and oxfendazole reduced the output of eggs in the faeces of the ewes significantly (P less than 0.05) and the period of suppressed egg output was extended when ivermectin was given by subcutaneous injection. Plasma pepsinogen activity was estimated as a measure of abomasal damage. Pepsinogen values were significantly (P less than 0.001) lower in those animals treated with ivermectin by subcutaneous injection than in control animals. Levamisole showed a poorer response in terms of the output of eggs in faeces than either ivermectin or oxfendazole.     

Biovailability of ivermectin administered orally to dogs

The bioavailability of three formulations of ivermectin was determined following oral administration to dogs. The average peak plasma level (C _max) of ivermectin administered in the standard tablet formulation at 6 and 100 µg/kg of body weight was 2.97 and 44.31 ng/g, respectively. This suggest dose-dependent pharmacokinetics.C _max and total ivermectin bioavailability, as assessed from the area under the plasma curve (AUC), were similar between two tablet formulations of ivermectin administered at 100 µg/kg. Furthermore,C _max was similar following administration of radiolabelled ivermectin at 6 µg/kg in either a beef-based chewable formulation or in the standard tablet formulation.     

The safety of ivermectin administered orally to pregnant mares

The effect of ivermectin on the first 3 months of equine fetal development was investigated by postnatal evaluation of ontogeny; one trial was conducted in New Jersey, USA and another was conducted simultaneously in Dammartin-en-Serve, France. A total of 58 mares were used including 32 horse-mares (USA) and 26 Welsh-type pony mares (France). An oral dose of 600 micrograms ivermectin per kilogram of body weight (therapeutic dose x 3) was given to each treated mare as a paste formulation during the first 2 weeks following refusal of breeding service and at 2-week intervals thereafter for a total of 6 doses during fetal organogenesis. Control groups were given drug-free paste vehicle at 12 weekly intervals or were not dosed. Teratogenic anatomical defects were not discernible in the progeny of either medicated or unmedicated mares. Production of weaned healthy yearlings was used as a measure of reproductive efficiency. Such yearlings were produced by 65.5% of the pregnant mares that received no ivermectin. In contrast, a higher reproductive efficiency of 75.8% occurred in pregnant mares that received six timed elevated doses of ivermectin during the first 13 weeks of fetal development. Ivermectin did not adversely affect the fertility of mares or the organogenesis of their developing foals.     

The persistence of the anthelmintic activity of ivermectin in sheep

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.     

Breed differences in the pharmacokinetics of ivermectin administered subcutaneously to Holstein and Belgian Blue calves

Belgian Blue (BB) cattle are very sensitive to mange caused by Psoroptes ovis and, in contrast to the case in Holstein cattle, single treatments with ivermectin do not result in complete elimination of the parasite. The objective of the present study was to determine the concentration of ivermectin in plasma, skin and hair following subcutaneous administration to Holstein and BB calves and to assess the influence of breed on drug pharmacokinetics and availability. Two groups of six healthy female Holstein and BB calves were treated with ivermectin (SC formulation) at a dose of 0.2 mg/kg. Blood, skin and hair were collected before treatment and up to 21 days after treatment. Ivermectin was analyzed in plasma and tissue by high-performance liquid chromatography (HPLC). The peak concentrations (Cmax), time-peak concentrations (Tmax), the area under the plasma concentration-time curves (AUC) and the mean residence time (MRT) were determined. The patterns of plasma and tissue ivermectin concentrations were similar in the two breeds of animals, however, the AUC and Cmax levels for plasma and skin were significantly higher in the BB calves. In hair, ivermectin was detected later than in plasma and skin, with the Tmax ranging between 4 days (Holstein group) and 6 days (BB group). The possible reasons for the significantly higher levels in plasma and skin in BB calves compared to Holstein calves are discussed.     

Changes to oxfendazole chiral kinetics and anthelmintic efficacy induced by piperonyl butoxide in horses

REASONS FOR PERFORMING THE STUDY: The study of novel pharmacological strategies to control parasitism in horses is required since many parasite species have developed resistance to anthelmintic drugs. OBJECTIVES: To evaluate the effects of piperonyl butoxide (PB) (a metabolic inhibitor) on the plasma availability and enantiomeric behaviour of oxfendazole (OFZ) given orally to horses, and to compare the clinical efficacy of OFZ given either alone or co-administered with PB in naturally parasitised horses. METHODS: Fifteen naturally parasitised crossbred male ponies were allocated into 3 groups (n = 5) and treated orally as follows: Group I (control) received distilled water as placebo; Group II was dosed with OFZ (10 mg/kg bwt); and Group III was treated with OFZ (10 mg/kg bwt) co-administered with PB (63 mg/kg bwt). Jugular blood samples were obtained over 120 h post treatment. Three weeks after treatments, all experimental horses were subjected to euthanasia. RESULTS: The observed maximum plasma concentration (Cmax) and area under the concentration vs. time curve (AUC) values for OFZ increased 3- and 5-fold, respectively, in the presence of PB. The plasma concentration profiles of fenbendazole (FBZ), a metabolite generated from OFZ, were significantly lower after the treatment with OFZ alone (AUC = 0.8 microg x h/ml) compared to those obtained after the OFZ + PB treatment (AUC = 2.7 microg x h/ml). The enhanced pharmacokinetic profiles correlated with increased anthelmintic efficacy. The combination OFZ + PB showed 100% efficacy against mature nematode parasites. The efficacy against cyathostome L3 larvae increased from 94% (Group II) to 98.7% (Group III). Consistently, the number of L4 larvae recovered from OFZ + PB treated horses (Group III) (n = 146) was significantly lower (P<0.05) than that recovered from Group II (n = 1397). CONCLUSIONS: The use of PB as a metabolic inhibitor may be useful to enhance OFZ activity against mature and migrating larvae of different parasite species in horses. POTENTIAL RELEVANCE: Metabolic inhibitors may be used to enhance the activity of benzimidazole anthelmintics and extend the effective lifespan of benzimidazole drugs in the face of increasing resistance.     

Disposition of oxfendazole in goats and efficacy compared with sheep

The disposition of intraruminally administered oxfendazole (OFZ) in goats was studied at 5, 10 and 20 mg kg-1. The area under the plasma concentration with time curve (AUC) increased with increasing dose but at a declining rate. AUC was lower after intra-abomasal compared with intraruminal administration. OFZ was less effective against drug resistant Trichostrongylus colubriformis in goats than in sheep but was of similar efficacy against drug resistant Haemonchus contortus in both host species. In the same experiment peak plasma levels of OFZ in goats were about half those in sheep given the same dose. Of 70 goats tested in the field, total rumen bypass occurred in 12 per cent and partial bypass in 67 per cent. Lower systemic availability due to bypass would be expected to reduce further anthelmintic efficacy in goats. From the results of these experiments a dose rate of 10 mg kg-1 is recommended for goats. When given at this rate as a divided dose at 12 hourly intervals over 24 hours, OFZ was significantly more effective than a single dose in reducing egg counts.     

Biokinetics and biliary excretion of radiotocopherol administered orally to sheep.

Four adult sheep were given .4 microCi/kg of BW of D-alpha[5-Me-3H]tocopherol orally. Plasma alpha-tocopherol specific activities were measured serially during a 72-h period, after which the sheep were killed. The disposition kinetics were best described by the use of a two-compartment model. The radiotocopherol had a slow distribution phase followed by a relatively slow elimination phase. During the 72-h period of serial monitoring the peak plasma specific activities were observed between 32 to 48 h. At slaughter (72 h after dosing) tissue radioactivity distribution indicated a high rate of accumulation in some glandular organs such as the liver and adrenals. Identification of radioactive components excreted in bile, using HPLC or thin-layer chromatography, showed that unchanged radiotocopherol was present only at very low concentrations (less than 3% of the total recovered radioactivity).     

The steady-state pharmacokinetics and bioequivalence of carprofen administered orally and subcutaneously in dogs

Eighteen male Beagle dogs were randomized to oral (p.o.) or subcutaneous (s.c.) carprofen administration in a two-sequence, two-period crossover design with a 10-day washout between periods. Twenty-five milligrams of carprofen was administered p.o. or s.c. every 12 h for 7 days. Plasma concentrations of carprofen collected after the first and last treatments were determined by high-performance liquid chromatography. Carprofen concentration data were natural log transformed and geometric means were calculated for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0--12) following the first dose and Cmax and AUC0--12 following administration of the last dose. Formulations were considered bioequivalent if the 90% confidence interval (CI) of the mean difference for each variable between formulations were within -20% and 25% of the oral formulation. The mean Cmax and AUC0--12 were 16.9 microg/mL and 73.1 microg. h/mL, respectively, following a single oral dose and 8.0 microg/mL and 64.3 microg x h/mL, respectively, following a single s.c. injection. The 90% CI for Cmax (-56.8 to -48.7%) was outside of the bioequivalence criteria whereas the 90% CI for AUC0--12 (-16.3 to -7.5%) was within the bioequivalence criteria. At steady-state, the mean Cmax and AUC0--12 were 18.7 microg/mL and 101.9 microg x h/mL, respectively, following p.o. administration and 14.7 microg/mL and 111.0 microg x h/mL, respectively, following s.c. injection. The 90% CI was outside the bioequivalence criteria for Cmax (-30.8 to -10.8) but within the bioequivalence criteria for AUC0--12 (2.3-15.9%). The results of this study indicate that peak plasma concentrations of carprofen differ when administered p.o. and s.c., but that total drug exposure following a single dose and at steady-state are bioequivalent.     

Pharmacokinetic behaviour and anthelmintic efficacy of 1-n-butyl carbamoyl oxfendazole given by intramuscular injection

Oxfendazole (OFZ) was chemically modified to 1-n-butyl carbamoyl OFZ (C₄-OFZ) in an attempt to improve the solubility of OFZ and enable it to be administered by injection. After intramuscular injection to sheep and cattle, C₄-OFZ was metabolised to OFZ which resulted in higher plasma OFZ concentrations that persisted for a considerably longer period than those observed following administration of OFZ orally. The anthelmintic efficacy of injected C₄-OFZ was tested, in sheep, against strains ofTrichostrongylus colubriformis,Haemonchus contortus andOstertagia circumcincta, which were highly resistant to benzimidazoles. In all cases, the C₄-OFZ treatment showed a significant improvement in efficacy over the conventional oral OFZ drench.     

Comparison of a combination of oxfendazole and fenthion versus ivermectin in feedlot calves

A trial involving 6,169 feedlot calves was conducted under commercial feedlot conditions in western Canada to compare the relative efficacy of treatment with a combination of oxfendazole and fenthion (O/F) versus ivermectin (I) with respect to the outcome variables, final weight, gain, days on feed (DOF), dry matter intake (DMI), average daily gain (ADG), dry matter intake to gain ratio (DM:G), and morbidity, mortality, and carcass grade parameters.

There were no significant differences (p ≥ 0.05) between the treatment groups for final weight, gain, DOF, DMI, ADG and DM:G. In addition, there were no significant differences (p ≥ 0.05) in the carcass grading parameters between the treatment groups. The bovine respiratory disease (BRD) relapse rates, the overall mortality rates, and the cause specific mortality rates were not significantly different (p ≥ 0.05) between the treatment groups. The BRD treatment rate in the O/F group was significantly lower (p ≤ 0.05) than in the I group, but this difference was not economically important.

These data indicate that a combination of oxfendazole and fenthion is comparable to ivermectin with respect to performance, animal health, and carcass grade parameters.

     

Failure of orally administered zinc to prevent experimentally induced footrot in sheep

Two groups of adult Merino sheep, initially grazed on pasture, were dosed daily with zinc sulphate (1 mg Zn/kg LW) or zinc oxide (15 mg Zn/kg LW) for six and seven weeks, respectively. On the 18th day, both groups were transferred to indoor pens together with unmedicated control sheep, and five days later the feet of all animals were infected artificially with a virulent strain of Bacteroides nodosus. By the fourth week after challenge, 85% or more of the feet challenged had developed advanced footrot, and no significant differences in the incidence and severity of lesions between dosed and un-dosed groups were recorded. Plasma zinc concentrations, monitored throughout the experiment, remained at similar levels in sheep receiving the lower dose rate and in the controls. At the higher dose rate, plasma zinc levels increased till Day 23, but thereafter declined to values comparable to those of undosed animals. At post mortem, no evidence of zinc toxicosis was found, and only the kidneys of sheep receiving the higher dosage showed a significant accumulation of zinc compared with the controls.     

Fecundity of anthelmintic resistant adult Haemonchus contortus after exposure to ivermectin or benzimidazoles in vivo

A strain of Haemonchus contortus resistant to the benzimidazoles, ivermectin and salicylanilides was used to study the effect of exposure to ivermectin or oxfendazole on the number of eggs produced by adult female parasites. After anthelmintic administration there was a reduction in the faecal egg count of the infected lambs. Ivermectin caused a reduction in the number of eggs within adult parasites for up to 72 hours but this returned to higher than pre-treatment levels at 168 hours after treatment. After oxfendazole treatment there was an increase in the number of eggs stored in the adult parasites at 24 hours and then a significant reduction in the number of eggs for over 168 hours. This suggested that both ivermectin and oxfendazole have a deleterious effect on the reproductive potential of female H contortus although the parasites are resistant to these drugs. These results confirm the importance of allowing up to 10 days to elapse between the time of administration of an anthelmintic and the collecting of faecal samples when using the faecal egg count reduction test to identify anthelmintic resistance, especially when using benzimidazoles. The more prolonged effect on fecundity produced by oxfendazole may reflect the antimitotic action of the benzimidazole anthelmintics.