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.     

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 effect of feed quality on the kinetic disposition of orally administered triclabendazole in sheep

The effect of two qualities of feed on the kinetic disposition of triclabendazole (TCBZ) metabolites was investigated in sheep (n = 4) following oral administration of TCBZ at 10 mg/kg body weight. The same sheep were given sequentially two qualitatively different diets: a low-quality (LQ) diet based on wheat straw ad libitum, and a high-quality (HQ) diet based on barley+alfalfa. The triclabendazole sulphoxide (TCBZSO) and triclabendazole sulphone (TCBZSO₂) concentrations were determined in blood samples taken serially from the jugular vein between 5 min and 9 days after TCBZ administration. The parent drug TCBZ was not detected in any of the samples. The quality of feed affected the kinetics of both TCBZ metabolites. The rate of appearance (T_lag and T_max) in the jugular blood was slower and the formed amount (AUC) of TCBZSO was slightly higher when the sheep were on the LQ diet (T_lag = 7.74 h; T_max = 27.91 h; AUC = 1042 g.h/ml) than when they were offered the HQ diet (T_lag = 1.90 h; T_max = 16.01 h; AUC = 832.4 g.h/ml). The MRT of TCBZSO was about 40% longer with the LQ diet than with the HQ diet. Similarly, the rate of appearance of TCBZSO₂ in plasma of sheep was slower when they were on the LQ diet than when they were on the HQ diet, suggesting an impairment of the hepatic enzymatic activity involved in the oxidation of TCBZSO to TCBZSO₂.     

Comparison of the anthelmintic efficacy of oxfendazole or ivermectin administered orally and ivermectin administered subcutaneously to sheep during the periparturient period

The suppression of nematode egg output in faeces was measured in ewes treated just before lambing with either oxfendazole or ivermectin by oral drench or with ivermectin by subcutaneous injection. Ivermectin and oxfendazole given orally were similarly effective, whereas ivermectin given by subcutaneous injection extended the period of suppressed egg output by about one week. The more persistent anthelmintic effect of ivermectin given subcutaneously was probably due to its extended half-life in the plasma of treated sheep. Plasma pepsinogen activity was less in the sheep given anthelmintic than in the untreated controls. Ivermectin caused a significantly greater reduction in pepsinogen activity than oxfendazole and was more effective when given subcutaneously than when given orally.     

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.     

Teratogenicity and embryotoxicity of orally administered fenchlorphos in blue foxes

Pregnant blue foxes (Alopex lagopus) were administered fenchlorphos (0-0-dimethyl-0-(2,4,5-trichlorophenyl) phos-phorothioate) orally at a dose of 100 mg/kg/day in different periods of gestation. The dose chosen represents the therapeutic dose for the treatment of parasitic lesions. At term the mean number of whelps were recorded, and they were killed and examined for external, visceral and skeletal malformations. Of 19 medicated vixens the mean number of live whelps at term was 1.2 per vixen versus 9.5 in the control group. There was an evident predominance of males in the medicated groups. Several malformations of the head were registered, among them incomplete ossification of the skull bones, cleft palate, hydrocephalus internus and externus. Minor malformations like extra ribs or missing ribs occurred in the medicated groups. Congenital alopecia, hypoplastic kidneys, and hydronephrosis were observed in all the whelps in 1 medicated group. No significant difference in total brain weight, cerebellum weight or the cerebellum-to-total-brain weight was observed.Histological examination of the cerebellum showed a narrowing or absence of the granular and the molecular layers of the cortical zone.Key words: teratogenicity, embryotoxicity, fenchí orphos, blue fox     

Hemodynamic effects of orally administered carvedilol in healthy conscious dogs

OBJECTIVE: To evaluate the hemodynamic effects of orally administered carvedilol in healthy dogs with doses that might be used to initiate treatment in dogs with congestive heart failure. ANIMALS: 24 healthy dogs. PROCEDURE: Dogs were randomly allocated to receive carvedilol PO at a dose of 1.56, 3.125, or 12.5 mg, twice daily for 7 to 10 days; 6 dogs served as controls. Investigators were blinded to group assignment. Hemodynamic variables were recorded prior to administration of the drug on day 1 and then 2, 4, and 6 hours after the morning dose on day 1 and days 7 to 10. Change in heart rate after IV administration of 1microg of isoproterenol/kg and change in systemic arterial blood pressure after IV administration of 8 microg of phenylephrine/kg were recorded 2 and 6 hours after administration of carvedilol. RESULTS: Administration of carvedilol did not significantly affect resting hemodynamic variables or response to phenylephrine. The interaction of day and carvedilol dose had a significant effect on resting heart rate, but a significant main effect of carvedilol dose on resting heart rate was not detected. Increasing carvedilol dose resulted in a significant linear decrease in heart rate response to isoproterenol. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy conscious dogs, orally administered carvedilol at mean doses from 0.08 to 0.54 mg/kg given twice daily did not affect resting hemodynamics. Over the dose range evaluated, there was a dose-dependent attenuation of the response to isoproterenol, which provided evidence of beta-adrenergic receptor antagonism.     

Pharmacokinetics of intravenously and orally administered pyrimethamine in horses.

Single-dose pharmacokinetic variables of pyrimethamine were studied in horses. Pyrimethamine (1 mg/kg of body weight) was administered IV and orally to 6 adult horses, and plasma samples were obtained at frequent intervals thereafter. Plasma pyrimethamine concentration was assayed by gas chromatography, and concentration-time data were analyzed, using a pharmacokinetic computer program. The IV and oral administration data were best described by 3-compartment and 1-compartment models, respectively. The median volume of distribution at steady state after IV administration was 1,521 ml/kg and the median elimination half-time was 12.06 hours. Mean plasma concentration after oral administration fluctuated between a maximal concentration of 0.18 microgram/ml and 0.09 microgram/ml (24 hours after dosing). Bioavailability after oral administration was 56%.     

Pharmacodynamics and pharmacokinetics of orally administered bishydroxycoumarin in the goat

Eight goats, 2 nontreated controls and 6 treated, were used to study the pharmacodynamics and pharmacokinetics of bishydroxycoumarin. In 5 of the 6 treated goats, there was a significant relationship between prothrombin times and drug concentrations. Activated clotting times did not change with time in either the controls or the treated goats. Five of 6 treated goats reached a plateau of drug concentration after 24 to 36 hours. Lag times for onset of pharmacologic effect ranged from 12 to 24 hours. The one goat (No. 3) that did not respond in concert with the other 5 was extremely nervous and became anorectic during the period of indoor confinement.     

Pharmacokinetics of orally administered pirfenidone in male and female beagles

Pirfenidone, a promising antifibrotic agent, was administered orally to dogs at 0, 40, 140, and 400 mg/kg/day. Serum was collected for pirfenidone assay at 0, 26 and 39 weeks of treatment. From the pirfenidone concentrations, pharmacokinetic parameters were determined for each dog at each treatment interval. The only significant differences because of gender were for concentration maxima. Unsurprisingly, there were many significant differences because of dose in concentration maximum and area under curve (AUC), and significant, positive linear correlations of both parameters with dose. There were few significant differences in time of maximal concentration and no correlation with dose. The mean +/- SE clearances were 1.99 +/- 0.13, 1.64 +/- 0.13 and 1.78 +/- 0.14 L/h/kg for doses of 40, 140, and 400 mg/kg, respectively, with no significant differences attributable to dose. There was an unexplained pattern in maximal concentration and AUC with regard to duration of treatment, with the parameters being highest at week 0, lowest at week 26, and intermediate at week 39. Clearance had the reverse pattern; time of maximal concentration had no pattern.     

Pharmacokinetics of enrofloxacin administered intravenously and orally to foals

OBJECTIVE: To determine the pharmacokinetics of enrofloxacin administered IV and orally to foals. ANIMALS: 5 clinically normal foals. PROCEDURE: A 2-dose cross-over trial with IV and oral administration was performed. Enrofloxacin was administered once IV (5 mg/kg of body weight) to 1-week-old foals, followed by 1 oral administration (10 mg/kg) after a 7-day washout period. Blood samples were collected for 48 hours after the single dose IV and oral administrations and analyzed for plasma enrofloxacin and ciprofloxacin concentrations by use of high-performance liquid chromatography. RESULTS: For IV administration, mean +/- SD total area under the curve (AUC0-infinity) was 48.54 +/- 10.46 microg x h/ml, clearance was 103.72 +/- 0.06 ml/kg/h, half-life (t1/2beta) was 17.10 +/- 0.09 hours, and apparent volume of distribution was 2.49 +/- 0.43 L/kg. For oral administration, AUC0-infinity was 58.47 +/- 16.37 microg x h/ml, t1/2beta was 18.39 +/- 0.06 hours, maximum concentration (Cmax) was 2.12 +/- 00.51 microg/ml, time to Cmax was 2.20 +/- 2.17 hours, mean absorption time was 2.09 +/- 0.51 hours, and bioavailability was 42 +/- 0.42%. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with adult horses given 5 mg of enrofloxacin/kg IV, foals have higher AUC0-infinity, longer t1/2beta, and lower clearance. Concentration of ciprofloxacin was negligible. Using a target Cmax to minimum inhibitory concentration ratio of 1:8 to 1:10, computer modeling suggests that 2.5 to 10 mg of enrofloxacin/kg administered every 24 hours would be effective in foals, depending on minimum inhibitory concentration of the pathogen.     

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.