Histological studies on the hypothalamic adenohypophyseal-gonadal system after mestranol and chlormadinone acetate administration in fattening bulls]

Seventy-six young steers were examined to elucidate the action of the steroid oestrogen Mestranol and the gestagen chloromadinone acetate upon the morphology of hypothalamus, adenohypophysis, testes, and accessory sexual glands. The doses used were those applicable also to real animal husbandry. The mechanisms of action of the above pharmaceutical products are discussed against the background of the experimental results. No pathological alteration was observed that might prohibit application of the tested sexual steroids to young steers.     

Linearity of eprinomectin pharmacokinetics in lactating dairy sheep following pour-on administration: excretion in milk and exposure of suckling lambs

Pharmacokinetics of eprinomectin (EPR) were studied in blood plasma and milk in two groups of six Istrian Pramenka dairy sheep and their suckling lambs following pour-on administration of EPR to ewes at dose levels of 0.5 and 1 mg/kg. Maximum concentration in plasma was 2.22 and 5.25 μg/l, and AUC was 13.6 and 33.7 μg day/l for the 0.5 and 1.0 mg/kg dose, respectively. These results indicate that drug exposure with a dose of 0.5 mg/kg, which is commonly used in cattle, may be subtherapeutic. The concentration time course in milk paralleled plasma concentrations. In the dose range studied, linear pharmacokinetics of EPR were demonstrated. Milk-to-plasma AUC ratio was 0.79 ± 0.12 and 1.12 ± 0.43; the fraction of dose recovered in milk was 0.037 ± 0.011 and 0.058 ± 0.027% for the low and high dose, respectively. Maximum residual levels in milk were below the maximum acceptable level of 20 μg/kg; however, EPR was detected in all samples investigated. Despite low permeability in milk, AUC in plasma of suckling lambs was between 20 and 30% of the AUC in plasma of ewes.     

Plasma pharmacokinetics and faecal excretion of ivermectin (Eqvalan paste) and doramectin (Dectomax, 1%) following oral administration in donkeys

Ivermectin (IVM- Eqvalan paste, 1.87%) and doramectin (DRM-Dectomax 1%) were each administered orally to donkeys at 200 microgkg(-1) bodyweight. Blood and faecal samples were collected at predetermined times over 30 days and plasma pharmacokinetics and faecal excretion determined. Maximum plasma concentrations (C(max)) of IVM (23.6 ngml(-1)) and DRM (33.9 ngml(-1)) were obtained at (t(max)) 19.2 and 24h, respectively. The area under the concentration curve (AUC) of DRM (228.9 ngdayml(-1)) was significantly larger than that of IVM (119.3 ngdayml(-1)) and mean residence time (MRT) was 6.5 days for IVM and 9.1days for DRM. The highest (dry weight) faecal concentrations (9.33 microgg(-1) - IVM, 12.12 microgg(-1) - DRM) were detected at 55.9 and 48.0 h, respectively and each compound was detected (0.05 microgg(-1)) in faeces between 11h and 9 days following oral administration in donkeys.     

Plasma concentration, mammary excretion and side-effects of phenylbutazone after repeated oral administration in healthy cows

Seven clinically healthy dairy cows were each given 2.5 gphenylbutazone (approximately 5 mg/kg body weight) by oral administration twice daily for 8 days. The concentrations of phenylbutazone in plasma and milk and several blood parameters were studied. The minium plasma concentration during steady state was 100.4 ± 7.3 μg/ml. During the same period the milk concentration never exceeded 1% of the plasma concentration. The elimination half-life in plasma was 38.6 ± 3.7 h. Five days after administration had been discontinued, the milk concentration was 0.05 ± 0.01 μg/ml. All seven cows were clinically healthy throughout the experiment. The most pronounced side-effect of the blood parameters studied was a decreased concentration of leucocytes to about two-thirds of the control value. This might have a pronounced influence on the effectiveness of the immune system. There was also a significant decrease in total bilirubin indicating a decrease in the breakdown of erythrocytes.     

The fertility performance (litter characteristics) of laboratory mice over 6 generations after the administration of chlormadinone acetate and human chorionic gonadotropin

Chlormadinone-acetate and human chorionic gonadotrophin (HCG) were tested for their action on fertility (litter parameters) through 6 generations of laboratory mice. The fertility parameters recorded were in no way indicative of any fertility-depressing effect. HCG acted positively on ovulation rates and also had a somewhat favourable impact on body weight development of the mice involved in testing.     

Plasma disposition,faecal excretion and in vitro metabolism of oxibendazole following oral administration in horses

Oxibendazole (OBZ) was administered to eight horses at an oral dose of 10 mg kg(-1) bodyweight each. Parent OBZ could only be detected in plasma at the 0.5 and 1.0 hours post administration sampling times and the mean maximum plasma concentration was 0.008 microg ml(-1). Parent OBZ was detected in faeces between 12 and 72 hours after administration and the highest dry faecal concentration was detected at 24 hours. An unidentified metabolite was detected in plasma between 0.5 and 72 hours. The unidentified metabolite in the plasma of treated horses corresponded to the second eluted metabolite in the in vitro study. Metabolism of OBZ to its metabolite in vitro was significantly inhibited by co-incubation with the cytochrome P450 inhibitor piperonyl butoxide. These results indicated that first-pass metabolism decreases OBZ bioavailability in horses. The in vitro metabolism of OBZ was significantly inhibited by piperonyl butoxide and this could be utilised to extend the exposure of nematodes to the parent molecule.     

Pharmacokinetics, metabolism and excretion of phenylbutazone in cattle following intravenous, intramuscular and oral administration

The absorption, metabolism and urinary excretion of phenylbutazone were investigated in six adult cattle in a cross-over study involving administration intravenously, intramuscularly and orally at a dose rate of 4.4 mg kg-1. Following intravenous injection plasma disposition was described by a three compartment open model with mean elimination half-life (t1/2 beta) and clearance (ClB) values of 35.9 hours and 2.77 ml kg-1 h-1, respectively. Somewhat longer t1/2 beta values were obtained after oral and intramuscular dosing and these may have resulted from sequestration within and slow absorption from the gastrointestinal tract and continual uptake from intramuscular sites following precipitation as a depot. Absorption was more complete after intramuscular than after oral dosing; area under curve values were almost twice as high for the intramuscular route. Double peaks in the plasma concentration time curves after oral dosing were recorded in some cows. These may have resulted from drug adsorption on to and subsequent desorption from hay or as a consequence of enterohepatic shunting. There was no evidence for opening of the oesophageal groove and direct passage of the drug into the abomasum. Two hydroxylated metabolites of phenylbutazone, oxyphenbutazone and gamma-hydroxyphenylbutazone were detected in trace amounts in plasma for 72 hours and in much higher concentrations in urine for 168 hours. Approximate urine:plasma (U/P) concentration ratios for the metabolites approached and occasionally exceeded the U/P ratio for endogenous creatinine, indicating poor reabsorption and, possibly, tubular secretion. Cumulative urinary excretion data indicated that the hydroxylated derivatives of phenylbutazone are probably formed more slowly in cattle than in horses.     

Plasma pharmacokinetics and faecal excretion of ivermectin, doramectin and moxidectin following oral administration in horses

The present study was carried out to investigate whether the pharmacokinetics of avermectins or a milbemycin could explain their known or predicted efficacy in the horse. The avermectins, ivermectin (IVM) and doramectin (DRM), and the milbemycin, moxidectin (MXD), were each administered orally to horses at 200 microg/kg bwt. Blood and faecal samples were collected at predetermined times over 80 days (197 days for MXD) and 30 days, respectively, and plasma pharmacokinetics and faecal excretion determined. Maximum plasma concentrations (Cmax) (IVM: 21.4 ng/ml; DRM: 21.3 ng/ml; MXD: 30.1 ng/ml) were obtained at (tmax) 7.9 h (IVM), 8 h (DRM) and 7.9 h (MXD). The area under the concentration time curve (AUC) of MXD (92.8 ng x day/ml) was significantly larger than that of IVM (46.1 ng x day/ml) but not of DRM (53.3 ng x day/ml) and mean residence time of MXD (17.5 days) was significantly longer than that of either avermectin, while that of DRM (3 days) was significantly longer than that of IVM (2:3 days). The highest (dry weight) faecal concentrations (IVM: 19.5 microg/g; DRM: 20.5 microg/g; MXD: 16.6 microg/g) were detected at 24 h for all molecules and each compound was detected (> or = 0.05 microg/g) in faeces between 8 h and 8 days following administration. The avermectins and milbemycin with longer residence times may have extended prophylactic activity in horses and may be more effective against emerging and maturing cyathostomes during therapy. This will be dependent upon the relative potency of the drugs and should be confirmed in efficacy studies.     

Quantifiable morphokinesis on parts of the hypothalamo-adenohypophyseal-gonadal axis of hormonally castrated boars. I. Studies on boars treated with chlormadinone acetate]

A clearly morphokinetic effect was recorded from the parts of the hypothalamo-adenohypophyseo-gonadal axis in boars that had been treated with chloromadinone acetate (CAP). Luteinising hormone release is inhibited by CAP, which is reflected in an increase of luteinising hormone cells in their storage form. This leads to statistically significant decline in androgenic testicular tissue percentage and in the cell nucleus volumes of Leydig's cells. Excessive weight decrease of the testicle is caused primarily by some 60 per cent reduction in tube length. The neurons of the tested hypothalamic nuclear region, that is the nucleus praeopticus medialis, have shown that in treated animals cell nucleus volumes were significantly depressed.