bluuebunny/crossref_metadata_2025 huggingface dataset:
Zearanol metabolism by subcellular fractions from lamb liver
Authors: POMPA G. , MONTESISSA C. , LAURO F. M. DI , FADINI L. , CAPUA C.
Published: April 2008

Pompa, G., Montesissa, C., Di Lauro, F.M., Fadini, L. & Capua, C. Zearanol metabolism by subcellular fractions from lamb liver.J, vet. Pharmacol. Therap. 11, 197–203.

Zearanol (7‐α‐zearalanol or α‐ZAL) metabolism in vitro by subcellular fractions (microsome and cytosol) from lamb livers was investigated. The use of a high performance liquid chromatography (HPLC) technique capable of resolving epimers, revealed that when nicotinamide adenine dinucleotide (NAD) was added as a co‐factor to metabolic mixtures, the oxidized form, zearalanone (ZAN) was the major metabolite, although a small amount of 7‐β‐zearalanol (β‐ZAL) was also produced. In order to confirm β‐ZAL as a product of ZAN reduction, the metabolism of the latter, by microsome and cytosol in the presence of NADH as co‐factor, was investigated. The results obtained revealed that both α‐ZAL and β‐ZAL were present at the end of the incubation, the former at a higher concentration than the latter. When NAD and NADH were added as co‐factors to incubation mixtures containing α‐ZAL, the production of β‐ZAL was increased as a consequence of the higher ZAN reduction in the presence of the reducing co‐factor. Nevertheless, ZAN remained the major metabolite produced from α‐ZAL by both the subcellular fractions investigated.
Pharmacokinetics of single doses of gentamicin given intravenously and intramuscularly to turkeys
Authors: PEDERSOLI W. M. , RAVIS W. R. , ASKINS D. R. , KRISTA L. M. , SPANO J. S. , WHITESIDES J. F. , TOLBERT D. S.
Published: April 2008

The disposition and absorption kinetics of gentamicin were studied in healthy, mature male and female turkeys (n= 10). Single doses of gentamicin (5 mg/kg) were injected either i.v. or i.m. with a 30‐day rest period between each treatment. Baseline and serial venous blood samples (n = 17) were collected from each turkey. Serum concentrations of gentamicin were determined in duplicate for 24 h after each treatment, using radio‐immunoassay. Using nonlinear least‐square regression methods, the combined data of the i.v. and i.m. treatments were best described by a two‐compartment open model. Kinetic analysis of the data after a single i.v. dose provided the following mean values: tl/2α= 0.170 ± 0.093 h, tl/2α= 2.57 ± 0.79 h, MRT= 3.62 ± 0.96 h, Vc= 0.090 ± 0.017 l/kg, Vd(ss)= 0.172 ± 0.024 l/kg, Vd(area)= 0190 ± 0.030 l/kg. and Clt= 49.8 ± 9.8 ml/h/kg. After a single i.m. dose, the following mean values were determined: MRT= 5.10 ± 1.73 h, t1/2 abs= 0.74 ± 0.66 h, ttag= 0.07 ± 0.19 h, Cl±/F = 50.7 ± 12.5 ml/h/kg, Vd(area/F= 0.193 ± 0.044 l/kg, and F= 102 ± 21%. Kinetic calculations made with the single i.m. data predicted that an i.m. injection of gentamicin at the dosage rate of 3 mg/kg q. every 12 h would provide average steady state serum concentrations of 4.93 μg/ml.
Involvement of α‐adrenoreceptors in the regulation of omasal cyclic myoelectrical activity in sheep
Authors: BRIKAS P.
Published: April 2008

In five conscious adult ewes at rest, chronically implanted with electrodes in the musculature of the omasal wall, intravenous (i.v.) infusion for 30 min of α1‐ or α2‐adrenergic receptor blockers, prazosin (20 μg/kg/min) and yohimbine (30 μg/kg/min), respectively, had no significant effects on omasal myoelectrical activity. The i.v. administration for 15 min of α1‐ or α2‐agonists phenylephrine (4 μg/kg/min) or naphazoline (2.5 μg/kg/min), respectively, increased the frequency and the amplitude of groups of myoelectrical discharges of omasum, as well as the duration of its activity. Pretreatment of animals with prazosin blocked the responses to phenylephrine. Yohimbine prevented the effects of naphazoline dose‐dependently. It is suggested that both α1‐ and α2‐adreno‐receptors are involved in regulation of the sheep's omasal notility. This regulation did not seem to be a simple consequence of the changes in the reticular motility.
Cardiopulmonary effects of ephedrine in halothane‐anesthetized horses
Authors: GRANDY J. L. , HODGSON D. S. , DUNLOP C. I. , CHAPMAN P. L. , HEATH R. B.
Published: April 2008

The cardiopulmonary effects of intravenous (i.v.) administration of the sympathomimetic drug ephedrine during two different levels of halothane anesthesia [end‐tidal concentration of 1.37% (light anesthesia) and 2.1% (deep anesthesia)] were studied in eight horses. Anesthesia was induced and maintained using only halothane in O2. Ventilation was controlled to maintain a Paco2 of 38–42 mmHg. Following instrumentation and stabilization of the horse at the halothane concentration being studied, baseline measurements of cardiac output (®), arterial blood pressure (AP), pulmonary artery pressure, heart rate, Po2, Paco2 and pH were made. Ephedrine was then administered (0.06 mg/kg i.v.) and these measurements repeated at 10, 20, 30, 45 and 60 min after injection. At both doses of halothane there was a significant (P < 0.05) increase in ®, stroke volume (SV), and systolic AP following ephedrine administration. In addition, at 2.1% halothane, ephedrine administration resulted in a significant (P < 0.05) increase in mean AP and Pao2 and a decrease in total peripheral resistance. The increase in systolic AP, ®, and SV was significantly (P < 0.05) greater at 2.1% halothane than at 1.37% halothane. Ephedrine administration to horses during both light and deep halothane anesthesia results in an increase in AP that is due to an increase in ® and SV.
Pharmacokinetics, metabolism and renal clearance of flumequine in veal calves
Authors: MEVIUS D.J. , BREUKINK H.J. , GUELEN P. J. M. , JANSEN T. , De GRÈVE B.
Published: April 2008

Mevius, D.J., Breukink, H.J., Guelen, P.J.M., Jansen, T. & de Grève, B. Pharmacokinetics, metabolism and renal clearance of flumequine in veal calves. J. vet. Pharmacol. Therap. 13, 159–169.

The pharmacokinetics of flumequine was studied in 1‐, 5‐and 18‐week‐old veal calves. A two‐compartment model was used to fit the plasma concentration‐time curve of flumequine after the intravenous injection of 10 mg/kg of a 10% solution. The elimination half‐life (t1/2 ß) of the drug ranged from 6 to 7 h. The Vd ß and ClB of 1‐week‐old calves (1.07 1/kg, 1.78 ml/min/kg) were significantly lower than those of 5‐week‐old (1.89 1/kg, 3.23 ml/min/kg) and 18‐week‐old calves (1.57 1/kg, 3.10 ml/min/kg). After the oral administration of 10 mg/kg of a 2% flumequine formulation mixed with milk replacer, the Cmax was highest in 1‐week‐old (9.27 μg/ml) and lowest in 18‐week‐old calves (4.47 μg/ml). The absorption was rapid (Tmax of approximately 3 h) and complete. When flumequine itself and a formulation containing 2% flumequine and 20 times 106 iu of colistin sulphate were mixed with milk replacer and administered at the same dose rate, absorption was incomplete and Cmax was lower. The main urinary metabolite of flumequine was the glucuronide conjugate (approximately 40% recovery within 48 h of intravenous injection) and the second most important metabolite was 7‐hydroxy‐flumequine (approximately 3% recovery within 12 h of intravenous injection). Only 3.2–6.5% was excreted in the urine unchanged. After oral administration a ‘first‐pass’ effect was observed, with a significant increase in the excretion of conjugated drug. For 1‐week‐old calves it is recommended that the 2% formulation should be administered at a dose rate of 8 mg/kg every 24 h or 4 mg/kg every 12 h; for calves over 6 weeks old, the dose should be increased to 15 mg/kg every 24 h or 7.5 mg/kg every 12 h. The formulation containing colistin sulphate should be administered to 1‐week‐old calves at a flumequine dose of 12 mg/kg every 24 h or 6 mg/kg every 12 h.

Dr D. J. Mevius, Department of Large Animal Medicine and Nutrition, Yalelaan 16, 3508 TD Utrecht, the Netherlands.
The effects of dexamethasone, betamethasone, flunixin and phenylbutazone on bovine naturalkiller‐cell cytotoxicity
Authors: O'BRIEN M. A. , DUFFUS W. P. H.
Published: April 2008

O'Brien, M.A. & Duffus, W.P.H. The effects of dexamethasone, betamethasone, flunixin and phenylbutazone on bovine natural‐killer‐cell cytotoxicity. J. vet. Pharmacol. Therap, 13, 292–297.

A series of in‐vitro experiments was performed utilizing the ability of bovine peripheral‐blood mononuclear cells (PBMC) to induce lysis of Madin‐Darby bovine kidney (MDBK) cells infected with bovine herpesvirus 1 (BHV1), in an antibody‐independent natural‐killer(NK)‐cell cytotoxic assay. The effects of dexamethasone (dexamethasone sodium phosphate), betamethasone (betamethasone sodium phosphate), flunixin (flunixin meglumine) and phenylbutazone on this NK cytolysis were studied using concentrations of the drugs ranging from well below to well above those normally attained in plasma at recommended therapeutic doses. All four drugs inhibited NK activity. For each agent a minimum inhibitory concentration (MIC50) required to inhibit NK activity by approximately 50% was calculated. For dexamethasone, betamethasone and flunixin the MIC50 was lower after a 24‐h pre‐incubation of PBMC with each drug, although a marked inhibition was seen when the drug was only present during the 5‐h NK assay itself. In contrast the MIC50 for phenylbutazone rose after a 24‐h pre‐incubation with PBMC.

Dr W. P. H. Duffus, Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 OES, UK.
Influence of feeding on the bioavailability of ronidazole prolonged‐release formulations in pigeons
Authors: BAERT L. , HERMAN J. , REMON J. P.
Published: April 2008

Baert, L., Herman, J. & Remon, J.P. Influence of feeding on the bioavailability of ronidazole prolonged‐release formulations in pigeons. J. vet. Pharmacol Therap. 13, 304–308.

The influence of feeding on the bioavailability of ronidazole (5 mg per animal) formulated as a hydrophilic‐matrix tablet or as lipophilic pellets, was evaluated in pigeons. Administered to fed pigeons, prolonged drug absorption was obtained for both formulations. In non‐fed pigeons an immediate grinding of the formulations in the gizzard resulted in rapid drug absorption. This indicates that prolonged residence of the prolonged‐release formulations in the crop obtained in the fed condition seemed the only possible means of obtaining prolonged drug release in pigeons.

J. P. Remon, Laboratory of Pharmaceutical Technology, State University of Gent, Harelbekestraat 72, B‐9000 Gent, Belgium.
The development of drug‐metabolizing enzymes in female sheep livers
Authors: KADDOURI M. , LARRIEU G. , EECKHOUTTE C. , GALTIER P.
Published: April 2008

Kaddouri, M., Larrieu, G., Eeckhoutte, C. & Galtier, P. The development of drug‐metabolizing enzymes in female sheep livers. J. vet. Pharmacol. Therap. 13, 340–349.

The purpose of this investigation was to determine age‐related changes of some hepatic drug‐metabolizing activities in Lacaune ewes in the foetal, neonatal (1 and 4 weeks), growing (7 months), pregnant (11 months) and adult (6 years) stages. Although microsomal cytochrome P‐450 was not detected in 3‐month‐old foetuses, it increased regularly from 1‐week‐to 11‐month‐old animals. Among mixed‐function oxidases, the development of aminopyrine and ethylmorphine N‐demethylases, benzo(α)pyrene hydroxylase and ethoxycoumarin O‐deethylase were correlated to that of total cytochrome P‐450. Due to their presence in foetal liver or their more rapid evolution, cytochrome b5, NADPH cytochrone c reductase, aniline hydroxylase, benzphetamine N‐demethylase and erythromycin N‐demethylase did not parallel the ontogenesis of cytochrome P‐450. Hepatic transferases showed different developmental patterns from mono‐oxygenases, so UDP glucuronyltransferase was detected in the foetus, reached maximum activity in all young ages up to the pregnant stage and subsequently fell in adult ewes. Concerning glutathione S‐transferase accepting l‐chloro‐2,4‐dinitrobenzene as substrate, similar values were obtained in the foetus and all young animals, whereas five‐to tenfold higher values were obtained in both pregnant and adult female sheep. N‐acetyltransferase using sulphamethazine did not significantly change from foetuses to adults but there were large differences in the capacity of hepatic acetylation between animals belonging to the same group.

P. Galtier, Laboratoire de Pharmacologie‐Toxicologie, INRA, 180 chemin de Tournefeuille, BP 3, 31931 Toulouse, France.
A comparative study of the pharmacokinetics of thiopental in the rabbit, sheep and dog
Authors: ILKIW J.E. , BENTHUYSEN J.A. , EBLING W. F. , McNEAL D.
Published: April 2008

The central arterial pharmacokinetics of thiopental were studied in six rabbits, six sheep and six dogs after a short infusion at approximately 10 mg/kg min. Thiopental was infused to a defined electro‐encephalographic endpoint (EEG burst suppression). The time to reach early burst suppression was longer in the dog (3.9 ± 0.5 min) compared with the sheep (3.0 ± 0.6 min) and the rabbit (2.5 ± 0.5 min). The total dose required to produce the same level of EEG activity was higher in the dog (35.9 ± 6.8 mg/kg) compared with the sheep (24.3 ± 5.3 mg/kg) and the rabbit (21.6 ± 6.8 mg/kg). The plasma concentration‐time data for each animal was fitted using non‐linear regression to a bior tri‐exponential function. In all animals, the plasma‐time profile was best described as a tri‐exponential decay. The initial volume of distribution was similar in all three species (rabbit, 38.6 ± 10.0 mg/kg; sheep, 44.5 ± 9.1 ml/kg; dog, 38.1 ± 18.4 ml/kg). The maximum arterial plasma thiopental concentration achieved at EEG burst suppression was higher in the sheep (221.8 ± 27.9 μg/ml) than the dog (164.7 ± 29.9 μg/ml) or the rabbit (112.3 ± 15.1 μg/ml). Thiopental distribution clearance was slower in the sheep (43.6 ± 15.1 ml/min kg) compared with the rabbit (110.5 ± 18.7 ml/min kg) and the dog (97.2 ± 47.2 ml/min kg). Elimination half‐life was extended in the sheep (251.9 ± 107.8 min) and dog (182.4 ± 57.9 min) relative to the rabbit (43.1 ± 3.4 min). The rapid half‐life in the rabbit resulted from a large elimination clearance (14.6 ± 6.8 ml/min kg) and a small steady‐state volume of distribution (648.1 ± 180.5 ml/kg). Relative to the rabbit, the other species had large steady‐state volumes of distribution (dog, 815.8 ± 119.0 ml/kg; sheep, 947.3 ± 141.2 ml/kg), and small elimination clearances (dog, 3.4 ± 1.0 ml/min kg; sheep, 3.0 ± 0.9 ml/min kg). The initial disposition kinetics of thiopental in the sheep and dog were similar; however, the sheep tended to demonstrate a slower distribution clearance. The rapid and extended fall in arterial thiopental concentrations following administration in the rabbit may cause a short period of anesthesia and rapid recovery in that species. Additionally, the rabbit may require lower arterial concentrations to achieve EEG silence. The rabbit brain may be intrinsically more sensitive to barbiturates or thiopental may be capable of equilibrating with rabbit brain more rapidly than either dog or sheep brain.
The effect of isoprinosine and levamisole on factors relevant to protection of calves against respiratory disease
Authors: MULCAHY G. , QUINN P. J. , HANNAN J.
Published: April 2008

Experiments to characterize the effects of two immunomodulators, namely, isoprinosine and levamisole, on factors relevant to the resistance of calves to respiratory infection were undertaken. Daily oral doses of isoprinosine decreased the influx of neutrophils into the respiratory tract, increased membrane immunoglobulin and complement receptor expression on cells from bronchoalveolar lavage samples and decreased the severity of respiratory disease. Additional intravenous doses produced similar effects on neutrophil migration to the respiratory tract and on membrane receptor expression, but the changes were no greater than those seen with oral isoprinosine alone. No significant changes in the anti‐bacterial activity of cells in bronchoalveolar lavage samples followed isoprinosine treatment. In vitro incubation of pulmonary alveolar macrophages harvested from normal calves with isoprinosine increased their expression of immunoglobulin and complement receptors. Levamisole did not affect neutrophil migration to the lower respiratory tract or membrane receptor expression by pulmonary alveolar macrophages after in vivo or in vitro treatment. The immunomodulatory effects of isoprinosine beneficially increase the resistance of calves to respiratory disease, and are potentially useful in the control of infectious diseases of farm animals.
Phmacodynamics and pharmacokinetics of carprofen, a non‐steroidal anti‐inflammatory drug, in healthy cows and cows with Escherichia coli endotoxin‐induced mastitis
Authors: LOHUIS J. A. C. M. , van WERVEN T. , BRAND A. , van MIERT A. S. J. P. A. M. , ROHDE E. , LUDWIG B. , HEIZMANN P. , REHM W. F.
Published: April 2008

The pharmacodynamics of carprofen and its pharmacokinetics in plasma and milk of healthy cows and cows with endotoxin‐induced mastitis were studied after a single intravenous dose of 0.7 mg/kg body weight. Carprofen was administered to five clinically healthy cows and to the same cows 3 weeks later, 2 h after intramammary infusion of endotoxin. Mastitis developed in all endotoxin‐infused quarters. The pharmacokinetic characteristics of carprofen in healthy cows were a small volume of distribution (0.09 I/kg), a relatively low systemic clearance (2.4 ml/h kg), and a long elimination half‐life (30.7 h). In the mastitic cows, systemic clearance (1.4 ml/h kg) was significantly lower (P < 0.01), and elimination half‐life (43.0 h) was significantly longer (P < 0.01) than in the normal animals. Concentrations of carprofen in milk from healthy quarters were below the limit of detection for the assay (0.022 (xg/ml). In milk from mastitic quarters, concentrations of carprofen increased up to 0.164 Hg/ml during the first 12 h after induction of mastitis, but were less than 0.022 ug/ml at 24 to 48 h. Compared with the untreated mastitic controls, carprofen treatment significantly reduced heart rate (P < 0.01), rectal temperature (P < 0.001), quarter swelling (P < 0.01) and other parameters measured. Local and systemic adverse reactions to carprofen were not observed.
Relaxant effects of theophylline and clenbuterol on tracheal smooth muscle from horse and rat in vitro
Authors: INGVAST‐LARSSON C.
Published: April 2008

A comparison between the relaxant effects of clenbuterol and theophylline on horse tracheal smooth muscle has been made in vitro. Rat tracheal smooth muscle was also investigated as a reference. The tracheal preparations were initially contracted with carbachol since the smooth muscle did not spontaneously develop tone. The response of the carbachol‐contracted preparations to theophylline was the same in the two species. The response to clenbuterol varied. In only five out of eleven horses were the tracheal smooth muscles sensitive to clenbuterol (mean pD2= 7.92 m). In the remaining six horses the tracheal smooth muscles were insensitive to clenbuterol (mean pD2= 3.59 m), yet the preparations responded well to theophylline with complete relaxation. All rat tracheal preparations were insensitive to clenbuterol.
Pharmacokinetics and bioavailability of 2‐mercaptopropionylglycine administered intravenously and orally in dogs
Authors: HOPPE A. , DENNEBERG T. , EMANUELSSON B.‐M. , KÅGEDAL B. , LINDGREN S.
Published: April 2008

The pharmacokinetic disposition of 2‐mercaptopropionylglycine (2‐MPG) given as a single intravenous injection and/or as a single oral dose was studied in 9 normal and 13 cystinuric dogs. After intravenous injection of approximately 10 or 20mg/kg body weight the pharmacokinetics were best described by a three‐exponential function. The first phase involved a distribution process apparently including establishment of drug‐plasma protein and drug‐tissue binding. The second phase involved rapid renal elimination and 60% of the drug was excreted within 3h of administration. There was also a slow terminal third phase with a long half‐life after both intravenous (t1‐2=23h) and oral (t1/2=22h) administration. No dose dependency was observed. A deep pool of reversibly tissue‐bound 2‐MPG was indicated by a Vss of 3.3±0.9l/kg body weight and the long terminal elimination phase. Total clearance was estimated as 4.1±0.9ml/min/kg body weight. 2‐MPG was eliminated mainly by renal excretion, but there was a difference in recovery of dose between normal and cystinuric dogs. During the first 24h after intravenous and oral administration, 69% and 54%, respectively, of the drug was recovered in the urine of normal dogs. The corresponding figures in cystinuric dogs were 44% and 29%, respectively. The absolute bioavailability (FAUC) was 88±20% in normal dogs.
Bioavailability of oral penicillins in the horse: a comparison of pivampicillin and amoxicillin
Authors: ENSINK J. M. , KLEIN W. R. , MEVIUS D. J. , KLARENBEEK A. , VULTO A. G.
Published: April 2008

The pharmacokinetics of ampicillin and amoxicillin following intravenous administration at a dose rate of 15 and 10 rng/kg respectively were studied in four healthy adult horses. Pharmacokinetics of pivampicillin and amoxicillin were studied after oral administration to four healthy adult horses. Pivampicillin, a prodrug of ampicillin, was administered orally to starved and fed horses at a dose rate of 19.9 mg/kg, which is equivalent on a molecular basis to 15 mg/kg ampicillin. Amoxicillin was administered orally to starved horses only, at a dose rate of 20 mgkg. Ampicillin and amoxicillin concentrations in plasma, synovial fluid and urine were determined. Mean biological half‐life of intravenously administered ampicillin and amoxicillin was 1.72 and 1.43 h respectively, whilst the distribution volume (Vss) appeared to be 0.180 and 0.192 l/kg. Orally administered pivampicillin' and amoxicillin were rapidly absorhed. A maximum concentration in plasma of 3.80 μg/ml was reached. 2 h after administration of pivampicillin to starved horses; in fed horses a maximum concentration of 5.12 μg/ml was reached 1 h after administration. After oral administration of amoxicillin a maximum concentration of 2.03 μg/ml was reached after 1 h. The (absolute) bioavailability of pivampicillin administered orally was 30.9% in starved horses and 35.9% in fed horses. The bioavailability of amoxicillin administered orally was 5.3% in starved horses.
Acyclovir (Zovirax®) pharmacokinetics in Quaker parakeets,Myiopsitta monachus
Authors: NORTON T. M. , KOLLIAS G. V. , CLARK C. H. , CASKIN J. , WILSON R. C. , CONIGLARIO J.
Published: April 2008

The pharmacokinetics of intravenous (i.v.) and intramuscular (i.m.) single‐dose administration of acyclovir were determined in Quaker parakeets. After i.v. injection at a dose of 20 mg/kg of acyclovir, elimination half‐life was estimated at 0.65 h, volume of distribution at steady state was 627.65 ml/kg, and clearance was 11.22 ml/kg/min. The estimated pharmacokinetic values after i.m. injection at a dose of 40 mg/kg of acyclovir were an elimination half‐life of 0.71 h and a bioavailability of 90.1%. The peak plasma acyclovir concentration occurred at 15 min when the drug was administered i.m. Plasma concentrations of acyclovir were undetectable 4–6 h after i.v. administration and 68 h after i.m. administration. Oral (capsules) and intravenous (sodium salt) formulations of acyclovir were given by gavage at 80 mg/kg. Peak concentrations with the sodium salt formulation were lower and developed more slowly than with the capsules. In studies designed to detect excessive drug accumulation or adverse side effects, acyclovir was administered i.m. at 40 mg/kg every 8 h for 7 days. Plasma concentrations were determined 15 min after (peak) and just prior to drug administration (trough). In another study acyclovir was gavaged at a dose of 80 mg/kg every 8 h for 4 days. Acyclovir plasma concentrations were determined just prior to and 2 h after drug administration. In both experiments, the birds maintained normal appetite and weight and did not exhibit excessive drug accumulation. Acyclovir plasma concentrations ranging from 2.07 ± 1.09 μg/ml to 3.93 ± 1.13 μg/ml were maintained for 4 days when acyclovir was administered in the feed and water (sole source of food and water). The feed contained 400 mg of acyclovir in 2 quarts of parrot seed and the water contained 1 mg of acyclovir per ml of water.
Quantitative electroencephalography for measurement of central nervous system responses to diazepam and the benzodiazepine antagonist, flumazenil, in isoflurane‐anaesthetized dogs
Authors: GREENE S. A. , MOORE M. P. , KEEGAN R. D. , GALLAGHER L. V.
Published: April 2008

Quantitative EEG was assessed in six dogs anaesthetized with 1.8% end‐tidal isoflurane concentration and following diazepam (0.2 mg/kg i.v.) administration. Ventilation was controlled to maintain pormocapnia. Five dogs were subsequently given the benzodiazepine antagonist, flumazenil (0.04 mg/kg i.v.), and quantitative EEG was recorded. One dog received a saline injection following diazepam (as a control) and quantitative EEG was recorded for an additional 2.5 h. Heart rate, arterial blood pressure, esophageal temperature, arterial pH and blood gas tensions, end‐tidal CO2tension and end‐tidal isoflurane concentration were monitored throughout the study. A 21 lead linked‐ear montage was used for recording EEG. Quantitative EEG data were stored on an optical disc for analysis at a later date. Values for absolute power of EEG were determined for θ, δ, α, and β frequencies. Cardiovascular parameters remained stable throughout the study. Diazepam administration was associated with decreased absolute power in all frequencies of EEG at all electrode sites. The duration of diazepam‐induced decreased absolute power of EEG was at least 3 h in one dog. Administration of flumazenil antagonized diazepam‐induced decreased absolute power of EEG in all frequencies at all electrode sites. We conclude that quantitative EEG provides a relatively non‐invasive, objective measure of diazepam‐ and flumazenil‐induced changes in cortical activity during isoflurane anaesthesia.
Distribution studies of theophylline: microdialysis in rat and horse and whole body autoradiography in rat
Authors: INGVAST‐LARSSON C. , APPELGREN L.‐E. , NYMAN G.
Published: April 2008

After intravenous administration of theophylline, microdialysis has been used for studying the non protein bound theophylline concentration in blood and in lung tissue in the rat as well as in two horses. The distribution pattern of 14C‐theophylline in the rat was also investigated. When the distribution of theophylline was completed the time course of free drug in the interstitial fluid in lung tissue was in good agreement with the total concentration‐time profile in plasma in both species. In the rat the free concentration of theophylline in the lung was slightly lower than the free concentration in the blood from 40 to 300 min. The in vivo protein binding in blood was 48.8 ± 6.2% in the rats (n= 9) and 8–25% in the horses (n= 2). The whole body autoradiography study in rat showed that the concentration of radioactivity in the lung followed the blood concentration very closely up to 24 h after injection. The effect of theophylline in the lung can be assumed to be related to the plasma concentration of theophylline, since the concentration‐time profile in plasma reflects the time course in the lung.
Biliary secretion and enterohepatic recycling of fenbendazole metabolites in sheep
Authors: HENNESSY D. R. , STEEL J. W. , PRICHARD R. K.
Published: April 2008

Fenbendazole (FBZ) was administered intraruminally at 5.0 mg/kg, containing a trace of [14C]‐FBZ, to sheep fitted with a permanent bile duct cannula and the behaviour of FBZ and its metabolites examined in bile and plasma. Of the administered radiolabeled dose, 47% was secreted in bile of which 34% was accounted for as conjugated and 4% as unconjugated (free) metabolites. Hydroxylated oxfendazole (OH.OFZ) was the major biliary metabolite contributing 66%, and hydroxy‐FBZ (OH.FBZ) 27%, of the total metabolites characterized. Small amounts of OFZ and hydroxy FBZ sulphone (OH. FBZ.SO2) were also present in bile. The rapid appearance of OH.OFZ in bile, even before maximum concentrations of OFZ occurred in plasma, indicated that sulphoxidation and hydroxylation was the major route of FBZ metabolism.

Following intraduodenal infusion of free biliary metabolites, FBZ and its metabolites rapidly appeared in bile indicating absorption from the small intestine. When conjugated metabolites were infused they continued to appear in bile for a further 15–20 h after cessation of infusion indicating that absorption of hydroxylated metabolites occurred largely after bacterial deconjugation in the large intestine. Approximately 40% of biliary metabolites were estimated to undergo enterohepatic reabsorption but they contributed minimally to the metabolite content in plasma. It is suggested that during the process of recycling, biliary metabolites make substantial contact with parasites in the mucosa of the small and large intestine thereby contributing to the anthelmintic activity of FBZ.
Oral absorption and bioavailability of fenbendazole in the dog and the effect of concurrent ingestion of food
Authors: McKELLAR Q. A. , GALBRAITH E. A. , BAXTER P.
Published: April 2008

Fenbendazole was administered orally without food to six beagle dogs at 2.5, 5.0, 10, 20, 40 and 80 mg/kg of body weight. Increasing the dose rate did not significantly increase the amount of fenbendazole absorbed. In a separate study fenbendazole was administered to the same six beagle dogs at a dose rate of 20 mg/kg of bodyweight in food with high, medium and low fat content. The food provided 1.52, 0.70 or 0.34 g of fat per kg of body weight. Administration of fenbendazole in food with different fat contents did not affect its relative bioavailability. Administration of fenbendazole at a dose rate of 20 mg/kg in food, irrespective of fat content, did however significantly increase its bioavailability when compared to administration of the same dose as a bolus on an empty stomach.
Three phase elimination of oxytetracycline in veal calves; the presence of an extended terminal elimination phase
Authors: MEIJER L. A. , CEYSSENS K. G. F. , DEJONG W. TH. , GREVE B. I.J. A. C. DE
Published: April 2008

The pharmacokinetics of oxytetracycline were studied after both intravenous (i.v.) and intramuscular (i.m.) administration to a group of five veal calves. Blood samples were taken frequently during the terminal elimination phase in order to calculate a reliable elimination rate constant. Because of the low limit of quantification of the method of analysis used, oxytetracycline plasma concentrations could be monitored over a 12‐day period of time.

After the intravenous administration of oxytetracycline, data were fitted according a three‐compartment model. After i.m. administration, plasma‐concentration‐time curves could best be described by a two‐compartment model. It was demonstrated that a very slow terminal elimination phase was present both after i.v. and i.m. administration with a half‐life of approximately 95 h. The data show that this phase cannot be explained by slow absorption from the injection site and that release of oxytetracycline incorporated into bone is not a likely explanation.
Pharmacokinetics and anthelmintic efficacy of febantel in the racing pigeon (Columba livia)
Authors: BAERT L. , POUCKE S. VAN , VERMEERSCH H. , REMON J. P. , VERCRUYSSE J. , BASTIAENSEN P. , BACKER P. DE
Published: April 2008

This paper reports on the pharmacokinetics and the efficacy of febantel against Capillaria obsignata and Ascaridia columbae in the racing pigeon. Febantel was rapidly cleared from the circulation and highly metabolized. The efficacy of febantel against Capillaria and Ascaridia was studied on lightly and heavily infected pigeons. The efficacy against Ascaridia was 100% for the faecal egg count reduction (FECR) as well as for the worm reduction in all treated pigeons. After two treatments with febantel against Capillaria in heavily infected pigeons the FECR amounted to 96.7% and worm reduction was 95%. In order to effectively remove both parasites from the host, repeated treatments with febantel at a short interval could be the treatment of choice.
The effects of halothane and nitrous oxide on the pharmacokinetics of propofol in dogs
Authors: NOLAN A. M. , REID J. , GRANT S.
Published: April 2008

The pharmacokinetics of propofol, 6.5 mg/kg, administered as a bolus dose intravenously (i.v.) were studied in six dogs (group 1). The effect of maintaining anaesthesia with halothane and nitrous oxide in oxygen on propofol pharmacokinetics was also investigated in six dogs undergoing routine anaesthesia (group 2). Induction of anaesthesia was rapid in all animals. Post‐induction apnoea was a feature in three of the 12 dogs. The blood propofol concentration‐time profile was best described by a bi‐exponential decline in two dogs in group 1 and in 3 dogs in group 2, and by a tri‐exponential decline in four dogs in group 1 and 3 dogs in group 2. The elimination half‐life was long in both groups (90.9 min and 75.2 min, respectively), the volume of distribution at steady state large (4889 and 4863 ml/kg) and the clearance rapid (58.6 and 56.3 ml/kg.min). There were no significant differences between the groups, thus indicating that maintenance of anaesthesia with halothane and nitrous oxide had no effect on the pharmacokinetics of propofol in the dog.
Bioavailability of levamisole administered by subcutaneous and oral routes in rabbits
Authors: GARCÍA J. J. , DIEZ M J , SIERRA M. , TERÁN M. T.
Published: April 2008

The bioavailability of levamisole in rabbits was determined after subcutaneous and oral administration at three dose levels of 12.5, 16.0 and 20.0 mg/kg. After non‐compartmental analysis the mean values obtained were: Cmax=3.54, 4.51 and 5.39 μg/ml; tmax= 12.0, 22.0 and 20.0 min; F= 134.8, 105.4 and 124.1% after subcutaneous administration for each dose, respectively, and Cmax= 0.71, 1.32 and 1.77 μg/ml; tmax= 46.0, 96.0 and 84.0 min; F= 53.0, 62.0 and 80.7% after oral administration. The extent and rate of absorption from the two routes differed significantly, except for tmax at the 12.5 mg/kg dose. After compartmental analysis the pharmacokinetics of levamisole was characteristic of a two‐compartment open model in 13 rabbits and of a one‐compartment open model in two rabbits after subcutaneous administration, while it was two compartmental in nine and one compartmental in six rabbits after oral administration. The ka values were 0.321, 0.145 and 0.145 min‐1 after subcutaneous administration and 0.054, 0.023 and 0.027 min1 after oral administration. There were no significant differences between the values of Cmax, tmax and AUC calculated by compartmental and non‐compartmental analysis.
Effects of medetomidine on intestinal and colonic motility in the dog
Authors: MAUGERI S. , FERRÈ I P , INTORRE L. , SOLDANI G.
Published: April 2008

The motor responses of the jejunum and colon to stimulation of α2‐adrenoceptors by medetomidine and clonidine were investigated in four dogs. In fasting dogs, medetomidine, at a dose rate of 30 μg/kg i.v., disrupted the migrating myoelectric complex (MMC) pattern of the small intestine for about 2 h. Similar, but shorter‐lasting effects were also induced by clonidine (30 μg/kg i.v.) on the jejunum. The administration of α2‐agonists inhibited colonic motility in fasting dogs, although medetomidine‐induced inhibition was preceded by a short period of increased muscle tone. All these effects were reversed by the α2‐antagonists atipamezole (0.15 mg/kg i.v.) and yohimbine (0.20 mg/kg i.v.). In fed dogs, medetomidine (30 μg/kg i.v.) induced a strong increase of the tone on the proximal colon, while the activity of the medium and distal colon was completely suppressed. Yohimbine (0.50 mg/kg i.v.) immediately restored the activity of the colon and induced a propagated giant contraction and defaecation by the animal. These data confirm the importance of a2‐adrenergic receptors in the control of intestinal and colonic motility in the dog.
Equine coronary artery responds to 5‐hydroxytryptamine with relaxation in vitro
Authors: OBIT T. , KABEYAMA A. , NISHIO A.
Published: April 2008

Isolated equine coronary arteries responded to 5‐hydroxytryptamine (5‐HT) with relaxations in both endothelium‐dependent and endothelium‐independent mechanisms. Experiments were designed to characterize the 5‐HT receptor sub type mediating these relaxations. Both 5‐HT and alpha‐methyl‐5‐HT (α‐Me‐5‐ HT; 5‐HT2 agonist) produced concentration‐dependent relaxations in equine coronary arteries precontracted with a thromboxane A2 derivative (0N011113). The degree of the maximal relaxation induced by α t‐Me‐5‐HT was about one‐half of that induced by 5‐HT. In the coronary arteries without endothelium, α ‐Me‐5‐HT produced no relaxation, but 5‐HT caused relaxation, which was inhibited by a 5‐HT1 antagonist (methysergide, mianserin and methiothepin), but was inhibited neither by ketanserin (5‐HT2 antagonist) nor by MDL72222 (5‐HT3 antagonist). In the coronary arteries with endothelium, however, the relaxation induced by α ‐Me‐5‐HT was inhibited by ketanserin, L‐nitro‐arginine (NO synthase inhibitor) and methylene blue (soluble guanylate cyclase inhibitor). These results suggest that the relaxation induced by 5‐HT in equine coronary arteries depends mainly on the stimulation of both 5‐HTi receptor subtype on smooth muscle cells directly, and 5‐HT2 receptor subtype on endothelial cells indirectly by liberating endothe‐lium‐derived NO.
In vitro effects of tachykinins on the smooth musculature of horse gut
Authors: BELLOLI C. , ARIOLI F. , BERETTA C. , MADONNA M.
Published: April 2008

The contractile effects of the tachykinins eledoisin, substance P and neurokinin A and B were investigated in vitro on circular and longitudinal muscle strips from horse duodenum, ileum and colon. Circular smooth muscle of the small intestine was highly responsive, large intestine circular smooth muscle less so, while longitudinal muscle from all gut segments was much less sensitive. pD2 values and intrinsic activities on small intestine circular muscle indicated differences in receptor distribution between the duodenum and ileum: NK3 and a smaller number of NK2 receptors being present in the duodenum, and NK2 receptors predominating in the ileum. Notwithstanding this, eledoisin and neurokinin B were the most active substances on duodenum and ileum, respectively. These findings suggest that tachykinins may play a role in equine gastrointestinal pathophysiology.
Specific binding of dl‐cloprostenol and d‐cloprostenol to PG F2α receptors in bovine corpus luteum and myometrial cell membranes
Authors: RE G. , BADINO P. , NOVELLI A. , VALLISNERI A. , GIRARDI C.
Published: April 2008

Prostaglandin F2α receptors (PGF2α Rs) were measured in bovine corpus luteum and myometrial cell membranes using a radiometric method. The inhibition of labelled PGF2α binding exerted by d‐cloprostenol, dl‐cloprostenol, PGF2α and PGE1 (l0–11 M to 10–4 M) was evaluated in vitro. Results strongly suggest that cloprostenol binding to PGF2αRs is stereospecific. d‐Cloprostenol and PGF2α were equipotent, about 150 times more potent than d‐cloprostenol (P < 0.05) and approximately 280 times more potent than PGE, (P < 0.05) in inhibiting [3H]PGF2α binding to corpus luteum cell membranes. Such differences were less evident in myometrial cell membranes, where d‐cloprostenol and PGF2α were about 10 times more potent than d‐cloprostenol (P < 0.05) and approximately 95 times more potent than PGEl (P < 0.05).
The effects on the pharmacokinetics of intravenous ceftiofur sodium in dairy cattle of simultaneous intravenous acetyl salicylate (aspirin) or probenecid
Authors: WHITTEM T. , FREEMAN D.A. , HANLON D. , PARTON K.
Published: April 2008

Ceftiofur sodium is a third‐generation cephalosporin antibiotic. It is possible that non‐steroidal anti‐inflammatory drugs such as acetyl salicylate (aspirin) may be used concomitantly with ceftiofur sodium in dairy cattle. Therefore this study evaluated potential pharmacokinetic interactions between ceftiofur sodium and aspirin. In addition, this study evaluated the potential for interaction between ceftiofur and its active metabolites and the organic anion transporter. The organic anion transporter substrate used in this evaluation was probenecid. Ten healthy, non‐pregnant, non‐lactating dairy cows were used in a randomized complete three‐way crossover design. In repeated experiments all cows were administered: (1) 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (2) 10 mg of probenecid per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (3) 26 mg of aspirin per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus. For treatment with ceftiofur sodium alone, the mean volume of distribution at steady‐state Vd(33) was 0.2 ± 0.06 L/kg, the mean volume of distribution by the area method Vd(area) was 0.38 ± 0.22 L/kg, mean residence time (MRT) was 6.5 ± 1.8 h, mean residence time in peripheral tissues (MRTp) was 2.6 ± 1.0 h, total body clearance (Cf) was 0.032 ± 0.013 L/kg/h and elimination rate constant (P) was 0.097 ± 0.044 h‐1(mean ± standard deviation). No statistically significant changes were detected as a result of preceding treatment with aspirin. Preceding treatment with probenecid resulted in a decrease in both Cl (0.007 ± 0.005 L/kg/h) and MRTp (0.89 ± 0.45 h). These results suggest that ceftiofur or its metabolites may interact with the organic anion transporter, but that consideration of alterations to dose and dose interval may not be necessary when ceftiofur sodium is administered to the cow concomitantly with a single dose of aspirin.
Pharmacokinetics of ketoprofen after multiple intravenous doses to mares
Authors: SAMS R. , GERKEN D. F. , ASHCRAFT S. M.
Published: April 2008

The pharmacokinetics and urinary excretion of ketoprofen in six healthy mares after the first and last of five daily intravenous doses of 2.2 mg of ketoprofen per kg body weight were investigated using a high‐performance liquid chromatographic (HPLC) method for determining plasma and urinary ketoprofen concentrations. Plasma ketoprofen concentrations declined triexponentially after each dose with no significant differences in plasma concentrations or pharmacokinetic parameter values between the first and last doses. The harmonic mean of the terminal elimination half‐life of ketoprofen after the first and last dose was 98.2 and 78.0 min, respectively. The median values of the total plasma clearance and the renal clearance after the first dose were 4.81 and 1.93 mL/min/kg, respectively. Total plasma clearance was attributed to renal excretion of ketoprofen and metabolism of ketoprofen to a base‐labile conjugate which was also excreted in the urine. Renal clearance of ketoprofen was attributed to renal tubular secretion since renal clearance was greater than filtration clearance. Urinary recovery of ketoprofen during the first 420 min after the first dose accounted for 26.4% of the dose as unconjugated ketoprofen and 29.8% of the dose as a base‐labile conjugate of ketoprofen. Total urinary recovery of ketoprofen as unchanged ketoprofen and from base‐labile conjugate represented 56.2% of the dose. Plasma protein binding of ketoprofen was extensive; the mean plasma protein binding of ketoprofen was 92.8% (SD 3.0%) at 500 ng/mL and 91.6% (SD 0.60%) at 10.0 μg/mL.
Kinetics, dose response, tachyphylaxis and cross‐tachyphylaxis of vascular leakage induced by endotoxin, zymosan‐activated plasma and platelet‐activating factor in the horse
Authors: MILLS P.C. , NG J.C. , SEAWRIGHT A.A. , AUER D.E.
Published: April 2008

Vascular leakage induced by intradermal injection of endotoxin, zymosan‐activated plasma (ZAP) and platelet‐activating factor (PAF) was measured in nine Thoroughbreds using 125‐iodine human serum albumin (125I‐HSA) as a marker in the blood. ZAP and PAF produced dose‐dependent increases in vascular permeability with the maximum occurring within the first 15 min after injection. The vascular leakage induced by endotoxin was also dose‐dependent, but the maximum occurred 2 h after intradermal injection. Intradermal sites previously injected with endotoxin were refractory to a second injection of endotoxin for up to 5 days. However, sites injected with endotoxin and re‐injected with either ZAP or PAF remained responsive with increased vascular leakage compared to saline injected control sites re‐injected with either ZAP or PAF. Diminished response to endotoxin challenge may contribute to the poor prognosis of endotoxaemia in the horse.
Pharmacokinetics and metabolism of amitraz in ponies and sheep
Authors: PASS M.A. , MOGG T.D.
Published: April 2008

Amitraz and its active metabolite BTS2 7271 were given intravenously to ponies and sheep at equimolar doses of 1 mg/kg and 0.68 mg/kg, respectively, and the plasma concentrations of amitraz and BTS27271 estimated at various times thereafter. Amitraz was hydrolysed to BTS2 7271 in both species. Amitraz was undetectable in sheep plasma after approximately 5 min but persisted in the plasma of ponies for at least 90 min. The persistence of unmetabolized amitraz in ponies may have implications for the toxicity of amitraz in that species. The primary and secondary disposition half‐lives of amitraz in ponies were 2 and 39 min, respectively. BTS27271 was distributed rapidly outside the plasma in both species with a primary disposition half‐life of 4.4 min in sheep and 5.9 min in ponies. The secondary disposition half‐lives were 51 and 55 min, respectively. The secondary phase of the disposition of BTS27271 was similar whether BTS27271 was given directly or derived by hydrolysis from amitraz. However, significant differences were evident in the primary phase of the disposition of BTS27271. Sheep demonstrated a larger apparent volume of distribution of BTS27271 than ponies and more rapid body clearance.
Pharmacokinetics of sulfadimethoxine and sulfamethoxazole in combination with trimethoprim after intravenous administration to healthy and pneumonic pigs
Authors: MENGELERS M.J.B. , VAN GOGH E.R. , KUIPER H.A. , PIJPERS A. , VERHEIJDEN J.H.M. , VAN MIERT A.S.J.P.A.M.
Published: April 2008

The pharmacokinetics of two sulfonamide/trimethoprim combinations were investigated after intravenous administration to clinically healthy pigs and to the same pigs following a challenge withActinobacillus pleuropneumoniaetoxins. Endobronchial challenge withA.pleuropneumoniaetoxins resulted in fever, increased white blood cell counts and decreased water and feed consumption. Healthy, as well as febrile, pigs were given sulfadimethoxine (SDM) or sulfamethoxazole (SMX) intravenously at a dose of 25 mg/kg b.w. in combination with 5 mg trimethoprim (TMP) per kg body weight. The pharmacokinetic parameters of the sulfonamides as well as their main metabolites (acetyl sulfonamides) were not significantly different in healthy and febrile pigs. In healthy and pneumonic pigs, the mean elimination half‐lives of SDM were 12.9 h and 13.4 h, respectively, those of SMX 2.5 h and 2.7 h, respectively, and those of TMP 2.8 h and 2.6 h, respectively. Distribution volumes in healthy and febrile pigs of SDM and SMX varied between 0.2 and 0.4 L/kg, and those of TMP between 1.1 and 1.6 L/kg. The meanAUCof TMP was decreased and the volume of distribution and total body clearance of TMP were increased in febrile pigs. Protein binding of the drugs and metabolites studied were not significantly changed after toxin‐induced fever. The extent of protein binding of SDM, SMX and TMP was in the range 94–99%, 45–56% and 40–50%, respectively. Based on knowledge ofin vitroantimicrobial activity of the drug combinations againstA.pleuropneumoniaeit was concluded that after intravenous administration of the dose administered (30 mg/kg of the combination preparations) to healthy and pneumonic pigs, plasma concentrations of SMX and TMP were above the concentration required for growth inhibition of 50% of A.,pleuropneumoniaestrains for approximately 16 h, whereas bacteriostatic plasma concentrations of SDM were still present after TMP had been eliminated from plasma. Because of similar elimination half‐lives of SMX and TMP in pigs this combination is preferred to the combination of SDM with TMP.