bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of inhalation anaesthetics on total respiratory resistance in conscious ponies
Authors: HALL L. W. , YOUNG S. S.
Published: April 2008

Total respiratory resistance was measured rapidly and non‐invasively in 6 conscious ponies before and after they inhaled approximately 25% of the minimal anaesthetic concentration (0.25 MAC) of either enflurane, halothane, or isoflurane, over a 10 min period. The forced random noise (FRN) method was used to measure the impedance over the frequency range of 5 to 40 Hz and its real part, the resistance, was extracted from these impedance measurements. At the concentrations used, halothane appeared to have no effect on the total respiratory resistance; enflurane and isoflurane seemed to increase it but the changes were not statistically significant.
Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration
Authors: SUNDLOF S. F. , WHITLOCK T. W.
Published: April 2008

Clorsulon was measured in plasma and urine of sheep and goats after administration of a single intravenous (i.v.) and after a single oral dose of 7 mg/ kg. A three‐compartment model with elimination occurring from the central compartment was determined to best describe the i.v. data, whereas a one‐compartment model with a single exponential absorption phase best described the oral plasma data. The bioavailability of orally administered clorsulon was approximately 55% in goats and 60% in sheep. Peak plasma concentrations occurred at 14 h and 15 h after oral administration in goats and sheep, respectively. Absorption from the gastro‐intestinal tract effectively prolonged the elimination of clorsulon by increasing the elimination half‐life from 17 to 28 h in sheep and from 12 to 23 h in goats for the i.v. and oral routes, respectively. In both goats and sheep, approximately 50% of the i.v. dose was recovered in urine as parent drug at 48 h after administration, whereas 41 % and 30% of the dose was recovered after oral administration for goats and sheep, respectively. The elimination rate constant (kel) in goats was nearly twice as large as the value determined in sheep, and the area under the i.v. plasma curve in goats was only 63% of the value in sheep indicating that goats are more effective in their capacity to eliminate clorsulon than are sheep. These differences in drug disposition between sheep and goats may account for the reduced efficacy of clorsulon reported in goats.
Effects of age and indomethacin on response and sensitivity of pulmonary artery to phenylephrine and to histamine in pigs
Authors: GUSTIN P. , ANSAY M. , ADVENIER C.
Published: April 2008

The vasoconstrictor effects of phenylephrine and histamine were investigated in isolated strips of pulmonary arteries in pigs during ageing. Interactions between phenylephrine‐induced responses and arachidonic acid derivatives were also studied by incubating the blood‐vessels with indomethacin. Potency (pD2 values) and maximal effects (Emaxx) recorded in 5‐week‐old piglets (group I, n= 5) with phenylephrine [5.71 ± 0.17 and 0.76 ± 0.22 g/mg of dry tissue respectively (mean ± SEM)] were similar to values found in 12‐week‐old animals (group 2, n = 5) (5.49 ± 0.30 and 1.06 ± 0.27 g/mg of dry tissue respectively). The sensitivity and responsiveness of tissues to this agonist were significantly reduced in 26‐week‐old mature pigs (group 3, n = 6) as indicated by the decrease in pD2 (3.91 ± 0.23; P < 0.01) and Emax (0.27 ± 0.13 g/mg of dry tissue; P < 0.05) values observed in this group. Histamine (10_3M)‐induced maximal responses (Emax) were significantly higher in group 2 (2.23 ± 0.49 g/mg) than in group 1 (0.85 ± 0.11 g/mg; P < 0.05) and in group 3 (0.48 ± 0.10 g/mg; P < 0.01). In 5‐week‐old animals, indomethacin (3.10˜5M) significantly (P < 0.05) shifted the concentration‐response curve to phenylephrine to the right (0.28 log. units) and depressed contractions to this drug as shown by the significant decrease of 39.5% (P < 0.05) in Emax. This cyclo‐oxygenase inhibitor had no effect in other groups. These data indicate that phenylephrine is a potent and effective vasoconstrictor agent for the main pulmonary arteries in 5‐week‐old piglets and that alpha‐1‐adrenergic‐induced contractions are enhanced by cyclo‐oxygenase products. These findings can be related with the high reactivity of pulmonary vascular smooth muscles in these animals.
Pharmacokinetic–pharmacodynamic modelling of meperidine in goats (I): pharmacokinetics
Authors: QIAO G.‐L. , FUNG K.‐F.
Published: April 2008

Qiao, G.‐L., Fung, K.‐F. Pharmacokinetic‐pharmacodynamic modelling of meperidine in goats (I): pharmacokinetics. J. vet. Pharmacol. Therap. 16, 426–437.

Plasma and cerebrospinal fluid (CSF) pharmacokinetics of meperidine were investigated after intramuscular (i.m.) or intravenous (i.v.) administration at a dose of 5 mg/kg in adult goats. After i.m. dosing, the plasma profile was best described by a one‐compartment open model. In healthy (n = 16) and postoperative (n = 16) goats, the parameters were, respectively: /max 8.3 ± 3.9 and 9.2 ± 5.5 min, Vd 2.763 ±1.231 and 3.929 ±2.101 1/kg, Clb 0.125 ± 0.036 and 0.087 ± 0.025 1/kg/min, Kc 0.0563 ± 0.0358 and 0.0271 ± 0.0136 min‐1. The plasma profile was best fitted by a two‐compartment open model following i.v. injection. In this case, the parameters for healthy (n= 7) and post‐operative (n= 13) goats were, respectively: Vd 5.212 ± 1.992 and 5.085 ± 2.288 1/kg, Clb 0.096 ± 0.028 and 0.075 ± 0.026 1/kg/min, P 0.0211 ± 0.0093 and 0.0160 ± 0.0052 min.‐1. There were, however, a few individuals with a prolonged elimination phase. Bioavailability of i.m. meperidine was 66.5 ± 15.8% in healthy (n= 6) goats, but much higher in postoperative (n = 10) ones at 94.6 ± 30.0%. Meperidine diffused into and out of CSF according to a first‐order rate process. The time‐course of CSF drug concentration was simulated by a biexponential function. CSF kinetic parameters of i.m. meperidine for healthy (n = 7) and postoperative (n = 13) goats were: elimination rate constant (Kei) 0.0269 ± 0.0131 and 0.0305 ± 0.0177 min“1, peak CSF concentration time (Tnaxl) 15.9 ± 5.0 and 17.0 ± 6.9 min. For the i.v. dosed healthy (n = 6) and postoperative (n = 8) animals, Kel was 0.0408 ± 0.0107, 0.0414 ± 0.0123 min‐1 and 7maxt was 10.0 ± 5.0 and 7.7 ± 2.5 min, respectively. It was demonstrated that an obviously lower peak concentration can be reached significantly later in CSF than in plasma, and the kinetic behaviour of meperidine in plasma is different from that in the CSF, indicating meperidine analgesia might not be predicted by simple extrapolation from the kinetic data.
Sulfadimidine metabolism in vitro: II. comparative studies in cultured rat, goat, sheep and cattle hepatocytes
Authors: KLOOSTER G. A. E. VAN T , BLAAUBOER B.J. , NOORDHOEK J‐ , MIERT A. S.J. P. A. M. VAN
Published: April 2008

van't Klooster, G.A.E., Blaauboer, B.J., Noordhoek, J. & van Miert, A.S.J.P.A.M. Sulfadimidine metabolism in vitro: II. comparative studies in cultured rat, goat, sheep and cattle hepatocytes. J. vet. Pharmacol. Therap. 16, 454–461.

Hydroxylation and acetylation of sulphadimidine (SDD) and the deacetylation of N4‐acetyl SDD was investigated in cultured hepatocytes from male and female rats, from male and female goats and from female sheep and cattle. Significant sex differences were observed for hydroxylation of SDD in hepatocytes from rat and goat. In goat, sheep and cow hepatocytes, the hydroxylation pathway is relatively important, whereas in rat hepatocytes, acetylation is predominant. Hepatocytes of all four species deacetylated N4‐acetyl SDD. In ruminant hepatocytes, deacetylating activity was of considerable importance, whereas in rat hepatocytes, it appeared a minor pathway of metabolism. Similar to thein vivosituation, formation of N4‐acetyl SDD in cultured hepatocytes results from an equilibrium of acetylation and deacetylation. A good correlation was found between results in isolated hepatocytes and previous findingsin vivo, both in levels of species‐related activities and in acetylation‐hydroxylation ratios. In conclusion, cultured hepatocytes appear a usefulin vitromodel to study comparative sulfonamide metabolism.
Pharmacokinetics and applications of ampicillin sodium as an intravenous infusion in the horse
Authors: SARASOLA P. , McKELLAR Q. A.
Published: April 2008

A regime for administration of ampicillin sodium by continuous intravenous infusions to horses was designed. The aim was to achieve plasma ampicillin concentrations between 5 and 10 pgiml over a 4‐h period. A 2 mgikg bodyweight loading dose of ampicillin sodium was administered intravenously at the beginning of the infusion in order to achieve steady‐state plasma concentra‐tions rapidly. The infusion system subsequently administered ampicillin at a rate of approximately 19.2 pglminikg bodyweight. The plasma concentrations obtained over the infusion period correlated very well with predicted calculations based on pharmacokinetic parameters. A mean ± SEM steady‐state plasma concentration (Cpss) of 5.94 ± 0.33 was obtained and ampicillin was shown to have an apparent steady‐state volume of distribution (Vdss) of 175.43 ± 13.63 ml/kg. When the pump was disconnected the concentrations declined over the following 4 h in an exponential way with an elimination half‐life (t1/2β) of 0.62 h. In addition, three different infusion dose rates (13.78, 19.34 and 2 l 4 8 pg/min/kg) were administered to a single animal showing that a good correlation(correlation coefficient > 0.99) existed between the dose administered the steady‐state plasma concentrations and the corresponding areas under the plasma concentration versus time curve.
Pharmacodynamics, pharmacokinetics and faecal persistence of morantel in cattle and goats
Authors: McKELLAR Q. A. , SCOTT E. W. , BAXTER P. , ANDERSON L. A. , BAIRDEN K.
Published: April 2008

Morantel could not be detected (<0.05 pg/ml)in the plasma of cattle or goats followingthe oral administration of morantel tartrate at a dose rate of 10 mg/kg

bodyweight. No morantel was detected in the milk of lactating goats except in

one animal where a concentration of 0.092 pg/ml was detected at 8 h after drug

administration. Morantel was highly effective against Cooperia oncophora infec‐

tions in calves treated 6, 9 or 18 days after infection; however, was highly

effective against Ostertagia ostertagi only when treated 18 days after infection.

Morantel did not affect the fecundity of adult 0.ostertagi surviving treatment 18

days after infection which had similar average numbers of eggs in their uteri

(range 13.4 f 0.73‐16.8 L 0.98) as did parasites from control animals (range

12.0 k 0.70‐13.6 2 0.66). Morantel could be detected at a concentration of 96 k

4.5 pgig (dry weight) in the faeces of a calf 24 h after treatment with I0 mgikg

bodyweight of morantel tartrate. The concentration of morantel in replicate

samples of this faeces exposed to natural atmosphere, but not to soil or soil

organisms, declined slowly over the following 322 days. At day 322 after the start

of the experiment 8.8 pg/g of morantel could be measured in the remaining

faecal material. Throughout the faecal degradation study the concentration of

morantel in the crusts of the replicate sample pats was lower than the

concentration in the core samples.
Pharmacokinetic‐pharmacodynamic modelling of meperidine in goats (II): modelling
Authors: QIAO G.‐L. , FUNG K.‐F.
Published: April 2008

Simultaneous pharmacokinetic‐pharmacodynamic (PK‐PD) models of meperidine in Soats were established by utilizing the P3 wave of the cerebral evoked potentials as an analgesic measurement. An effect compartment linked to the central compartment was postulated in the models. The hypothetical drug amount in the effect compartment was related to the observed analgesia through the Hill equation. After intramuscular (i. m., n= 16) and intravenous (i. v., n= 13) dosing (5 mg/kg), the elimination rate constants of meperidine in the effect compartment (KeO) were 0.3744 ± 0.2546 and 0.1123 ± 0.0428 min‐1, drug concentrations in the effect compartment generating half maximal analgesia (EC(50)) were 0.70 ± 0.33 and 0.41 ± 0.26 μg/ml, the maximal effects (Emax) were 89.63 ± 15.63 and 85.92 ± 9.64%, and the Hill coefficients (S) were 2.61 ± 1.21 and 2.37 ± 1.15, respectively. KeO and EC(50) with i.m. dosing were significantly greater than with i.v. injection. However, administration route had no influence on S, Emax and the total amount of effect (AUE). The predicted peak effect (Emax^) of 64.44 ± 14.64 and 66.02 ± 11.51% were achieved at 14.7 ± 7.4 and 8.5 ± 2.2 min after i.m. and i.v. dosing, respectively. Peak analgesia appeared much later than peak plasma concentration, but simultaneously with peak CSF level both after i.m. and i.v. dosing. An obvious hysteresis was demonstrated between plasma concentration and analgesic effect. This study demonstrates that meperidine analgesia can be predicted using a PK‐PD model, but not by PK data alone. Both i.m. and i.v. administration routes were evaluated kinetically and dynamically.
Monitoring furosemide in racehorses participating in an EIPH program
Authors: STEVENSON A. J. , WEBER M. P. , TRUDEL R. , LEAVITT R. , WOODARD D. , TODI F. , MENDONCA M. , ROBILLO V. , YOUNG L. , KACEW S.
Published: April 2008

Analytical procedures were developed to monitor furosemide concentrations in post‐race serum and urine samples obtained from horses participating in an exercise‐induced pulmonary haemorrhage (EIPH) program. High performance liquid chromatography with ultraviolet light detection proved a reliable, sensitive method for measuring urinary furosemide concentrations up to 12 h after administration of either 150 or 250 mg of the drug to race horses. However, this method was unreliable for determination of serum furosemide concentration. High performance liquid chromatography with fluorescence detection proved a reliable, sensitive method for measuring serum furosemide concentrations in horses administered 250 mg of the diuretic, permitting detection approximately 5–10 ng/ml 6 h after treatment. This method was applied field conditions where furosemide was administered to horses (between 150 and 250 mg intravenously) 4 h prior to the race. Analytical results assisted establishing a threshold concentration of 85 ng/ml for serum furosemide. was found that serum furosemide concentrations are a valid measure of compliance with furosemide administration in the EIPH program.
Yohimbine prevents the retrograde flow of spermatozoa into the urinary bladder of dogs induced by xylazine
Authors: PINEDA M. H. , DOOLEY M. P.
Published: April 2008

This study was carried out to determine whether yohimbine antagonizes the retrograde flow of spermatozoa into the urinary bladder of dogs caused by xylazine. Adult dogs were assigned to one of four groups of six dogs each and treated as follows: saline control, xylazine (2.2 mg/kg, i.m.), yohimbine (0.2 mg/kg, im.), yohimbine/xylazine (yohimbine, 0.2 mg/kg, i.m., followed 10 min later by xylazine. 2.2 mg/kg, i.m.). Pre‐ and post‐treatment urine were collected by cystocentesis from all dogs. The mean (± SD) adjusted total number of spermatozoa in the post‐treatment urine of xylazine‐treated dogs (141.02 ± 136.75 × 106) was 15 times higher (P< 0.05) than the number in the post‐treatment urine of control dogs (9.16 ± 20.26 × 106), 1763 times higher (P< 0.05) than the number in the urine of yohimbine‐treated dogs (0.08 ± 0.20 × 106), and 56 times higher (P< 0.05) than the total number in the post‐treatment urine of yohimbine/xylazine‐treated dogs (2.54 ± 4.54 × 106). These results confirm that xylazine induces a significant (P= 0.007) displacement of spermatozoa into the urinary bladder of dogs and demonstrate that pre‐treatment with yohimbine prevents this effect.
High performance liquid chromatography and pharmacokinetics of the non‐steroidal anti‐inflammatory drug oxindanac in calves
Authors: KING J. N. , MAURON C. , VOIROL M. J. , GOFF C. LE , HAUFFE S. A.
Published: April 2008

A high‐performance liquid chromatographic method for the determination of the non‐steroidal anti‐inflammatory drug, oxindanac, in calf plasma is described. Recoveries over the concentration range 0.3 75 to 62.5 μg/ml were 90.2–107.8% with interassay coefficients of variation of 2.1–22.3%. The limit of detection was estimated as 0.10 μg/ml and the limit of quantification calculated to be 0.24 pg/ml in a 1 ml plasma sample. This method was used to establish the pharmacokinetics following intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administration to calves of oxindanac at a dose rate of 2 mg/kg. The elimination t1/2, was long (t1/2 21.2 h after i.v. injection) and absorption was rapid (t1/2B 0.072 h) and complete (F > 100%) following i.m. administration. Bioavailability was incomplete (F= 66.6%) following p.o. administration to calves that had been fed on milk, and Wagner‐Nelson analysis revealed twoabsorption phases (t1/2's 0.20 and 1.9 h). Oxindanac produced long‐lasting inhibition of serum TxB2 production, with mean kmax values (% inhibition) of 96.8, 94.1 and 81.3 following i.v., i.m. and p.0. administration, respectively. A single i.v. or i.m. injection of 2 mg/kg oxindanac will probably be active in calves for at least 36–48 h.
Correlation between the pharmacokinetics of oxindanac and inhibition of serum thromboxane B2in calves
Authors: KING J. N.
Published: April 2008

The pharmacokinetics and pharmacodynamics of the non‐steroidal antiinflammatory drug, oxindanac, were assessed simultaneously in calves after intravenous (i.v.) administration at dose rates of 0.5, 1, 2, 4 and 8 mg/kg. Plasma pharmacokinetic data were fitted to either two or three compartment open models. The eliminationt1/2was constant in the dose range 0.5 to 4 mg/kg (20.2–22.8 h) and shorter at 8 mg/kg (14.7 h). The pharmacodynamics of oxindanac were assessed by its inhibition of serum TxB2, an index of platelet cyclo‐oxygenase activity. Plots of total plasma oxindanac concentration vs. inhibition of serum TxB2fitted in all cases a sigmoidal Emaxequation. There were no significant differences in the estimates for ED50(1.6‐1.9 μg/ml), Hill constant (1.3‐2.7) or Emax between the doses used in thein vivostudies or when blood was spiked with oxindanacin vitro.Plots of inhibition of serum TxB2vs. time were prepared from the pharmacokinetic model equations in each calf in combination with a single sigmoidal Emaxplot generatedin vitro.These data were not significantly different from the results producedin vivo.It is concluded that oxindanac causes reversible inhibition of platelet cyclo‐oxygenase in calves. Its inhibition of serum TxB2can be predicted from total plasma drug concentration, as described by a multicompartmental model, and sigmoidal Emaxenzyme kinetics. It was not necessary to take into account factors such as drug equilibration between plasma and its target site, free vs. total drug concentration or chirality. This simple model may be useful for predicting the pharmacodynamics of oxindanac in other species.
Effect of sodium cromoglycate on light racehorses with elevated metachromatic cell numbers on bronchoalveolar lavage and reduced exercise tolerance
Authors: HARE J. E. , VIEL L. , O'BYRNES P. M. , CONLON P. D.
Published: April 2008

Some young horses with clinical signs of small airway disease demonstrate increased metachromatic cell numbers on bronchoalveolar lavage. The purpose of this study was to determine the effect of sodium cromoglycate treatment on clinical signs, bronchoalveolar lavage cytology and bronchoalveolar lavage histamine parameters in these horses. Twelve racehorses (age: 3.4 ± 1.6 years) with a history of respiratory embarrassment at exercise, clinical signs of obstructive airway disease and bronchoalveolar lavage metachromatic cell differential greater than 2% were selected. Horses were randomly assigned to receive either 200 mg sodium cromoglycate or saline placebo nebulized twice daily for 7 days. A clinical respiratory score was assigned and bronchoalveolar lavage was performed on each animal on days 0 and 7. Measurements were made of the following bronchoalveolar lavage fluid parameters: total nucleated cell concentration, differential cell percentage and concentration, supernatant and lysate histamine concentration, lysate: supernatant histamine ratio and metachromatic cell histamine content. Between the two evaluation periods, sodium cromoglycate treated horses demonstrated an improvement in respiratory score (P = 0.01) and a stabilizing of metachromatic cell histamine content (P = 0.04) when compared with placebo treated horses. We conclude that sodium cromoglycate is effective for the treatment of small airway disease in this population of young racehorses although the pharmacodynamics of this drug in the horse require further investigation.
Effects of dietary protein conditioning on gentamicin pharmacokinetics in dogs*
Authors: BEHREND E. N. , GRAUER G F , GRECO D. S. , FETTMAN M J , ALLEN T.A.
Published: April 2008

Eighteen, six‐month‐old male Beagles with normal renal function were randomly divided into three groups of 6. Each group was fed a diet that was similar except for protein content (high = 26%, medium = 13% and low = 9%, all on an as fed basis) throughout the experimental period. After a 21 day dietary protein conditioning period (including a terminal 2 day testing period), gentamicin was administered at a dosage of 10 mg/kg q. 8 h for 8 days. The first dose on days 1 and 7 was administered i.v. and all others were given i.m. Pharmacokinetic parameters were determined using blood samples collected over an 8 h period following the i.v. dose on day 1. The elimination rate constant was calculated on days 1 and 7. The data best fit a two‐compartment open model for all dogs on day 1. The volume of distribution was higher and the clearance greater in the high protein group compared to the other two groups. No difference was found in the rate of elimination between days 1 and 7 for the high protein group: however, in the medium and low protein groups the rate of elimination decreased over the 7 days of treatment. Therefore, high dietary protein prior to and during gentamicin administration induced faster gentamicin clearance and a larger volume of distribution and preserved the ability to eliminate gentamicin in dogs with normal renal function.
The pharmacokinetics and pharmacodynamics of procainamide in horses after intravenous administration
Authors: ELLIS E. J. , RAVIS W. R. , MALLOY M. , DURAN S. H. , SMYTH B. G.
Published: April 2008

Six horses were administered either 15 or 20 mg/kg body weight (b.w.) procainamide (PA) as an intravenous (i.v.) dose over 10 min. The plasma concentrations of PA and N‐acetylprocainamide (NAPA) as well as the pharmacodynamic effect (prolongation of the QT interval) were monitored. The PA plasma concentrations could be described by a one‐compartment model with a t½ of 3.49 ± 0.61 h. The total body clearance of PA was 0.395 ± 0.090 1/hr/kg and the volume of distribution was 1.93 ± 0.27 l/kg. As observed after PA administration, NAPA (an active metabolite) had a t½ longer than PA of 6.31 ± 1.49 h. Peak NAPA concentrations (1.91 ± 0.51 μg/ml) occurred at 5.2 h after the PA i.v. dose. The ratio of area under the curves for NAPA to PA was 0.46 ± 0.15 which is similar to that expected in humans classified as slow acetylators. Percentage change in the QT interval was examined with respect to PA and PA + NAPA plasma concentrations. For PA, %ΔQT = 41.2 log (PA) ‐ 13.26 and correlations (r) ranged from 0.77 to 0.91 among the horses. In the case of PA + NAPA,%ΔQT= 57.3 log(PA+NAPA)‐31.83 andrangedfrom0.77to0.90. No evidence of toxicity was noted with respect to changes in the PR interval.
Effects of ketoprofen and flunixin in pigs experimentally infected with Actinobacillus pleuropneumoniae
Authors: SWINKELS J. M. , PIJPERS A. , VERNOOY J. C. M. , NES A VAN , VERHEIJDEN J. H. M
Published: April 2008

The antipyretic effect of the non‐steroidal anti‐inflammatory drugs (NSAIDs) ketoprofen (3 mg/kg) and flunixin (2 mg/kg) were studied in pigs. The drugs were administered intramuscularly at 8 and 32 h following endobronchial challenge with Actinobucillus pleuropneumoniae. Infected (non‐medicated) and non‐infected (non‐medicated) controls were used. Endobronchial challenge with Actinobucillus pleuropneumoniae induced laboured breathing, coughing, fever, reduced food and water consumption and increased white blood cell counts. At autopsy, pleuropneumonia was evident. Ketoprofen showed a highly significant antipyretic effect but flunixin did not. The decrease in food consumption of ketoprofen‐treated pigs was significantly less than that of the infected (non‐medicated) controls. Blood parameters were not significantly influenced by either NSAID and, at necropsy, gastric and renal side‐effects were not observed for either drug.
Fate of etiproston, a synthetic analogue of PGF2α, in cows
Authors: BENECH H. , BRUNE P. , PRUVOST A. , ARCHIMBAULT P. , GUILLOT P. , MURPHY R. C. , MACLOUF J. , GROGNET J.M.
Published: April 2008

The pharmacokinetics and metabolic fate of labelled compounds were investigated after intramuscular administration of 3H‐radiolabelled etiproston to nine cows. Elimination was rapid (t1/2β= 2.8 h). Forty‐eight h after administration 92.6% of the radioactivity had been eliminated, mainly via the urinary (66% at 48 h) and faecal routes (26% at 48 h). In comparison, little elimination in milk occurred (less than 0.034% dose/l by 24 h). Radioactivity at the injection site 48 h after administration was seen in one cow (< 4.68 × 10‐5% dose/g). No radioactivity was detected in the tissues. Urinary metabolites were purified and isolated using XAD‐2 extraction and preparative HPLC in reverse and normal phases. The main urinary metabolite, identified by mass spectrometry, was the tetranor acid derivative in equilibrium with its lactone form.
Thiamphenicol pharmacokinetics in beef and dairy cattle
Authors: ABDENNEBI E. H. , SAWCHUK R. J. , STOWE C. M.
Published: April 2008

The pharmacokinetics of thiamphenicol were investigated in 10 calves and six lactating cows. It was found that this drug is rapidly absorbed (1 5 min) following intramuscular injection with an absorption rate constant and a bioavailability of 8.7 h‐1 and 84%, respectively. The drug appears to be widely distributed into various body fluids, yielding a volume of distribution (Vd(area)) of approximately 0.9 l/kg. The micro‐rate constants indicated that the antibiotic rapidly diffuses into the peripheral compartment (k12 > k21). Elimination from plasma is relatively rapid, with a biological half‐life of about 1.75 h. Thiamphenicol appears shortly in milk (15 min) after its intravenous administration, and gives milk to plasma concentration ratios greater than one between 4 and 12 h.
Pharmacokinetics of gentamicin following single dose intravenous administration in normal and febrile goats
Authors: AHMAD A. H. , BAHGA H S , SHARMA L. D.“
Published: April 2008

A pharmacokinetic study of gentamicin (5 mg/kg intravenous (i.v.)) was conducted first in cinically healthy female goats and then in the same goats after induction of fever by Escherichia coli endotoxin (0.2 μg/kg i.v.). Rectal temperature increased 1 to 1.5°C in febrile goats. Differences in the blood serum concentrations of gentamicin were not observed at any time between febrile and normal goats. The disposition kinetics of gentamicin were described by a biex‐ponential expression CP= Ae‐αt+ Be‐β. Median values for the half‐lives of gentamicin were 103.6 min in normal and 136.0 min in febrile goats. The apparent volume of distribution (Vd) was 263.3 ml/kg in the febrile goats which was not different from that in the normal goats (240.6 ml/kg). The volume of the central compartment (Vc) was almost identical in normal and febrile goats. The body clearance (Clβ) was observed to be 1.7 and 1.6 ml/min‐kg in normal and febrile goats, respectively. Dosage regimens for gentamicin were calculated on the basis of median kinetic data.
Effects of phenylbutazone on thiamylal disposition and anaesthesia in ponies
Authors: YOUNG D. B. , EWING P. J. , BURROWS G E , LESSLEY B. A. , CLARKE C R , SHAWLEY R V
Published: April 2008

Phenylbutazone given during the perisurgical period has been reported to increase the intensity and duration of thiamylal anaesthesia in horses. A possible mechanism of competitive plasma protein binding has been suggested. The purpose of the present study was to experimentally reproduce the phenomenon of increased intensity and/or duration of thiamylal anaesthesia and to determine if there is competitive displacement of plasma protein bound thiamylal by phenylbutazone. Six ponies each received one of three treatments, 11 mg/kg intravenous (i.v.) thiamylal; 8.8 mg/kg i.v. phenylbutazone; and 11 mg/kg i.v. thiamylal with 8.8 mg/kg i.v. phenylbutazone given 9 min later. Thirteen blood samples were collected from 0 time through 600 min following drug administration and plasma drug concentrations quantified by high performance liquid chromatography. The pharmacokinetics of thiamylal and phenylbutazone were best described by three‐ and two‐compartment models, respectively. There were no significant differences in pharmacokinetic parameters for thiamylal in the presence of phenylbutazone. However, there were differences in phenylbutazone pharmacokinetics when preceded by thiamylal administration. Unbound phenylbutazone concentrations were increased at 171, 231 and 351 min when given with thiamylal, accompanied by decreases in per cent bound phenylbutazone (P < 0.05). There were also significant (P < 0.05) changes in per cent plasma protein binding of thiamylal and phenylbutazone between 120 and 360 min, when in combination. No changes in intensity or duration of anaesthesia were observed.
Pharmacokinetics of tobramycin in the camel
Authors: A/HADI A. A. , WASFI I. A. , GADIR F. A. , AMIRI M H , BASHIR A. K. , BAGGOT J. D.
Published: April 2008

A/Hadi, A.A., Wasfi, I.A., Gadir, F.A., Amiri, M.H., Bashir, A.K. Baggot, J.D. Pharmacokinetics of tobramycin in the camel. J. vet. Pharmacol. Therap. 17. 48–51.

The pharmacokinetics of tobramycin were determined in six healthy camels(Camelus dromedarius) following the intravenous (i.v.) and intramuscular (i.m. administration of single doses of tobramycin sulphate (40 mg/ml). The half‐life to tobramycin was 189 ± 21 min and the mean residence time was 254 ± 26 min. The apparent volume of distribution (area method) was 245 ± 21 ml/kg. while volume of the central compartment of the two‐compartment pharmaco‐kinetic model was 110 ± 12 ml/kg. The clearance (systemic) of tobramycin was 0.90 ± 0.10 ml/min/kg. Values of the pharmacokinetic parameters suggest that glomerular filtration rate is lower in camels than in other ruminant species, horses, dogs and cats. Following i.m. administration of the dose (1.0 mg/kg), the drug was rapidly absorbed with peak serum concentration of 3.32 ± o.59 m̈g/ml at 20–30 min; the absorption half‐life was 3.9 ± 0.9 min. The systemic availability of tobramycin was 90.7 ± 14.4%. The apparent half‐life was 201 ±40 min, which was not significantly longer than the half‐life following i.v. administration of the drug. Based on the pharmacokinetic values obtained in this study, a dosing rate of 2.5 mg/kg administered by i.m. injection at 12‐h intervals can be recommended. This dosage regimen should achieve an average steady state serum concentration of 4 m̈g/ml with peak serum concentration approaching, but not exceeding, 10 m̈g/ml.
Disposition of creatine kinase activity in dog plasma following intravenous and intramuscular injection of skeletal muscle homogenates
Authors: AKTAS M. , LEFEBVRE H.P. , TOUTAIN P.L. , BRAUN J.P.
Published: April 2008

The fate of skeletal muscle‐derived creatine kinase (CK) was investigated in six dogs. After i.m. and i.v. injections of 3000 g and 105 000 g supernatants of dog muscle homogenates, plasma CK activity was measured up to 48 h. There was no significant difference in pharmacokinetic parameters dependent on the type of supernatant injected. After i.v. injection, the volume of distribution of CK was equal to the plasma volume, CK clearance was relatively low (about 0.5 mL/kg/min) and its terminal half‐life of elimination was about 2.5 h. After i.m. injection, the CK terminal half‐life was about 6.5 h, demonstrating a flip‐flop mechanism, i.e. a limiting absorption process from the site of injection. Bioavail‐ability after i.m. injection was about 65%, and the rate of absorption from muscle injection site was relatively slow: peak activity occurred at the second hour post administration, and most CK activity had been absorbed by 24 h. These pharmacokinetic parameters can be used as a basis for a minimally invasive means of quantitating muscle damage either after intramuscular drug administration or in canine sports medicine.
Radioreceptor assay for determination of xylazine and medetomidine in sheep plasma
Authors: MUGE D.K. , CHAMBERS J.P. , LIVINGSTON A.
Published: April 2008

A radioreceptor assay technique is described for the measurement of xylazine and medetomidine in sheep plasma. The assay was based on the displacement of tritiated clonidine from a 2‐adrenoceptors in a rat brain homogenate by xylazine or medetomidine extracted from plasma. Plasma samples from sheep which had been given xylazine and medetomidine were treated with alumina to remove endogenous catecholamines which would otherwise have bound to α2‐‐ adrenoceptors and interfered with the assay. The drugs were then extracted using chloroform, reconstituted in buffer and used to displace [3H]clonidine. The concentration of α2‐agonist was calculated by reference to standard curves. The method had a detection limit of 2.5 ng/mL for xylazine and 0.24 ng/mL for medetomidine. The assay could also be used to detect metabolites capable of binding to α2‐receptors.
Rabbit model for estimating relative bioavailability, residues and tissue tolerance of intramuscular products: comparison of two ampicillin products
Authors: OLLING M. , VAN TWILLERT K. , WESTER P. , BOINK A.B.T. , RAUWS A.G.
Published: April 2008

A rabbit model for simultaneous investigation of the bioavailability, tissue residues and tissue tolerance of intramuscularly administered veterinary medicines is described. The bioavailability of ampicillin from two intramuscular products, which had been found to be different in calves, were compared in a two‐way crossover design. The ampicillin levels in plasma, ampicillin residues in tissues, the plasma creatine kinase activity and the tissue damage at the injection sites were studied. The absolute bioavailabilities for the products were 100% and 40%. Differences in pharmacokinetics of ampicillin between sexes were observed after intravenous and intramuscular administration. Only slight tissue damage could be detected at the injection sites after intramuscular administration of these products. The results were compared with those obtained previously in calves and were found to be similar. Further investigations with other intramuscular drug products to validate this model are under way.
Methoctramine, a cardioselective muscarinic cholinergic antagonist, prevents fentanyl‐induced bradycardia in the dog
Authors: HENDRIX P.K. , ROBINSON E.P. , RAFFE M.R.
Published: April 2008

A controlled study examining the effects of the cardioselective muscarinic cholinergic antagonist methoctramine on fentanyl‐induced bradycardia was performed in six dogs. Five doses of methoctramine (6, 10, 20, 30 and 60 |ig/kg) followed by fentanyl (20 μg/kg) were administered randomly on separate days. Fentanyl caused a significant reduction in heart rate from baseline values. Moreover, fentanyl produced a variety of arrhythmogenic actions indicative of vagal hyper‐activity, including sinus bradycardia, second‐degree atrioventricular block and ventricular and supraventricular escape beats. Administration of methoctramine 5 min before fentanyl injection prevented the bradycardic effects of fentanyl in a dose‐dependent manner, with high doses of methoctramine causing sinus tachycardia. Using regression analysis, the dose of methoctramine necessary to prevent fentanyl‐induced bradyarrhythmias without causing tachycardia was calculated as 14.4 μg/kg. The study confirmed that fentanyl administration in the conscious dog causes profound bradycardia with bradyarrhythmias. The cardioselective muscarinic antagonist agent methoctramine prevented the bradycardic effects of fentanyl.
Clinical pharmacology of cefixime in unweaned calves
Authors: ZIV G. , LAVY E. , GLICKMAN A. , WINKLER M.
Published: April 2008

Cefixime is a unique third‐generation oral cephalosporin. Itsin vitroactivity and pharmacokinetic properties have been studied to assess its potential for use in the therapy of newborn calf infections due to gram‐negative bacteria. The minimum inhibitory concentrations of cefixime for 90% (MIC50) of field isolates ofEscherichia coli. SalmonellaandPasteurellawere 0.10–0.40 μg/mL. The serum disposition kinetics of cefixime following intravenous and oral administration was evaluated. The elimination half‐life of cefixime after intravenous and oral administration was 3.5–4.0 h, the steady‐state volume of distribution was 0.34 L/kg and approximately 90% of the drug was bound to serum proteins. Oral absorption was comparatively slow and bioavailability values for single 5 mg/kg doses were 20.2% after the administration of 200 mg of cefixime in capsules, 28.3% after dosing an aqueous solution of cefixime and 35.7% after fasted calves received the solution of cefixime. Mean serum drug concentrations 12 h after the cefixime solution was administered orally (5 mg/kg) were 1.05 μg/mL for the milk‐fed calves and 1.76 μg/mL for the fasted calves. Computations showed that mean free drug concentrations equal to the MIC50of the drug for gram‐negative pathogens associated with newborn calf infections can be maintained in tissues by multiple treatments at 5 mg/kg every 12 h or 10 mg/kg every 24 h.
Intravenous disposition kinetics, oral and intramuscular bioavailability and urinary excretion of norfloxacin nicotinate in donkeys
Authors: LAVY E. , ZIV G. , GLICKMAN A.
Published: April 2008

An aqueous solution of norfloxacin nicotinate (NFN) was administered to donkeys (Aquus astnus) intravenously (once at 10 mg/kg), intramuscularly and orally (both routes once at 10 and 20 mg/kg, and for 5 days at 20 mg/kg/day). Blood samples were collected at predetermined times after each treatment and urine was sampled after intravenous drug administration. Serum NFN concentrations were determined by microbiological assay. Intravenous injection of NFN over 45–60 s resulted in seizures, profuse sweating and tachycardia. The intravenous half‐life (t1/2βwas 209 ± 36 min, the apparent volume of distribution (Vd(area)) was 3.34 ± 0.58 L/kg, the total body clearance (ClE) was 1.092 ± 0.123 ± 10‐‐2mL/min/kg and the renal clearance (C1R) was 0.411 ± 0.057 ± 10‐‐2mL/min/kg. Oral bioavailability was rather poor (9.6% and 6.4% for the 10 and 20 mg/kg doses respectively). Multiple oral treatments did not result in any clinical gastrointestinal disturbances.

After intramuscular administration (20 mg/kg), serum NFN concentrations > 0.25 μg/mL (necessary to inhibit the majority of gram‐negative bacteria isolated from horses) were maintained for 12 h. The intramuscular bioavailability was 31.5% and 18.8% for the 10 and 20 mg/kg doses respectively. After multiple dosing some local swelling was observed at the injection site. About 40% of the intravenous dose was recovered in the urine as parent drug. The results of comprehensive haematological and blood biochemistry tests indicated no abnormal findings except elevation in serum CPK (creatine phosphokinase) values after multiple intramuscular dosing. On the basis of thein vitro‐determined minimum inhibitory concentrations of the drug and serum concentrations after multiple dosing, the suggested intramuscular dosage schedules for the treatment of gram‐negative bacterial infections in Equidae are 10 mg/kg every 12 h or 20 mg/kg every 24 h.
Antipyrine disposition in the dehydrated camel
Authors: BEN‐ZVI Z. , RUBIN M. , VAN CREVELD C. , YAGIL R.
Published: April 2008

In the present study the effects of water deprivation in the camel (Camelus dromedarius) on the pharmacokinetic profile of antipyrine were assessed. A crossover design was used. The pharmacokinetics of antipyrine in adult and young camels were compared. Antipyrine was administered intravenously to young and adult female camels when water was available ad libitum and to the adult camels after 14 days of dehydration. The elimination half‐life of antipyrine in watered adult camels was 136.5 ± 16.7 min. The half‐life of elimination and the mean residence time of antipyrine were significantly prolonged following dehydration. The observed effects of water deprivation were not a function of age, as the pharmacokinetic profile of antipyrine in young camels was similar to that of the adults, but more likely due to the changes in oxidative metabolic capacity of the liver as a result of a reduced general metabolism. The results of the present study also show that the intrinsic clearance of antipyrine is proportional to the camel's body weight, as previously shown for other mammalian species.
Proteoglycan metabolism of equine articular cartilage and its modulation by insulin‐like growth factors
Authors: PLATT D. , BAYLISS M.T.
Published: April 2008

The effect of human recombinant insulin‐like growth factor 1 (rhIGF‐1) on proteoglycan (PG) metabolism of full thickness equine articular cartilage explants was investigated. PG synthesis was stimulated at all ages, but higher concentrations of rhIGF‐1 were required for maximal stimulation of adult cartilage. There were no changes in the hydrodynamic size, electrophoretic heterogeneity or composition of proteoglycans isolated from rhIGF‐1‐stimulated cartilage. rhIGF‐1 reduced the rate of turnover of both newly synthesized and endogenous proteoglycans in all ages of cartilage investigated. The structure of proteoglycan fragments retained within the matrix and those released into the culture medium was unaffected by IGF‐1 stimulation, suggesting that this peptide is a key regulator of the proteoglycan composition of equine articular cartilage extracellular matrix.
Pharmacokinetics and bioequivalence of parenterally administered doramectin in cattle
Authors: NOWAKOWSKI M.A. , LYNCH M.J. , SMITH D.G. , LOGAN N.B. , MOUZIN D.E. , LUKASZEWICZ J. , RYAN N.I. , HUNTER R.P. , JONES R.M.
Published: April 2008

Plasma concentrations of doramectin in 40 cattle dosed by subcutaneous (sc) or intramuscular (i.m.) injection (200 μg/kg) were compared to assess the bioequivalence of the two routes of administration. Peak concentration (Cmax), and areas under the concentration curve (AUC0–) were determined from plasma concentrations. Animals treated by the sc route showed a mean AUC0– of 457 ± 66 ng±day/mL (± SD) and a mean Cmax of 27.8 ± 7.9 ng/mL. Results from the i.m. treatment group showed a mean AUC0– of 475 ± 82 ng‐day/mL and a mean Cmax of 33.1 ± 9.0 ng/mL Absorption constants (ka) determined by modelling were 0.542 ± 0.336 day‐1after sc administration and 0.710 ± 0.357 day‐1after i.m. administration. The 90% confidence limits on the difference between mean AUC0– values for the sc and i.m. groups fell within 20% of the mean value for the subcutaneous group. Cmax was somewhat greater for the i.m. route. The 90% confidence limits on the difference in mean In (Tmax+1) also fell within 20% of the mean sc value. Based on this analysis, bioequivalence of the sc and i.m. formulation has been established.
Pharmacokinetics and pharmacodynamics of ketoprofen in calves applying PK/PD modelling
Authors: LANDONI M.F. , CUNNINGHAM F.M. , LEES P.
Published: April 2008

The pharmacokinetics (PK) and pharmacodynamics (PD) of ketoprofen (KTP) were studied in calves following intravenous administration of the drug racemate at a dose rate of 3 mg/kg. To evaluate the anti‐inflammatory properties of KTP, a model of acute inflammation, consisting of surgically implanted subcutaneous tissue cages stimulated by intracaveal injection of carrageenan, was used. No differences were observed between disposition curves of KTP enantiomers in plasma, exudate or transudate. This indicates that in calves KTP pharmacokinetics is not enantioselective. S(+)‐ and R(‐)‐ KTP each had a short elimination half‐life (t1/2β of 0.42 ± 0.08 h and 0.42 ± 0.09 h, respectively. The volume of distribution (Vd) was low, values of 0.20 ± 0.06 L/kg and 0.22 ± 0.06 L/kg being obtained for R(‐) and S(+)KTP, respectively. Body clearance (CI8) was high, correlating with the short elimination half‐life, 0.3 3 ± 0.03 L/kg/h [R(‐)KTP] and 0.32 ± 0.04 L/kg/h [S(+)‐KTP]. KTP pharmacodynamics was evaluated by determining the effects on serum thromboxane (TxB2), exudate prostaglandin (PGE2), leukotriene (LTB4) and β‐glucuronidase (β‐glu) and bradykinin (BK)‐induced oedematous swelling. Effect‐concentration inter‐relationships were analysed by PK/PD modelling. KTP did not affect exudate LTB4, but inhibition of the other variables was statistically significant. The mean EC50 values for inhibition of serum TxB2, exudate PGE2 and β‐glu and BK‐induced swelling were 0.118, 0.086, 0.06 and 0.00029 μg/mL, respectively. These data indicate that KTP exerted an inhibitory action, not only as expected, on eicosanoid (TxB2 and PGE2) synthesis but also on exudate β‐glu and BK‐induced oedema. The EC50 values for these actions indicate that they are likely to contribute to the overall anti‐inflammatory effects of KTP in calves. However, claims that KTP inhibits 5‐lipoxygenase and thereby blocks the production of inflammatory mediators such as LTB4 were not substantiated. PK/PD modelling has proved to be a useful tool for analysing the in vivo pharmacodynamics of KTP and for providing new approaches to elucidating its mechanism(s) of action.
Dietary intake estimates as a means to the harmonization of maximum residue levels for veterinary drugs. I. Concept
Authors: FITZPATRICK S.C. , BRYNES S.D. , GUEST G.B.
Published: April 2008

The harmonization of standards and procedures for establishing tolerances or maximum residue levels (MRLs) for veterinary drug residues in edible animal products is a major goal of the international veterinary drug community. Such harmonization would contribute to easing trade barriers. This paper proposes use of the toxicologically determined acceptable daily intake (ADI) for the drug as the safety standard for reaching conclusions on the acceptability of residues in meat for human consumption. Specifically, the ‘equivalence’ of different MRLs for the same veterinary drug would be determined by considering whether they are likely to result in dietary residues that exceed another country's ADI for the drug. Two methods of estimating dietary intake are described, and estimates are made for the veterinary drugs albendazole and ivermectin. Based on these estimates, the US and JECFA MRLs for each drug would be considered ‘equivalent’ for trade purposes.