bluuebunny/crossref_metadata_2025 huggingface dataset:
Chirality of the sulphoxide metabolites of fenbendazole and albendazole in sheep
Authors: DELATOUR P. , BENOIT E. , GARNIER F. , BESSE S.
Published: April 2008

Delatour, P., Benoit, E., Gamier, F. & Besse, S. Chirality of the sulphoxide metabolites of fenbendazole and albendazole in sheep. J. vet. Pharmacol. Therap. 13, 361–366.

Two prochiral sulphide drugs, fenbendazole (FBZ) and albendazole (ABZ) were administered orally to sheep. Blood samples were analysed for parent drug and S‐oxidation metabolites and the chirality of the sulphoxide metabolites was determined. The plasma concentrations of the enantiomers of the sulphoxides were never a racemate. On the contrary, the ratios were greater than 1 as soon as the sulphoxide compounds could be detected in plasma. They subsequently increased linearly throughout the time course of the kinetics, reaching the level 86:14 after FBZ and 95:5 after ABZ treatment. The major enantiomer represented 74% and 86% of the total AUC of SO FBZ and SO ABZ, respectively.

P. Delatour, Department of Biochemistry, National School of Veterinary Medicine of Lyon, BP 83, 69280‐Marcy I'Etoile, France.
Bioavailability of ascorbic acid in horses
Authors: SNOW D. H. , FRIGG M.
Published: April 2008

Snow, D.H. & Frigg, M. Bioavailability of ascorbic acid in horses. J. vet. Pharmacol. Therap. 13, 393–403.

The bioavailability of ascorbic acid administered to thoroughbreds by intramuscular injection was investigated. For intramuscular injection two preparations were studied, and the percentage bioavailability up to 24h of 10g of ascorbic acid was 95%±22 in four horses and 60% in two horses with preparations A and B, respectively. Bioavailability at 24h in three horses injected subcutaneously with 10g of preparation B was 82%. Intramuscular injection of both preparations was apparently well tolerated while subcutaneous injection of preparation B (pH 6.0) was associated with marked irritancy. In a cross‐over trial in seven thoroughbreds the effect of 13 or 15 days of oral administration of crystalline ascorbic acid (20g) or ascorbyl palmitate (47g) on plasma ascorbic‐acid concentrations was investigated. Marked differences occurred between individuals. There was a greater increase in plasma ascorbic‐acid concentration with ascorbyl palmitate compared to ascorbic acid at 6 and 24h following administration. In two horses there was no increase in plasma ascorbic acid at 6h following either oral preparation. The finding of lowered plasma ascorbic‐acid concentrations following a period of supplementation warrants further investigation to assess its significance.

D. H. Snow, 18 Rowe Street, Roseville Chase, 2069 NSW, Australia.
Allometric analysis of doxycycline pharmacokinetic parameters
Authors: RIOND J.‐L. , RIVIERE J. E.
Published: April 2008

Riond, J.‐L. & Riviere, J.E. Allometric analysis of doxycycline pharmacokinetic parameters.J. vet. Pharmacol. Therap.13, 404–407.

Doxycycline serum concentration‐time profiles and elimination half‐lives in several species were evaluated by allometric techniques. Doxycycline elimination half‐life increased with body weight. Interspecies scaling of total or free doxycycline serum concentration‐time profiles was possible by use of Dedrick plots with the exception of doxycycline total concentrations in cats. The observed difference in cats was attributed to more extensive binding to plasma proteins.

Dr Jean‐Luc Riond, Pathophysiologisches Jnstitut, Universität Bern, Murtenstrasse 35, CH‐3010 Bern, Switzerland.
Pharmacokinetics and bioavailability of ticarcillin and clavulanate in foals after intravenous and intramuscular administration
Authors: WILSON W. D. , SPENSLEY M. S. , BAGGOT J. D. , HIETALA S. K. , PRYOR P.
Published: April 2008

The pharmacokinetics and bioavailability of ticarcillin and clavulanate were determined after intravenous (i.v.) or intramuscular (i.m.) administration of ticarcillin disodium (50 mg/kg) combined with clavulanate potassium (1.67 mg/kg) to groups of healthy foals at 3 days and 28 days of age. After i.v. administration of the combination to five foals, the disposition kinetics of ticarcillin and clavulanate were best described using a two‐compartment open model. Mean plasma elimination‐rate constant (ß) and clearance (Clb) for ticarcillin were significantly less (P < 0.01), and volume of distribution at steady state (Vd(ss)) was significantly larger (P < 0.05), in the foals at 3 days compared with 28 days of age. This indicated that renal excretion mechanisms were immature and ticarcillin was more widely distributed in 3‐day‐old foals. The mean elimination rate constant for clavulanate was significantly less (P < 0.01) at 3 days than at 28 days of age. Values of the major kinetic terms describing the disposition of ticarcillin after i.m. administration to five 3‐day‐old foals were not significantly different from values of these parameters in the same foals at 28 days of age. After i.m. administration of the drug combination, plasma clavulanate concentrations peaked significantly later (P<0.01), and the elimination‐rate constant (kd) for clavulanate was significantly less (P < 0.01), in 3‐day‐old foals than in 28‐day‐old foals. The bioavailabilities of ticarcillin and clavulanate after i.m. administration in 3‐day‐old foals were 100% and 88.3%, respectively, and in 28‐day‐old foals were 100% and 27.4%, respectively.

Mean plasma ticarcillin concentrations exceeded 16 (μg/ml for a longer period after i.m. administration of the drug combination than after i.v. administration to foals of both age groups. By virtue of the frequency of administration required and the painful response elicited by i.m. injection, it is recommended that when the combination of ticarcillin disodium (50 mg/kg) and clavulanate potassium (1.67 mg/kg) is used in foals to treat infections caused by susceptible organisms (MIC ≤16 μ/ml), it should be administered i.v. four times daily.
Pharmacokinetics of gentamicin after intravenous and subcutaneous injection in obese cats
Authors: WRIGHT L. C. , HORTON C. R. , JERNIGAN A. D. , WILSON R. C. , CLARK C. H.
Published: April 2008

Six adult domestic shorthair obese cats were given 3‐mg/kg gentamicin sulfate by rapid i.v. and by s.c. injection in a cross‐over design. The plasma concentration time data were analyzed using statistical moment theory with no assumption of a specific compartmental model. Means ± SD for the half‐life, which was calculated from the terminal slope of the log concentration‐time curve, were 1.37 ± 0.24 and 1.24 ± 0.22 h following i.v. and s.c. injection, respectively. The apparent volume of distribution at steady state was 118.55 ± 19.83 ml/kg, and total body clearance was 1.07 ± 0.25 ml/kg/min. Bioavailability was 83.58 ± 14.83% after s.c. administration. The calculated s.c. dose in obese cats to produce an average steady‐state concentration of 4 μg/ml is 2.5 mg/kg every 8 h compared to 3 mg/kg in normal‐weight cats.
An evaluation of the information given on veterinary prescriptions in Norway. Compliance with the legal regulations
Authors: GRAVE K. , BANGEN M. , ENGELSTAD M. , SøLI N. E.
Published: April 2008

Compliance with Norwegian legal regulations for veterinary prescriptions was investigated and evaluated. The study was designed as a cross‐sectional prescription survey, and the prescriptions were recorded in Dbase III. Of the 6505 written and telephone prescriptions collected only about one in five fulfilled the legal requirements, namely, giving information about the animal species the drug was intended for, indication for the prescribed drug and directions for use. On average 86% contained information about the animal species, while 26% and 80%, respectively, contained information about the indication for the prescribed drug and directions for use. The number of prescriptions on which indication and directions for use were given, was significantly higher for written prescriptions than for telephone prescriptions, and for prescriptions of human preparations compared with prescriptions of veterinary preparations. For pets, the number of prescriptions containing directions for use was significantly higher than for production animals. The proportion of prescriptions for pets giving a statement of the indication was not significantly different from prescriptions for production animals.
Intramuscular and oral disposition of enrofloxacin in African grey parrots following single and multiple doses
Authors: FLAMMER K. , AUCOIN D. P. , WHITT D. A.
Published: April 2008

The intramuscular (IM) and oral (PO) disposition of enrofloxacin, a new fluoroquinolone antimicrobial drug, were evaluated in African grey parrots. Peak enrofloxacin concentration, mean (± SEM), at 1h following a 15‐mg/kg IM dose was 3.87 (± 0.27) μg/ml and declined with a mean residence time of 3.05 h. Peak enrofloxacin plasma concentrations at 2 to 4h following oral doses of 3, 15, and 30 mg/kg were 0.31 (± 0.11), 1.12 (± 0.11), and 1.69 (± 0.23) μg/ml, respectively, and declined with a mean residence time of 3.44‐5.28 h. The relative bioavailability of the 15‐mg/kg oral dose was 48%. An equipotent metabolite, ciprofloxacin, was detected in plasma at concentrations ranging from 3 to 78% of those of enrofloxacin. Enrofloxacin concentrations and area under the curve were significantly lower, the mean residence time significantly shorter and the ciprofloxacin/enrofloxacin ratios higher, following 10 days of oral treatment at 30 mg/kg every 12 h. Following 10 days of treatment, no significant biochemical changes were noted; however, polydipsia and polyuria occurred in treated birds, but resolved quickly upon discontinuation of enrofloxacin administration. These studies indicate that a rational starting dose for enrofloxacin in psittacines (7.5‐30 mg/kg BID) should be higher than those in other domestic animals.
The effect of co‐administration of parbendazole on the disposition of oxfendazole in sheep
Authors: HENNESSY D. R. , STEEL J. W. , PRICHARD R. K. , LACEY E.
Published: April 2008

The effect of intraruminal administration of parbendazole (PBZ) on the flow rate of bile and the pharmacokinetic behaviour of oxfendazole (OFZ) was examined in sheep. PBZ given at 18, 9 and 4.5 mg/kg resulted in a dose‐related reduction in bile flow rate which was also inversely related to changing concentration of PBZ and its metabolites in plasma.

Co‐administration of 4.5 mg PBZ/kg with 5.0 mg [14C]‐OFZ/kg resulted in increased concentrations of fenbendazole (FBZ), OFZ and fenbendazole sulphone (FBZ‐SO2) in plasma, although total 14C levels remained unchanged compared with that observed when OFZ alone was administered. The presence of PBZ also reduced biliary secretion of 14C by 22% and ‐altered the relative proportions of OFZ metabolites in bile during the 72‐h experimental period. The ratio of 4′‐hydroxy‐OFZ (OH‐OFZ) to 4′‐hydroxy‐FBZ (OH‐FBZ) changed from 7:1 in the absence of PBZ to approximately 1:1 in the presence of PBZ. There was no change in urinary or faecal 14C excretion. The PBZ‐induced effects were temporary since the pharmacokinetic behaviour of OFZ given alone two weeks before was similar to that given two weeks after PBZ co‐administration.

It is suggested that the presence of PBZ temporarily slowed hepatic metabolism and biliary secretion of OFZ metabolites butconcomitantly increased extra‐biliary transfer of OFZ andor its metabolites from plasma into the gastrointestinal tract. Elevated exposure of parasites in the gut wall to plasmaderived drug, coupled with higher concentrations of anthelmintically active OH‐FBZ secreted in bile, could contribute to the previously reported increased efficacy of OFZ when co‐administered with PBZ.
Pharmacokinetics of enrofloxacin in fingerling rainbow trout (Oncorhynchus mykiss)
Authors: BOWSER P. R. , WOOSTER G. A. , STLEGER J. , BABISH J. G.
Published: April 2008

The pharmacokinetics of intravenously and orally administered enrofloxacin was determined in fingerling rainbow trout (Oncorhymhur mykiss). Doses of 5 or 10 mg enrofloxacin /kg body weight were administered intravenously to 26 fish for each dose and blood was sampled over a 60‐h period at 15°C. Two groups of fish were treated orally with 5, 10, or 50 mg/kg (80 fish/dose at each temperature) and held at 15°C or 10°C during the 60‐h sampling period. Following intravenous administration, the serum concentration—time data of enrofloxacin in rainbow trout were best described by a two‐compartment open model for both doses of 5 and 10 mg enrofloxacin/kg. The hybrid rate constants a and β did not differ between doses. The distributional phase was rapid with a half‐life of 6–7 min for both doses. Overall half‐lives of elimination were 24.4 h (95% CI = 20.2–30.8) and 30.4 h (24.241.0), respectively, for the 5– and 10‐mg/ kg doses. A large Vd(area) was observed following dosing of either 5 or 10 mg enrofloxacin/kg,: 3.22 and 2.56 l/kg, respectively. Whole body clearance for 5 mg/kg was 92 ml/h.kg and 58 ml/h‐kg at the 10‐mg/kg dose. Following oral administration, the serum concentration—time data for enrofloxacin were best described as a one‐compartment open model with first‐order absorption and elimination. Apparent Ka over all doses at 10°C averaged 62% less than apparent Ka, at 15°C. Estimates of the apparent t(1/2)e over both temperatures ranged from 29.5 h (18.4–73.4) to 56.3 h (38.3–106.6). Bioavailability averaged 42% over all doses at 15°C and was decreased to an average of 25% at 10°C. Peak serum concentrations appeared between 6 and 8 h following dosing. A dose of 5 mg/kg/ day was estimated to provide average steady‐state serum concentrations at 10°C that are approximately 4.5 times the highest reported MIC values for Streptococcus spp., the fish pathogen least sensitive to enrofloxacin. Owing to the long apparent half‐life of elimination of enrofloxacin in fingerling trout, it would take approximately 5 to 9 days to achieve these predicted steady‐state serum concentrations; this estimate is important when considering the duration of therapy in clinical trials.
Effects of metoclopramide and quipazine on serum molactin concentrations in steers
Authors: LIPHAM L. B. , THOMPSON F. N. , STUEDEMANN J. A.
Published: April 2008

The dopamine antagonist metoclopramide monohydrochloride (MC) and the serotonin agonist quipazine maleate (Q were administered to steers by both the oral and intravenous (i.v.) routes. Dose‐response studies were designed to determine the effects of these drugs on serum prolactin (PRL) concentrations. Parameters subjected to analysis included maximal serum PRL concentrations within 1 h and the areas under the PRL response curves over time. At 1,4, and 8 mg/kg i.v., and at 15, 30, 45, and 60 mg/kg orally, MC increased (P < 0.05) serum PRL concentrations (difference between maximal and basal serum PRL concentrations) and increased (P < 0.05) areas under the PRL response curves except for 1.0 mg/kg i.v. Doses of MC greater than 60 mg/kg and Q at all dosage rates were considered toxic. These studies determined a dose‐response to MC in terms of serum PRL concentration and indicate that MC is well tolerated and effective for elevating serum PRL concentrations in steers. Furthermore, 4 mg/kg i.v. and 15 mg/kg orally could be considered the preferred dosage rates due to a plateau in the response above those rates.
The pharmacokinetics and pharmacodynamics of furosernide in the anaesthetized dog
Authors: HIRAI J. , MIYAZAKI H. , TANEIKE T.
Published: April 2008

The correlation between pharmacokinetics and dynamics of furosemide was investigated in anaesthetized dogs. After intravenous administration (i.v.) of furosemide (5 mg/kg), the plasma concentration declined rapidly with biexpo‐nential decay. The half‐life (t1/2β) of the late phase of elimination was 0.931 ± 0.187 h and the apparent volume of distribution at steady state was 0.25 ± 0.043 1/Kg. The total clearance (ClIOL) was 0.435 ± 0.031 1/h/kg, in which the renal clearance was 0.260 ± 0.020 (about 60% of CltOt). The change in rate of urinary excretion of furosemide was similar to the plasma concentration decay curve. The diuretic effect of furosemide was accompanied by an extreme increase in the excretion rate of sodium and chloride, but not potassium. The relationships between;he diuretic response and the plasma concentration or the urinary excretion rate of furosemide was depicted by sigmoidal dose‐response curves in both cases. The half‐maximum effect was obtained at 1.5 μg/ml of plasma concentration or at 80 μg/min of excretion rate of furosernide.
Synovial and serum levels of triamcinolone following intra‐articular administration of triamcinolone acetonide in the horse*
Authors: CHEN C. L. , SAILOR J. A. , COLLIER J. , WIEGAND J.
Published: April 2008

Seven mature thoroughbred horses, weighing between 400 and 541 kg, were each injected intra‐articularly into three joints with 6 mg/joint of triamcinolone acetonide (Vetalog). The fourth joint, the control, was injected with saline. Synovial fluid was taken from all four legs of the horses on days 1, 2, 3, 4, 5, 6, 7, 8, 11, and 15 following the injections. Triamcinolone acetonide was assayed by a radioimmunoassay. Blood was collected at 1, 2, 4, 6, 12 h and on days 1, 2, 3, 4, 5, 6, 7, 8, 11, and 15 following injection of either triamcinolone or saline. Both cortisol and triamcinolone were assayed. The results show that the synovial fluid level of triamcinolone was 7.5 μg/ml 1 day following treatment and decreased to 10 ng/ml by the 4th day. These low levels were maintained for approximately 14 days. By the 15th day, the triamcinolone was below a detectable level. Serum levels of triamcinolone increased to 3 ng/ml within 1 h and further increased to a peak of 4.3 ng/ml at 4th h. The level then decreased to 2 ng/ml at 24 h and to nearly an undetectable level in 48 h. The mean level of serum cortisol, on the other hand, gradually decreased as the serum level of triamcinolone increased. As the serum level of triamcinolone reached an undetectable level on the 2nd day, the serum cortisol level gradually increased and returned to the pre‐administration level by the 5th day. These results showed that the intra‐articular administration of triarncinolone maintained triamcinolone in the synovial fluid for 4–14 days and that the triamcinolone reached the blood within 1 h. The serum level of triamcinolone was maintained for 2 days and resulted in the inhibition of adrenal function for 4 days.
Pharmacokinetics and preliminary observations of behavioral changes following administration of midazolam to dogs
Authors: COURT M. H. , CREENBLATT D. J.
Published: April 2008

The pharmacokinetics of midazolam were investigated following intravenous and intramuscular administration of 0.5 mg of midazolam hydrochloride/kg of body weight to five healthy mixed‐breed dogs. One dog also received the same dose of midazolam by oral and rectal routes. The disposition of midazolam following intravenous administration was characterized by very rapid and relatively extensive distribution followed by rapid elimination. Mean (± SD) apparent volume of distribution was 3.0 ± 0.9 1/kg, mean elimination half‐life was 77 ± 18 min, and clearance was 27 ± 3 ml/kg/min. Following intramuscular administration, absorption was rapid and complete. A mean peak midazolam concentration of 549 ± 121 ng/ml was reached within 15 min, and systemic availability was over 90% in each dog. Oral administration to one dog resulted in peak midazolam concentrations within 10 min and a systemic availability of 69%. Rectal administration to the same dog yielded very low systemic availability. Midazolam was extensively bound to canine plasma proteins, with the unbound fraction representing less than 4% of the total plasma midazolam concentration. Plasma samples were also assayed for the presence of the major metabolites, 1‐OH and 4‐OH midazolam. Neither metabolite were detected, probably as a result of rapid elimination of these compounds by hepatic glucuronidation. Behavioral responses to administration of midazolam included initial signs of profound weakness, ataxia and transient agitation followed by a period of quiesence. A normal behavior pattern returned within 2 h of midazolam administration.
Beta‐endorphin‐induced inhibition of rumen contractions in sheep. The effect of hypothalamic de‐efferentiation
Authors: KANIA B. F. , VAN MIERT A. S. J. P. A. M.
Published: April 2008

In conscious sheep, beta‐endorphin (1 and 2 μg/kg) administered into the third cerebral ventricle caused psychomotor excitability and a significant inhibition of the frequency of rumen contractions. The amplitude of the first rumen contractions, following immediately after the end of endorphin infusion, and the average amplitude of primary rumen contractions were also inhibited. De‐efferentiation at the level of the hypothalamus prevented both the inhibitory effect of beta‐endorphin on the Frequency of rumen contractions and the drug‐induced psychomotor excitability. However, de‐efferentiation did not prevent beta‐endorphin‐induced inhibition of the niean amplitude of rumen contractions. The character of pathohistological changes induced by de‐efferentiation showed descending degenerative changes of the nerve tracts connecting the hypothalamus with the pons and the medulla oblongata. These results, together with previously published evidence, do suggest that de‐efferentiation at the level of the hypothalamus causes degeneration of inhibitory descending opioidnoradrenergic pathways connecting the hypothalanius with the gastric centres in the medulla oblongata.
The postnatal development of drug‐metabolizing enzymes in hepatic, pulmonary and renal tissues of the goat
Authors: ELTOM S. E. , BABISH J. G. , SCHWARK W. S.
Published: April 2008

It is important to study the development of drug biotransformation enzymes, because from a pharmacological and therapeutic point of view these enzymes are responsible for eliminating most drugs. Their concentration at each age is critical when deciding the dose regimen, particularly in the neonates who are deficient or have very low levels of these enzymes. From a toxicological perspective, the role of these enzymes varies, with some of them being directly responsible for activation of certain chemicals to reactive intermediates with deleterious consequences to the animal. The time course of appearance of these enzymes throughout the life of the animal could be depicted from the study of their ontogeny and therefore the prediction of when the animal would be at risk should be possible. Experiments were designed to measure in vitro, the activity of drug‐metabolizing enzymes in liver, lung and kidney of newborn, 1‐week‐, 4‐week and 6‐week‐old and adult goats. The microsomal mono‐oxygenase activities were measured utilizing substrates designed to characterize the development of the cytochrome P450 (P450). For phase II enzymes, the activity of UDP‐glucuronyltransferase towards 1‐naphthol and p‐nitrophenol was measured in addition to the cytosolic glutathione S‐transferase activity towards, 1,2‐dichloro 3‐nitrobenzene. The results indicated that the newborn goat tissues exhibited very low activity of drug‐metabolizing capacity in all pathways studied. These activities increased to the adult values by 6 weeks of age. In general, the development of the mono‐oxygenase activities followed the same pattern as the overall P450. The UDP‐glucuronyltransferase activity towards both substrates was deficient at birth and surged to above adult values by the first week of age. The toxicologic and pharmacologic implications of the development of these enzyme activities are discussed.
Duration of antigen‐induced hyperresponsiveness in horses with allergic respiratory disease and possible links with early airway obstruction
Authors: FAIRBAIRN S. M. , LEES P. , PAGE C. P. , CUNNINGHAM F. M.
Published: April 2008

Fairbairn, S.M., Lees, P., Page, C.P., Cunningham, F.M. Duration of antigen‐induced hyperresponsiveness in horses with allergic respiratory disease and possible links with early airway obstruction. J. vet. Pharmacol. Therap. 16, 469–476.

Antigen‐induced airway hyperresponsiveness in allergic horses has previously been demonstrated when clinical signs of acute airway obstruction were apparent, as a consequence of exposure of animals to hay and straw for variable periods of time, and repeat measurements of hyperresponsiveness have been made no earlier than 1 week after challenge. In the present study airway responsiveness to methacholine has been measured in normal horses and allergic horses in clinical remission before and 24, 48 and 72 h after a hay and straw challenge of fixed, short, duration (7 h). Correlations between early increases in interpleural pressure and hyperresponsiveness have also been investigated. As in other studies, the mean airway responsiveness of groups of normal and allergic horses in clinical remission was not significantly different. The responsiveness to methacholine of allergic, but not normal, horses was increased after antigen challenge and was significantly greater than that of normal horses at 48 and 72 h after challenge (log PD8 cm: ‐0.77 ± 0.28 vs. 0.27 ± 0.14 at 48 h and ‐0.6 ± 0.25 vs. 044 ± 01 at 72 h; P < 0.05). There was also a significant correlation between interpleural presssure at the end of the 7‐h challenge in allergic horses and the increase in responsiveness to methacholine at 24, 48 and 72 h. These results demonstrate that antigen induces an increase in airway responsiveness in allergic horses that persists for up to 3 days and which may be linked to the initial increase in interpleural pressure.
Nicarbazin stimulates intestinal transport of L‐leucine in rabbit
Authors: SORRIBAS V. , ARRUEBO M. P. , NAVARRO H. , ALCALDE A.I.
Published: April 2008

Nicarbazin is an anticoccidial drug used mainly in birds, but also in rabbits. Besides the anticoccidial activity, riicarbazin has shown several other effects such as inhibition of growth and feed efficiency in poultries, and stimulation o f sugar intestinal absorption in rabbits. The present work has been performed in order to check whether nicarbazin also affects L‐leucine intestinal absorption. The results obtained show that nicarbazin decreases L‐leucine accumulation in the jejunal tissue, and increases mucosal to serosal transepithelial fluxes o f this amino acid in a dose‐dependent way, without modifying its diffusion across the intestinal epithelium. The drug stimulates the amino acid uptake in brush‐border and basolateral membrane vesicles, thus suggesting that nicarlxizin increases the absorption of L‐leucine mediated by carriers.
A comparison of the efficacy of danofloxacin and tylosin in the control of Mycoplasma gallisepticum infection in broiler chicks
Authors: JORDAN F. T. W. , HORROCKS B. K. , JONES S. K. , COOPER A. C. , GILES C. J.
Published: April 2008

Groups of chicks were infected with a virulent strain of Mycoplasma gallisepticum (MG) and treated with either danofloxacin or tylosin while one infected group was left untreated and a further group was uninfected and untreated. Control of

clinical signs and mortality was better with danofloxacin than tylosin and there

was significantly (P <0.05)greater weight gain with danofloxacin at 21 days

after infection. However ht necropsy the prevalence of lesions of the airsac walls

was similar in both groups. MG was recovered from fewer live chicks for the first

week following treatment with danofloxacin, but at 2 weeks and at necropsy, at

the termination of the experiment, it was recovered from a similar proportion of

birds in both treated groups. This was reflected also in the serological results at

the end of the trial.
Morphine‐isoflurane interaction in dogs, swine and Rhesus monkeys
Authors: STEFFEY E. P. , BAGGOT J. D. , EISELE J. H. , WILLITS N. , WOLINER M. J. , JARVIS K. A. , ELLIOTT A. R. , TAGAWA M.
Published: April 2008

In monkeys, dogs and swine (six each) we tested the reduction of the isoflurane MAC (minimal alveolar concentration) produced by 2 mg‐kg‐1 morphine intravenously (i‐v.) and the concurrent effect on Pco2 with spontaneous ventilation. MAC fell to a minimum of 55% of control at 53 min in monkeys, 50% at 38 min in dogs and 13% at 33 min in swine. Paco2 rose at constant MAC with morphine to 55–60 mmHg, but did not fall over the next several hours despite the decline of plasma morphine concentration, and the resulting needed rise in isoflurane concentration to keep the anaesthesia depth at 1 MAC. After isoflurane concentration had returned to pre‐morphine control levels, naloxone immediately reduced Paco2 to or below control level. Morphine pharmacokinetics in the three species studied conformed to a two‐compartment model.
Pharmacokinetic and toxicological aspects of the medication of beef‐type calves with an oral formulation of chloramphenicol palmitate
Authors: GASSNER B. , WUETHRICH A.
Published: April 2008

Gassner, B., Wuethrich, A. Pharmacokinetic and toxicological aspects of the medication of beef‐type calves with an oral formulation of chloramphenicolpalmitate.J. vet. Pharmacol. Therap. 17, 279–283.

Chloramphenicol (CAP) plasma levels were determined after oral administration of four doses of CAP palmitate (each dose corresponding to CAP 25 mg/kg/12 h) to four ruminating beef‐type calves. Steady‐state plasma concentrations of CAP were reached after the fourth oral dose and varied between 5 and 6 μg/ml. Half‐life of elimination of CAP was 4.5 h. In addition to CAP, dehdrochloramphenicol (DH‐CAP), a metabolite of chloramphenicol, was detected in plasma at concentrations between 3 and 7 ng/ml. DH‐CAP is known to be produced from CAP by intestinal bacteria. This is significant since DH‐CAP is suspected of being involved in the development of fatal aplastic anaemia, which occurs in man after exposure to CAP. Thus, it cannot be excluded that DH‐CAP residues may occur in edible tissues. A risk arising from DH‐CAP can neither be excluded for the animals being treated with CAP nor for consumers.
The sulfonamide‐diaminopyrimidine story*
Authors: MIERT A. S. J. P. A. M. VAN
Published: April 2008

This paper is devoted to chemotherapy in the sense that Paul Ehrlich (Nobel Prize winner in 1908) coined the word: to describe the cure of infectious diseases by chemical agents without injury to the organism infected. This approach, essentially that of selective toxicity, is applicable to the investigations performed by Gerhard Domagk (Nobel Prize winner in 1939), which resulted in the development of Prontosil rubrum. This agent was activein vivobut notin vitro.Trefouel supposed that thein vivoaction was due to a metabolite of the drug (sulfanilamide), a hypothesis later proved by Fuller in 193 7. Sulfanilamide was a simple agent, easy to manufacture and free of patent rights. Thus, more than 5400 derivatives were synthesized and studied in the decades that followed. Research on the side‐effects of sulfonamides resulted in the development of diuretics and antidiabetogenic agents. The resurgence of interest in sulfonamides in following years has been associated with the development of diaminopyrimidines by Hitchings (Nobel Prize winner in 1988). It soon became evident that combinations of these drugs produced potent synergistic effects. Trimethoprim, a potent antibacterial agent of this series, was selected for combining with sulfonamides such as sulfadiazine. This line is still continued and even recently new diaminopyrimidine derivatives such as aditoprim and baquiloprim have been synthesized having superior properties in farm animal species. Thus, even nowadays the principles of Ehrlich continue to have a major impact on the development of new veterinary drugs.
The effects of aspirin and paracetamol on the aggregation of equine blood platelets
Authors: HEATH M. F. , EVANS R. J. , POOLE A W , HAYES L. J. , EVOY R T Mc , LITTER R. M.
Published: April 2008

The responses of equine blood platelets in citrated platelet‐rich plasma to arachidonic acid, U44069 (prostaglandin endoperoxide analogue), adenosine 5′‐diphosphate, platelet‐activating factor or collagen were investigated by turbidimetric aggregometry. Pre‐treatment of the platelets with aspirin (1 mmol/1) or Paracetamo1 d‐3 mmol/1) abolished shape change and aggregation in response to arachidonic acid; decreased the rate of aggregation in response to collagen, with no separate effect on shape change; had no marked effect on aggregation caused by the other agonists; but in no case transformed irreversible aggregation to reversible aggregation. We conclude that thromboxane A2 generation is of minor importance in the aggregation of equine platelets, and in particular that thromboxane A2 is not a significant mediator of irreversible aggregation.
Percutaneous absorption of topical parathion through porcine skin: in vitro studies on the effect of environmental perturbations
Authors: CHANG S.‐K. , BROWNIE C. , RIVIERE J. E.
Published: April 2008

Topical use of pesticides in domestic animals such as swine is a common practice: however, the effect of environmental factors on the extent of absorption has not received attention. Since no single factor can exert its effects alone in the natural environment, the interaction of environmental factors on the percutaneous absorption of pesticides must be understood before potential toxicity of dermal absorption of pesticides can be effectively estimated. In the present studies, the effects of air temperature (Ta), perfusate temperature (Tp), perfusate flow (F) and relative humidity (%RH) on absorption of parathion were studied in vitro in porcine skin. Parathion absorption was determined by measuring radiolabel appearing in the perfusate over time. Three main environmental parameters were found to have a significant effect on parathion penetration. Increasing T, from 37'C to 42oC %RH from 60% to 90% or F from 4 ml/h to 8 ml/h each produced a significant increase in penetration. The following significantly positive two‐way interactions among test parameters were seen: T, x F and %RH x F at the 4 μg dose, % RH × F at the 40 μg dose and T, ×%RH, T, x F and %RH × F at the 400 μg dose. There were no three‐way interactions at any of the three doses tested. These results suggest that the factors tested are not independent variables and must be considered interactive when used in assessing pesticide percutaneous absorption.
Pharmacokinetic behaviour of fenbendazole in buffalo and cattle
Authors: SANYAL P. K.
Published: April 2008

Sanyal, P.K. Pharmacokinetic behaviour of fenbendazole in buffalo and cattle. J. vet. Pharmacol. Therap. 17, 1–4.

Concentrations of fenbendazole and of drug metabolites in plasma were measured in buffalo and cross‐bred cattle after single intraruminal administration at two different doses. Plasma concentrations of the parent compound fenbendazole and the two metabolites, viz. oxfendazole and fenbendazole sulfone, were much lower in buffalo compared with cattle, at a dose of 7.5 mg/kg body weight as indicated by lower area under concentration curve and concentration maximum. At a dose of 15 mg/kg body weight there were corresponding increases in plasma metabolite concentrations in cattle. However, buffaloes did not show a similar corresponding increase.
A field evaluation of the efficacy of tolfenamic acid and oxytetracycline in the treatment of bovine respiratory disease
Authors: DELEFORGE J. , THOMAS E. , DAVOT J. L. , BOISRAME B.
Published: April 2008

Deleforge, J., Thomas, E., Davot, J.L., Boisrame, B. A field evaluation of the efficacy of tolfenamic acid and oxytetracycline in the treatment of bovine respiratory disease. J. vet. Pharmacol Therap. 17,43–47.

In ablinded multicentre trial 313 cattle showing clinical signs of respiratory disease were allocated randomly into three groups, treated intramuscularly with a long‐acting oxytetracycline formulation at a dose rate of 20 mg/kg bodyweight in combination with vehicle alone (placebo) or with tolfenamic acid at 2mg/kg, bodyweight once or on two occasions with a 48‐h interdosing interval. The clinical status of the animals was monitored for 5 days using a specific scoring system and weight gain was calculated between day 0 and day 21. Relapses were monitored from day 5 until day 21. When oxytetracycline was combined with two injections of tolfenamic acid, there was a significant (P < 0.04) improvement in the clinical resolution. This regimen also produced non‐significant improvements in cure rate, reduced frequency of relapses and improved weight gain.
Pharmacokinetics of ciprofloxacin in ponies
Authors: DOWLING P.M. , WILSON R.C. , TYLER J.W. , DURAN S.H.
Published: April 2008

The pharmacokinetics of ciprofloxacin was investigated in healthy, mature ponies. Ciprofloxacin was administered intravenously to six ponies at a dose of 5 mg per kg body weight. Seven days later, ciprofloxacin was administered orally to each pony at the same dose. Intravenous ciprofloxacin concentration vs. time data best fit a two‐compartment open model with first‐order elimination from the central compartment. Mean plasma half‐life, based on the terminal phase, was 15 7.8 9 min (harmonic mean). Total body clearance of ciprofloxacin was 18.12 ± 3.99 mL/min/kg. Volume of distribution at steady‐state was 3.45 ± 0.72 L/kg. From the pharmacokinetic data and reported minimum inhibitory concentrations for equine gram‐negative pathogens, the appropriate dosage of ciprofloxacin was determined to be 5.32 mg per kg body weight at 12 h intervals. Bioavailability of oral ciprofloxacin in ponies was 6.8 ± 5.33%. Owing to the poor bioavailability, a dosage regimen could not be proposed for oral ciprofloxacin administration in horses. Ciprofloxacin concentrations were determined in tissues and body fluids at 1, 2 and 4 h after intravenous administration. At all times, tissue concentrations exceeded plasma concentrations of ciprofloxacin. Highest concentrations were achieved in kidneys and urine. Potentially therapeutic concentrations were obtained in cerebrospinal and joint fluid, but low concentrations were achieved in aqueous humour.
Comparative plasma disposition kinetics of albendazole, fenbendazole, oxfendazole and their metabolites in adult sheep
Authors: LANUSSE C.E. , GASCON L.H. , PRICHARD R.K.
Published: April 2008

The comparative plasma disposition kinetics of albendazole (ABZ), fenbendazole (FBZ) and oxfendazole (OFZ) following their oral administration (5 mg/kg) to adult sheep was characterized. Jugular blood samples were taken serially over a 144 h period and plasma was analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) (ABZ treatment), and for FBZ, OFZ and FBZ sulphone (FBZSO2) (FBZ and OFZ treatments). While the ABZ parent drug was not detected at any time post‐treatment, ABZSO and ABZSO2 were the analytes recovered in plasma, after oral administration of ABZ to sheep. The active ABZSO metabolite was the main analyte recovered in plasma (between 0.25 and 60h post‐treatment), accounting for 71 % of the total AUC. FBZ, OFZ and FBZSO2 were the analytes detected in plasma following the oral administration of both FBZ and OFZ to sheep. Low concentrations of FBZ were found in plasma between 4 (FBZ treatment) or 8 h (OFZ treatment) and 72 h post‐treatment. The plasma profile of each analyte followed a similar pattern after both treatments; OFZ being the main component detected in plasma. The plasma disposition of ABZ metabolites was markedly different to that of FBZ derivatives. ABZSO exhibited faster absorption and a higher Cmax than OFZ (both treatments). Furthermore, while ABZSO declined relatively rapidly in plasma reaching non‐detectable concentrations at 60 h post‐ABZ administration, OFZ was found in plasma for up to 120 (FBZ treatment) and 144 h (OFZ treatment). The extended detection of OFZ in plasma in both treatments correlated with the prolonged t1/2β (18 h) and mean residence time (MRT) (30–33 h) obtained for this metabolite compared to those of ABZSO (t1/2β= (7.0 h); MRT= 12.5 h). These differences between the disposition of ABZ and FBZ metabolites may account for differences in their patterns of efficacy and tissue residues.
Design of field trials for the evaluation of antibacterial products for therapy of bovine clinical mastitis
Authors: SCHUKKEN Y.H. , DELUYKER H.A.
Published: April 2008

In this paper, the design and statistical analysis of field trials for the evaluation of the efficacy of clinical mastitis therapeutics is covered. First, general issues underlying the design of clinical trials are reviewed. These include bias and confounding; randomization and blocking; and study objectives and choice of the corresponding hypothesis. Specific issues in the design of clinical mastitis trials are also discussed. Selection of subjects is discussed with regard to choice of experimental units, identification of reference population and study population, inclusion and exclusion criteria, and sample size calculation. Next, a section on treatment administration and evaluation of cure reviews treatment, blinding, choice of response measure, as well as compliance, withdrawal, and early termination. The statistical analysis section addresses possible statistical models, treatment of confounding, and fixed vs. random effects. In conclusion, well‐conducted clinical mastitis trials represent an invaluable, albeit difficult and expensive, effort to evaluate efficacy and tolerance under usual circumstances of use.
Tilmicosin antibacterial activity and pharmacokinetics in cows
Authors: ZIV G. , SHBM‐TOV M. , GLICKMAN A. , WINKLER M. , SARAN A.
Published: April 2008

The minimal inhibitory concentration (MIC) of tilmicosin for 90% of 112 Staphylococcus aureus isolates from the bovine udder was 0.78 μg/mL and 149 of 164 (90.8%) other gram‐positive udder pathogens were inhibited by tilmicosin concentrations < 3.12 μg/mL. The MIC of the drug for 19 of 22 S. aureus isolates was < 0.78 μg/mL when the test was conducted using Mueller‐Hinton (MH) agar or MH agar containing 7.5% skimmed milk. Acute cardiac toxicity followed intravenous (i.v.) injection of the drug at 10 mg/kg to 3 cows, but animals appeared clinically normal within 30 min after treatment. The pharmacokinetics of i.v.‐administered tilmicosin is typical for the macrolide class of antibiotics, i.e. low serum drug concentrations and a large volume of distribution (> 2.0 L/kg). The elimination half‐life (t1/2β values for 3 cows were 46.4. 56.0 and 72.8 min. The drug was administered subcutaneously (s.c.) to 5 cows at 10 mg/kg; the elimination half‐life (t1/2el) was 4.18 ± 0.55 h and the mean s.c. bioavailability was 22%. Rapid and extensive penetration of tilmicosin from blood into milk, and slow elimination from the milk were among the characteristic kinetic features of the drug after i.v. and s.c. administration. Tilmicosin was injected s.c. at 10 mg/kg once to 9 cows after the last milking of lactation; dry udder secretion samples were collected daily for 11 consecutive days and assayed microbiologically. Concentrations of drug > 0.78 μg/mL were found in the secretion for 8–9 days after dosing. Systemic side‐effects were not observed after s.c. drug administration.
Gentamicin pharmacokinetics in newborn and 42‐day‐old male piglets
Authors: GIROUX D. , SIROIS G. , MARTINEAU G.‐P.
Published: April 2008

The pharmacokinetics of gentamicin was investigated in six newborn male piglets, aged from 4 to 12 h at the time of administration of the drug, and six 42‐day‐old castrated male piglets, that had been weaned for 2 weeks following a single intravenous bolus of 5 mg/kg. Gentamicin was measured in serum and in urine by a fluorescence polarization immunoassay. The serum concentrationtime data were best described by a three‐compartment open model. A rapid initial distribution phase (± phase) was observed in every animal. The serum β half‐life (t1/2β) was significantly longer in the newborn piglets (mean ± SEM) (5.19 ± 0.30 h) than in the older group (3.50 ± 0.23 h) (P < 0.05). Mean residence time was similarly longer in younger piglets (6.62 ± 0.57 h) than in older animals (2.86 ± 0.11 h) (P < 0.05). The steady‐state volume of distribution (Vills was significantly larger for younger pigs (0.785 ± 0.036 L/kg) than in elder pigs (0.474 ± 0.029 L/kg) (P < 0.05). Urinary γ half‐life (t1/27u) was 72.66 ± 10.78 h in the newborn piglets and 69.20 ± 14.77 h in the 42‐day‐old animals. A urinary δ phase was observed in three of the 42‐day‐old piglets and gave a mean (t1/2δu of 232.01 ± 14.55 h. Percentages of urinary recovery of the administered dose after 144 h were 94.18 ± 1.01 and 94.04 ± 1.12 in the newborn and 42‐day‐old animals, respectively. Serum gentamicin clearance was significantly lower in younger animals (0.121 ± 0.007 L/h±kg) than in the 42‐day‐old group (0.166 ± 0.010 L/h·kg). It is suggested that in the newborn piglets, the increase of Vd(ss) could be explained by a higher proportion of extracellular water while the lower clearance could be attributed to a reduced glomerular filtration capacity. Gentamicin dosage requirement in the newborn piglets would therefore have to be adjusted, in order to take into consideration the observed differences in the mean values of these latter pharmacokinetic parameters.
Effects of age on the pharmacokinetics of single dose ceftiofur sodium administered intramuscularly or intravenously to cattle
Authors: BROWN S. A. , CHESTER S. T. , ROBB E. J.
Published: April 2008

The effects of maturation on the intravenous (IV) and intramuscular (IM) pharmacokinetics of ceftiofur sodium following a dose of 2.2 mg ceftiofur equivalents/kg body weight were evaluated in 16 one‐day‐old Holstein bull calves (33‐53 kg body weight initially; Group 1) and 14 six‐month‐old Holstein steers (217‐276 kg body weight initially; Group 2). Group 1 calves were fed unmedicated milk replacer until 30 days of age and were then converted to the same roughage/concentrate diet as Group 2. Groups 1‐IV and 2‐IV received ceftiofur sodium IV, and Groups 1‐IM and 2‐IM received ceftiofur sodium IM. Group 1 calves were dosed at 7 days of age and at 1 and 3 months of age; group 2 calves were dosed at 6 and 9 months of age. Blood samples were obtained serially from each calf, and plasma samples were analysed using an HPLC assay that converts ceftiofur and all desfuroylceftiofur metabolites to desfuroylceftiofur acetamide. Cmax values were similar in all calves, and were no higher in younger calves than in older calves. Plasma concentrations remained above 0.150 μg ceftiofur free acid equivalents/mL for 72 h in 7‐day‐old calves, but were less than 0.150 μg/mL within 48 h following IV or IM injection for 6‐ and 9‐month‐old calves. Intramuscular bioavailability, assessed by comparing the model‐derived area under the curve (AUCmod) from IM and IV injection at each age, appeared to be complete. After IV administration, the AUCmod in 7‐day‐old and 1‐month‐old calves (126.92±21.1 μg‐h/mL and 135.0±21.6 μg.h/mL, respectively) was significantly larger than in 3‐, 6‐ and 9‐month‐old calves (74.0±10.7 μg.h/mL, 61.0±17.7 μg.h/mL and 68.5±12.8 μg.h/mL, respectively; P< 0.0001). The Vd(ss) decreased linearly within the first 3 months of life in cattle (0.345±0.0616 L/kg, 0.335±0.919 L/kg and 0.284±0.0490 L/kg, respectively; P= 0.031), indicative of the decreasing extracellular fluid volume in maturing cattle. The Clb was significantly smaller in 7‐day‐old and 1‐month‐old calves (0.0178±0.00325 L/h.kg and 0.0167±0.00310 L/h.kg, respectively) than in 3‐, 6‐ and 9‐month‐old calves (0.0303±0.0046 L/h.kg, 0.0398±0.0149 L/h.kg and 0.0330±0.00552 L/h.kg, respectively; P≦0.001). This observation may be indicative of maturation of the metabolism and/or excretion processes for ceftiofur and desfuroylceftiofur metabolites. The approved dosage regimens for ceftiofur sodium of 1.1‐2.2 mg/kg administered once daily for up to 5 consecutive days will provide plasma concentrations above the MIC for bovine respiratory disease pathogens for a longer period of time in neonatal calves than in older calves. Peak plasma concentrations of ceftiofur and desfuroylceftiofur metabolites were no higher in neonatal calves than in more mature cattle, highly suggestive that peak tissue concentrations would be no higher in neonatal calves than in more mature cattle.