bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical pharmacokinetics of parenterally administered danofloxacin in cattle
Authors: GILES C.J. , MAGONIGLE R. A. , GRIMSHAW W. T. R. , TANNER A. C. , RISK J. E. , LYNCH M.J. , RICE J. R.
Published: April 2008

Danofloxacin is a new fluoroquinolone antibacterial, developed specifically for veterinary use. Its in vitro activity and pharmacokinetic properties have been investigated to assess its potential for use in the therapy of respiratory disease in cattle. The minimum inhibitory concentration of danofloxacin against 90%(MIC90) of contemporary European and North American field isolates of Pasteurella haemolytica, Pasteurella multocida and Haemophilus somnus, the most important bacterial respiratory pathogens of cattle, was 0.125μg/ml. The plasma and lung kinetics of danofloxacin following parenteral administration of 1.25mg/kg were evaluated in two studies. Danofloxacin was rapidly absorbed following intramuscular and subcutaneous injection and bioavailability was virtually complete (101% and 94% respectively). Plasma concentration profiles of danofloxacin were similar for intramuscular and subcutaneous routes with no significant differences in the area under the plasma concentration‐time curves (AUC) following one, three or five consecutive daily doses, although slightly higher peak plasma concentrations were achieved by the intramuscular route. Following intramuscular administration, the mean peak lung concentration of danofloxacin was 4.1 times greater than that of plasma. Similarly, the AUC for lung tissue was 3.7 times greater than that for plasma. These data indicate that danofloxacin should be particularly appropriate for the therapy of bacterial respiratory disease in cattle.
Comparative pharmacokinetics of amoxicillin administered intravenously to sheep and goats
Authors: CRAIGMILL A. L. , PASS M. A. , WETZLICH S.
Published: April 2008

The pharmacokinetic behavior of sodium amoxicillin was studied after intravenous administration to six sheep and five goats to determine if there are species differences in disposition. The plasma drug concentrations vs. time following intravenous administration of 10 mg/kg were best described by the biexponential equations Cp= 42.9e‐0.077.t+ 3.68e‐0.0134‐t for goats, and Cp= 53.5e‐0.06‐t+ 1.69e‐0.015‐t for sheep. The terminal disposition half‐lives for sheep and goats were 46.3 and 66.9 min respectively and were not significantly different. Amoxicillin clearance for sheep and goats were 10.1 and 11.4 ml/min.kg respectively. There were no significant differences between any of the pharmacokinetic parameters measured in sheep and goats.
Rifampin disposition in the horse: effects of age and method of oral administration
Authors: BURROWS G. E. , MACALLISTER C. G. , EWING P. , STAIR E. , TRIPP P. W.
Published: April 2008

The effects of time and method of administration of rifampin with respect to feeding were evaluated in five mature horses. There was a significant (P ≤ 0.05) delay in time of maximum serum concentration and an apparent but not significant decrease in oral absorption when rifampin was given as a top dressing on grain as compared with administration in corn syrup 2 h before or 2 h after feeding. Although there were no differences between administration before or after feeding, administration 2 h prior to feeding was selected as the method of choice for future experiments. The effects of age on rifampin disposition were subsequently examined using this method of administration in six, 1‐week old foals. Rifampin (10 mg/kg) was given at increasing age from 1 through 10 weeks and the pharmacokinetic disposition parameters compared. There were significant differences in the slope of the elimination phase (p) and area under the curve (AUC) at 1 week through 6 weeks compared with 10 weeks or with values in the five mature horses.
Comparative pharmacokinetics of the photosensitizer tin‐etiopurpurin in dogs and rats
Authors: FRAZIER D. L. , BARNHILL M. A. , VODINH T. , LEGENDRE A. M. , OVERHOLT B. F.
Published: April 2008

Photodynamic therapy is a promising new treatment for local eradication of cancer. Little work has been done to define the pharmacokinetics of photodynamic drugs or the variability in drug disposition that may occur between different species and pathophysiological states of tissues. Pharmacokinetic studies of tin‐etiopurpurin (SnET2), a lipophilic photosensitizer, were conducted on six Beagle dogs and six Sprague‐Dawley rats. Blood was collected up to 24 h following drug administration for measurement of tin‐etiopurpurin concentration. Dogs and rats were euthanatized 24 h post‐administration and tissues were collected for drug analyses. The plasma drug concentrations were best described by a 2‐comparment model (Ct = Ae‐αt+ Be‐βt). Median distribution and elimination half‐lives were 0.24 and 0.34 h and 10.21 and 5.25 h for dogs and rats, respectively. The apparent volumes of distribution were 4.26 ± 1.75 L/kg for dogs and 1.84 ± 0.36 L/kg for rats. Systemic clearance was 7.56 ± 2.45 ml/kg/min and 6.63 ± 0.91 ml/kg/min for dogs and rats, respectively. Drug was detected in all tissues analyzed 24 h after drug administration. Drug was detected only sporadically in skin and muscle and was generally below the limit of detection of the assay. Where comparisons could be made, concentrations of SnET2 were significantly greater in all tissues except jejunum of rats compared to dogs 24 h after drug administration.
Fever and acute phase response induced in dwarf goats by endotoxin and bovine and human recombinant tumour necrosis factor alpha
Authors: VAN MIEKT A. S. J. P. A. M. , VAN DUIN C. T. M. , WENSING Th.
Published: April 2008

Tumour necrosis Factor (TNF), a polypeptide produced by mononuclear phagocytes, has been implicated as an important mediator of inflammatory processes and of clinical manifestations in acute infectious diseases. To study further the potential role of TNF in infectious diseases, recombinant Escherichia colt (E. coli) derived human (r.HuTNF‐α) and bovine TNF (r.BoTNF‐α) were intravenously (i.v.) administered in dwarf goats. Rectal temperature, heart rate, rumen motility, plasma zinc and iron concentrations, and certain other blood biochemical and haematological values were studied and conipared with the changes seen after E. coli endotoxin (LPS) was administered (dose: 0.1 μg/kg i.v.). Following a single injection of 4 μg/kg of r‐.BoTNF‐α, shivering and biphasic febrile response were observed, accompanied by tachycardia, inhibition of rumen contractions, drop in plasma zinc and iron concentrations, lynipho‐penia, and neutropenia Followed by neutrophilia. The i.v. administration of a single injection of 4 μg/kg r.HuTNF‐α induced shivering and biphasic febrile responses, accompanied by anorexia and a similar drop in plasml trace metal concentrations when compared with r.BoTNF‐α‐treated goats. The TNF‐α‐induced symptoms were essentially the same as those that occurred after LPS administration. However, the time of onset of these changes after the injection of TNF‐a was significantly shorter than after LPS. Moreover, the r.BoTNF‐α induced a longer lasting neutrophilic leucopenia, less neutrophilia, and a more persistent lymphopenia than after LPS injection. Neither r.BoTNF‐α nor LPS caused severe haemo‐concentration. Furthermore, no cross‐tolerance between r.BoTNF‐α and LPS could be demonstrated.

We conclude that both r.BoTNF‐α and r.HuTNF‐α induce many of the physiologic, haemacologic and metabolic changes that characterize the acute phase response to LPS. The overlapping biological activities of r.‐BoTNF‐α, r.HuTNF‐α and LPS in dwarf goats may indicate that both recombinant tumour necrosis factors have some homology with caprine TNF‐α.
In vitro nitroimidazole resistance of Trichomonas gallinae and successful therapy with an increased dosage of ronidazole in racing pigeons (Columba livia domestica)
Authors: FRANSSEN F. F. J. , LUMEIJ J. T.
Published: April 2008

Six out of eight different Trichomonas gallinae strains isolated from racing pigeons proved to be resistant to the nitroimidazole drugs ronidazole, carnidazole and metronidazole. The minimal cytocidal concentration of ronidazole was determined in in vitro experiments. Moreover, a therapeutic close for ronidazole was determined for the control of trichomoniasis in pigeons from which the resistant T. gallinae strains were isolated. It was a 5‐fold increase of the recommended ronidazole dosage which eliminated the infection in affected pigeons.
Effect of dietary nitrogen intake on gentamicin disposition in sheep
Authors: OUKESSOU M. , TOUTAIN P. L.
Published: April 2008

The effect on gentamicin pharmacokinetics of a diet high (HP) (120 g/day) or low (LP) (25 g/day) in digestible proteins was studied in sheep. Gentamicin sulphate (4 mg/kg) and inulin (40 mg/kg) were administered by the intravenous route to six ewes of local Moroccan breed. The serum gentamicin concentrations were consistently higher in ewes that received a LP diet. Clearance was 0.93 ± 0.13 ml/mm/kg in the LP group and 1.64 ± 0.40 ml/mm/kg in the HP group. The volume of distribution at steady state (Vss) was lower in the LP group (11% of body weight) than in the HP group (21.8% of body weight). These diet‐linked variations in pharmacokinetic parameters were also obtained in the disposition of inulin following the intravenous administration of a single dose. This suggests that the protein content of the diet modifies the distribution of body water and kidney function. The therapeutic, toxicological and hygienic implications of these modifications are discussed.
Quantification of percutaneous absorption of metronidazole and levamisole in the fire‐bellied toad (Bombina orientalis)
Authors: MOMBARG M. , CLAESSEN H. , LAMBRECHTS L. , ZWART P.
Published: April 2008

Spot‐on application has proved to be an effective way to reach therapeutic doses of metronidazole and levamisole in fire‐bellied toads. The percutaneous absorption of metronidazole and levamisole was quantified, using an aqueous solution of 1.008 mg/ml of metronidazole and an aqueous solution of 3.767 mg/ ml of levamisole. High Performance Liquid Chromatography (HPLC) analysis of the percutaneous absorption revealed that of the amount applied, 75% of metronidazole and 90% of levarnisole was absorbed. This resulted during 3 days of application in dosages of 23 mg/kg BW of metronidazole and 94 mg/kg BW of levamisole. Of the absorbed substances, 48% of metronidazole and 9% of levamisole were excreted in urine and faeces as unmetabolised substances.
Effect of gonadal hormones on the plasma clearance and metabolite formation of antipyrine in the dwarf goat
Authors: WITKAMP R. F. , NIJMEIJER S. M. , KOLKER H.J. , NOORDHOEK J. , MIERT A.S.J.P. A. M. VAN
Published: April 2008

The effect of gonadal hormones on the plasma elimination and urinary metabolite profile of antipyrine was studied in dwarf goats. Female goats were treated with testosterone and male goats were treated with 17β‐oestradiol. Castrated males were treated with either testosterone or 17β‐oestradiol. Antipyrine (25 mg/kg, i.v.) was given both before and after the hormonal treatments. The effects of the hormonal status on the plasma elimination of the parent compound were not consistent. This was possibly due to the fact that formation of the main metabolite of antipyrine in the goat, 4‐hydroxy antipyrine (OHA), was not affected by sex or hormonal treatment. On the other hand, there were clear effects of hormonal status on urinary excretion of the three other metabolites. In females and castrated males testosterone suppressed the formation of norantipyrine (NORA), 3‐hydroxymethylantipyrine (HMA) and 4,4′‐dihydroxyantipyrine (DOHA). Intact males produced smaller amounts of these metabolites than females. It is concluded that distinct xenobiotic metabolizing pathways exist in the dwarf goat, which are influenced in their activity by gonadal hormones. This confirms previous findings in rats and mice. The possibility that sex hormones influence drug metabolism in food‐producing animals could have consequences for veterinary therapeutics and public health. This study also demonstrates that, when using the antipyrine test for the assessment of hepatic drug metabolism, it is very important to include the determination of metabolites.
Toxicologic effects of ribavirin in cats
Authors: WEISS R. C. , COX N. R. , BOUDREAUX M. K.
Published: April 2008

Ribavirin, a broad‐spectrum antiviral agent active in vitro against a number of RNA and DNA viruses, has been associated with moderate toxicity in laboratory animals and humans. Clinically, ribavirin has been used effectively in persons primarily to treat life‐threatening viral diseases such as acute haemorrhagic fever or viral pneumonia of infants. In order to evaluate the feasibility of using this antiviral agent in cats, the effects of oral (p.o.), intramuscular (i.m.) and intravenous (i.v.) doses of ribavirin in 27 9‐month‐old specific‐pathogen‐free cats were evaluated by haematology, clinical chemistries, bone marrow biopsies and histopathology. Ribavirin was administered once daily for 10 consecutive days at a dose of either 11, 22, or 44 mg/kg after which all cats were euthanatized and necropsied. Most cats receiving 22 or 44 mg of ribavirin/kg became anorectic and suffered some degree of weight loss (0.2 to 0.6 kg), and about one‐third of the cats developed diarrhoea and/or mucous membrane pallor. Icterus or haemorrhage was not observed. The most profound and consistent haemato‐logic change, particularly among the moderate and high dosage groups regardless of route of administration, was a significant and severe thrombocytopenia (range, 33–78% reduction in mean platelet counts vs. baseline). Other changes, particularly reductions in total WBC and neutrophils and reductions in RBC and PCV, tended to occur at lower ribavirin dosages, but generally they were not statistically significant. Cats given 44 mg of ribavirin/kg i.v. showed significant decreases in leukocyte variables, including total WBC (P = 0.016), neutrophils (P= 0.026) and lymphocytes (P= 0.047). Mild‐to‐moderate increases in serum alanine aminotransferase and alkaline phosphatase activities occurred at doses of 22 and 44 mg/kg. Evaluation of bone marrow biopsies before and after treatment revealed that cats given 11 mg of ribavirin/kg had mild megakaryocytic (MK) hypoplasia, whereas cats receiving 22 or 44 mg/kg had progressively severe degrees of MK hypoplasia and dysplasia, asynchronous MK maturation, and increased myeloidrerythroid ratio. Pathologic changes in ribavirin‐treated cats generally were mild and included primarily enteritis (seven cats) and hepatocellular vacuolation and/or centrilobular necrosis (seven cats). Results of this study in cats indicated that daily administration of ribavirin at a dose range of 11 to 44 mg/kg induced a dose‐related toxic effect on bone marrow, primarily on megakaryocytes and erythroid precursors, and at the higher dosages it suppressed numbers of circulating leukocytes.
Pharmacokinetics of midazolam administered concurrently with ketamine after intravenous bolus or infusion in dogs
Authors: BROWN S. A. , D.JACOBSON J. , HARTSFIELD S. M.
Published: April 2008

Brown, S.A., Jacobson, J.D., Hartsfield, S.M. Pharmacokinetics of midazolam administered concurrently with ketamine after intravenous bolus or infusion in dogs. J. vet. Pharmacol. Therap. 16, 419–425.

Midazolam, a water‐soluble benzodiazepine tranquilizer, has been considered by some veterinary anaesthesiologists to be suitable as a combination anaesthetic agent when administered concurrently with ketamine because of its water solubility and miscibility with ketamine. However, the pharmacokinetics of midazolam have not been extensively described in the dog. Twelve clinically healthy mixed breed dogs (22.2–33.4 kg) were divided into two groups at random and were administered ketamine (10 mg/kg) and midazolam (0.5 mg/kg) either as an intravenous bolus over 30 s (group 1) or as an i.v. infusion in 0.9% NaCl (2 ml/kg) over 15 min. Blood samples were obtained immediately before the drugs were injected and periodically for 6 h afterwards. Serum concentrations were determined using gas chromatography with electron‐capture detection. Serum concentrations were best described using a two‐compartment open model and indicated a t½α of 1.8 min and t½β.p of 27.8 min after i.v. bolus, and t½α f 1–35 min and t½β of 31.6 min after i.v. infusion. The calculated pharmacokinetic coefficient B was significantly smaller after i.v. infusion (429 ± 244 ng/ml) than after i.v. bolus (888 ± 130 ng/ml, P = 0.004). Furthermore, AUC was significantly smaller after i.v. infusion (29 800 ±6120 ng/h/ml) than after i.v. bolus (42 500 ± 8460 ng/h/ml, P < 0.05), resulting in a larger ClB after i.v. infusion (17.4 ± 4.00 ml/min/kg than after i.v. bolus (12.1 ± 2.24 ml/min/kg, P < 0.05). No other pharmacokinetic value was significantly affected by rate of intravenous administration.
A comparison of the actions of platelet activating factor (PAF) antagonists WEB 2170 and WEB 2086 in the horse
Authors: FOSTER A. P. , CUNNINGHAM F. M. , ANDREWS M.J. , LEES P.
Published: April 2008

Foster, A.P., Cunningham, F.M., Andrews, M.J., Lees, P. A comparison of platelet activating factor (PAF) antagonists WEB 2170 and WEB 2086 in the horse. J. vet. Pharmacol. Therap. 16, 477–487.

The effects of the selective platelet activating factor (PAF) receptor antagonist WEB 2170 on PAF‐induced responses in equine cells and tissues have been examined and compared with those of WEB 2086. In initial experiments WEB 2170 was shown to inhibit in vitro platelet aggregation in a dose‐dependent, competitive reversible manner (pA2= 7.21). Co‐administration of the antagonists with either PAF or histamine also inhibited PAF, but not histamine, induced wheal formation and PAF‐induced neutrophil accumulation in vivo in equine skin. Intravenous (i.v.) administration of both drugs at a dose of 0.1 mg/kg blocked PAF‐induced ex vivo platelet aggregation. The inhibition produced by WEB 2170 was greater and, at 30 min, this drug also reduced the slope and maximal response. Wheal formation in the skin was significantly inhibited for up to 6 h by WEB 2170 administered i.v., the reduction being more prolonged than that obtained with WEB 2086. Neutrophil accumulation in the skin was also significantly reduced for up to 24 h by WEB 2170, whilst no significant inhibition was produced by WEB 2086. These results demonstrate that WEB 2170, like WEB 2086, is an effective antagonist of PAF in the horse. Moreover, when given i.v., WEB 2170 appears to be a more potent PAF inhibitor than WEB 2086.
The intramuscular bioavailability of a phenylbutazone preparation in the horse
Authors: LANDUYT J. , DELBEKE F. T. , DEBACKERE M.
Published: April 2008

Landuyt, J., Delbeke, F.T. & Debackere, M. The intramuscular bioavailability of a phenylbutazone preparation in the horse.J vet. Pharmacol. Therap. 16, 494– 500.

The plasma concentrations of phenylbutazone (PBZ) and its major metabolites, oxyphenbutazone (OPBZ) and γ‐OH‐phenylbutazone (OHPBZ) were determined for up to 72 h in six horses, following intravenous (i.v.) and intramuscular (i.m.) administration of 4 g phenylbutazone, 20 ml Phenylarthrite® Ventoquinol (Vetoquinol Specialites Pharmaceutiques Veterinaires, Magny‐Vernois, 70200 Lure, France). After i.v. dosing the plasma disposition was best described by a two‐compartment open model. The hydroxylated metabolites OPBZ and OHPBZ were present in detectable concentrations for 72 h and 48 h, respectively. After 36 h the OPBZ concentrations exceeded plasma PBZ concentrations. The plasma disposition following i.m. injection could be described by a one‐compartment open model. The hydroxylated metabolites OPBZ and OHPBZ were present in detectable concentrations for 72 h and 36 h, respectively. Only after 72 h was the concentration of OPBZ in plasma higher than the concentration of PBZ. The mean i.m. bioavailability of phenylbutazone was calculated to be 91.7 ± 10.1%.
Lack of arrhythmogenicity of aminophylline in dogs
Authors: HAMLIN R. L. , SALLY J. L.
Published: April 2008

This study was designed to determine if doses of aminophylline up to 10 mg/kg given i.v. would produce ventricular arrhythmias in seven healthy dogs anaesthetized with fentanyl‐dropelidol‐pentobarbital. Arrhythmias were sought by inspection of ECGs before and after attempts at provoking them with 5 pg/ kg boluses of epinephrine given i.v., or by programmed electrical stimulation. After cumulative doses of 10 nig aminophylline/kg body weight, producing an estimated plasma concentration of greater than 30 pginil, no ventricular ectopia other than escape depolarizations were observed. We were unable t o document

an arrhythmogenic effect of aminophylline when given rapidly by the i.v. route. I t is possible that the anaesthetic regimen reduced the arrhythmogenic property of aminophylline, or that arrhythmias might be produced in either obese or ill dogs; but it is unlikely that chronic administration of aminophylline would be more arrhythmogenic.
Gastrointestinal distribution of albendazole metabolites following netobimin administration to cattle: relationship with plasma disposition kinetics
Authors: LANUSSE C. E. , GASCON L. H. , PRICHARD R. K.
Published: April 2008

The gastrointestinal (GI) distribution and plasma disposition kinetics of alberidazole (ABZ) metabolites after oral administration of netobirnin (NTB) to cattle were studied. Eight Holstein steers (150–180 kg) were surgically fitted with permanent cannulae in the rumen, abomasum and ileum. After post‐surgical recovery, the ariinials were treated orally with a suspension of neto1)imin zwitterion (400 mg/ml) at 20 nig/kg. Jugular blood and ruminal, abomasal arid ileal fluid samples were taken serially over a 96 h period and analysed by HPLC for NTB and its metabolites, including ABZ, ABZ sulphoxide (ABZSO), AH%

sulphone (ABZSO?) and amino‐albendazole sulphone (NHp4BZSOy). N T B parent drug was only fonnd in the G I tract and for only 12–18 h post‐treatment. ABZSO and ABZSOp were the main metabolites found in plasma, being present for 30–36 h. These metabolites were exchanged between plasma and different GI fluids and were greatly concentrated in the abomasum. This phenornenori may account for the presence of ABZ, ABZSO and ABZSO? in the GI tract f'or 72 h post‐treatment despite the fact that ABZ was riot detected in plasma and ABZSO and ABZSO.;, were detected for only 30–36 h in plasma. The presence o f ABZ and ABZSO in the abomasum and intestine for this extended period of time is probably relevant for anthelmintic efficacy against GI parasites. The NH2ABZSO2metabolite was detected in plasma, abomasum and ileum and its disposition kinetics were characterized for the first time.
Effects of hypertonic saline on myocardial contractility in anaesthetized pigs
Authors: HELLYER P. W. , MEYER R. E.
Published: April 2008

The cardiac effects of hypertonic saline (HS, 7.5% NaCl) were evaluated using a number of indices derived from the left ventricular (LV) pressurevolume relationship. Left ventricular end‐systolic elastance (elastance), the slope of the endsystolic pressure‐volume relationship, end‐systolic elastance normalized for enddiastolic volume (elastance(norm), the rate of rise of LV pressure (dP/dtmax), and dP/dtmax/end‐diastolic volume were used to assess myocardial contractility. Pigs were anaesthetized with isoflurane and instrumented for haemodynamic measurements, LV pressure, and volume (conductance catheter) determinations. Elastance was determined during transient (8–10 s) caudal vena caval balloon occlusion. Following instrumentation, the end‐tidal isoflurane concentration was reduced and maintained at 1 minimum alveolar concentration (1.5%). Pigs were randomly administered either 0.9% NaCl (n= 7) or HS (n =9) at a dose of 4 ml/kg, over 3 min into the right atrium. There were no significant differences in LV or haemodynamic measurements between isotonic saline and HS treated pigs at any time point. Elastance, elastance(norm) and dP/dtmax/end‐diastolic volume did not change in either treatment group. In contrast, dP/dtmax) increased significantly (P < 0.015) at 5 min compared to baseline after treatment with HS. End‐diastolic volume increased significantly from 5 to 30 min following treatment with HS. Left ventricular end‐diastolic pressure increased significantly at 5 and 60 min in HS treated pigs. Central venous and pulmonary arterial wedge pressures, and cardiac index increased significantly at 5 min after treatment with HS. Total peripheral resistance decreased significantly at 5 min, followed by a return to baseline in the HS group. These results suggest that HS is not a positive inotrope in the anaesthetized pig and that increases in cardiac index are primarily due to an increased preload.
Characterization of muscarinic receptor subtype mediating contraction and relaxation in equine coronary artery in vitro
Authors: OBI T. , KABEYAMA A. , NISHIO A.
Published: April 2008

In coronary arterial rings isolated from horses, 10‐‐8‐10‐6mol/l acetylcholine (ACh) induced concentration‐dependent contractions which were potentiated by the removal of endothelium and by pretreatment with I,‐nitro‐arginine (LNAG) or methylene blue (MB). Relatively lower concentrations of Ach 10‐14‐10‐8mol/l) induced relaxation when the coronary rings were contracted by phenylephrine (PE). ACh‐induced contractions in the coronary rings without endothelium were competitively inhibited by each muscarinic subtype selective antagonist in the following order of potency: 4‐diphenylacetoxy‐N‐methylpiperidine methiodide (4‐DAMP) > pirenzepine ≥ parafluoro‐hexahydrosiladiphenidol (pFHHSiD) > methoctramine. ACh‐induced relaxation in the rings with endothelium was inhibited by LNAG or MB, and by each selective antagonist in the following order of potency: 4‐DAMP < pFHHSiD ≥ pirenzepine ≥ methoctramine. These results suggest that the ACh‐induced contraction and relaxation in equine coronary arteries are mediated mainly by an M3‐receptor located on the smooth muscle cells and endothelial cells, respectively, and that the stimulation of the M3‐receptor on the endothelial cells liberates nitric oxide.
Tiamulin selectively inhibits oxidative hepatic steroid and drug metabolism in vitro in the pig
Authors: WITKAMP R. F. , NIJMEIJER S. M. , MIERT A. S. J. P. A. M. VAN
Published: April 2008

The simultaneous use of the antibiotic tiamulin with certain ionophoric antibiotics (monensin, salinomycin) may give rise to a toxic interaction in pigs and poultry. In the present study, effects of tiamulin on hepatic cytochrome P450 activities in vitro were studied using pig liver microsomes. When tiamulin was added to the incubation medium the N‐demethylation rate of ethylmorphine and the hydroxylation of testosterone at the 6β‐ and 1 lα‐ positions was sirongly inhibited. Tiamulin inhibited these activities more than SKF525A or cimetidine, but less than ketoconazole. The microsomal N‐demethylation rate of erythromycin and the hydroxylation of testosterone at the 28‐ position were inhibited to a lesser degree, whereas the ethoxyresorufin‐O‐deethylation, aniline hydroxylation and testosterone hydroxylations at the 15α‐ and 15β‐ positions were not affected by tiamulin. No in vitro complexation by tiamulin of cytochrome P450 resulting in a loss of CO‐binding capacity could be demonstrated. Results from the present study suggest a selective inhibition of cytochrome P450 enzymes in pigs, probably belonging to the P4503A subfamily. The mechanism of this interaction is still unclear. However, interactions between tiamulin and those veterinary drugs or endogenous compounds which undergo oxidative metabolism by P450 enzymes must be considered. More research is needed to reveal which of the P450 enzymes are affected by tiamulin in order to improve the understanding and probably the predictability of this interaction.
Pharmacokinetics of sulphamethoxazole and trimethoprim administered intravenously and orally to Japanese quails
Authors: LASHEV L. D. , MIHAILOV R.
Published: April 2008

The pharmacokinetic behaviour of sulphamethoxazole and trimethoprim was studied after combined intravenous (i.v.) administration at doses of 20 mg/kg and 4 mg/kg, respectively, and after oral administration at doses of 50 mg/kg and 10 mg/kg. The serum concentration versus time data after i.v. administration were best described by the biexponential equations C = 34.77.e‐2.655.t+ 39.03.e‐0.241.t for sulphamethoxazole and C = 3.29.e‐3.878.t+ 0.83.e‐0.306.t for trimethoprim. Mean biological half‐lives of the drugs were 2.89 ± 0.11 and 2.38 ± 0.33 h, respectively. The distribution volumes (Varea) were 0.475 ± 0.026 l/kg (sulphamethoxazole) and 3.89 ± 0.61 I/kg (trimethoprirn). Orally administered sulphamethoxazole and trimethoprim were rapidly absorbed. The maximum serum concentrations were reached 0.5‐1 h after administration. The bioavailability was 8 1% for sulphamethoxazole and 41% for trimethoprim.
Types of serotonergic receptors involved in the control of reticulo‐ruminal myoelectric activity in sheep
Authors: BRIKAS P. , FIORAMONTI J. , BUENO L.
Published: April 2008

The effects of peripheral (intravenous, i.v.) and central (intracerebroventricular, ICV) administrations of agonists of 5‐HT1A, 5‐HT2, 5‐HT3 and 5‐HT4 receptors were investigated in conscious sheep chronically fitted with intraparietal electrodes on the reticulum and the dorsal, ventral and caudo‐ventral rumen. The 5‐HT1A agonist 8‐hydroxydipropylaminotetralin increased reticular and decreased ruminal spike burst frequency when given i.v. (80 μg/kg) and ICV (8 μg/kg). The 5‐HT2 and 5‐HT3 agonists, α‐methylserotonin and 2‐methylserotonin, induced a moderate inhibition of rumino‐reticular contractions when given i.v. at 100 and 150 μg/kg, respectively, while marked inhibition was observed after ICV administration at doses of 10 and 5 μg/kg, respectively. The 5‐HT4 agonist 5‐methoxytryptamine strongly stimulated rumino‐reticular motility by the ICV (10 μg/kg) route, whereas it induced a moderate inhibition when administered i.v. (200 μg/kg). The selective antagonist of 5‐HT1A, 5‐HT2, 5‐HT3 and 5‐HT4 receptors, spiroxatrine, ritanserin, granisetron and DAU 6285, respectively, blocked the responses of the respective agonists given by the same route. Moreover, the antagonists given ICV blocked the effects of the agonists given i.v. except for DAU 6285 ICV, which did not antagonize the inhibition induced by 5‐methoxytryptamine i.v. It is concluded that the four types of serotonergic receptors investigated control rumino‐reticular motility at the central level. However, according to the receptor type and the forestomach area (reticulum or rumen) this control may be stimulatory or inhibitory, demonstrating a pleiotropic role of serotonin in the control of rumino‐reticular motility in sheep.
Stereospecific pharmacodynamics and pharmacokinetics of carprofen in the dog
Authors: McKELLAR Q. A. , DELATOUR P. , LEES P.
Published: April 2008

The non‐steroidal anti‐inflammatory drug (NSAID) carprofen (CPF) contains single chiral centre. It was administered orally to Beagle dogs as a racemate (rac‐CPF) at a dose of 4 mg per kg body weight and as individual (‐)(R) and (+)(S) enantiomers at 2 mg per kg body weight. Each of the enantiomers achieved similar plasma bioavailability following administration as the race‐mate as they did following their separate administration. Only the administered enantiomers were detectable when the drug was given in the (‐)(R) or (+) (S) form, indicating that chiral inversion did not occur in either direction. Higher plasma concentrations of the (‐)(R) (Cmax 18 μg/ml, AUC0–24 118 μg h/ml) than the (+)(S) (Cmax 14 μg/ml, AUC0–24 67 μg h/ml) enantiomer were achieved following administration of the racemate. Both enantiomers distributed into peripheral subcutaneous tissue cage fluids, but Cmax and AUC values were lower for both transudate (non‐stimulated tissue cage fluid) and exudate (induced by the intracaveal administration of the irritant carrageenan) than for plasma. Drug concentrations in transudate and exudate were similar, as indicated by Cmax and AUC values, although CPF penetrated more rapidly into exudate than into transudate. Neither rac‐CPF nor either enantiomer inhibited thromboxane B2 (T × B2) generation by platelets in clotting blood (serum T × B2, or prostaglandin E2, (PGE,) and 12‐hydroxyeicosatetraenoic acid (1 2‐HETE) synthesis in inflammatory exudate. Since other studies have shown that rac‐CPF at the 4 mg/kg dose rate possesses analgesic and anti‐inflammatory effects in the dog, it is concluded that the principal mode of action of the drug must be by mechanisms other than cyclooxygenase or 12‐lipoxygenase inhibition.
Plasma concentrations and therapeutic efficacy of phenylbutazone and flunixin meglumine in the horse: pharmacokinetic/pharmacodynamic modelling
Authors: TOUTAIN P.L. , AUTEFAGE A. , LEGRAND C. , ALVINERIE M.
Published: April 2008

The purpose of the present study was to establish in the horse the relationship between plasma concentration profiles of phenylbutazone (PBZ) and flunixin meglumine (FM) and their pharmacological effects in order to build a predictive pharmacokinetic/pharmacodynamic (PK/PD) model. In five horses, an experimental arthritis was induced by injecting Freund's adjuvant into a carpal joint. PBZ (4 mg/kg) and FM (1 mg/kg) were injected by the intravenous route as a single intravenous dose in two different trials. Five pharmacodynamic end‐points were regularly measured after test article injection using standardized procedures: local skin temperature, stride length, the rest angle flexion and the maximal carpal flexion of the injured leg and circumference of the inflamed joint. Plasma drug concentrations and pharmacodynamic data were analysed according to an integrated PK/PD model: for the stride length, the PBZ ECSOr i.e. the plasma concentration for which half the maximum effect could be obtained, was 3.6 ± 2.2 yglml and the maximum potential effect was 10.7 ± 9.4% above the control value. For FM, the corresponding values were 0.93 ± 0.35 μg/ml and 16.3 ± 4.6%. ECSO values for rest angle flexion and local skin temperature were similar to that obtained for stride length. Maximal carpal flexion was an unreliable end‐point, and circumference of the joint did not display significant response to the drugs. Using these experimental parameters, a dose‐effect relationship was simulated for both drugs: it was shown for PBZ that the model predicts an absence of effect for a 1 mg/kg dose and a maximum effect at about 2 mg/kg: at higher PBZ doses, the maximum effect was not modified, but its duration was increased from 8 h with a 2 mg/kg dose to about 24 h with an 8 mg/kg dose. For FM the model predicts that a dose of 0.5 mg/kg will be without significant effect, whereas a 1 mg/kg dose allows a nearly maximal effect with a return to the control value after a delay of 16 h. A 2 mg/kg dose allows the effect to be maintained for 24 h. It is concluded that PK/PD is a tool of potential value for the preclinical screening of a dosage regimen.
Disposition and bioavailability of neomycin in Holstein calves
Authors: PEDERSOLI W. M. , RAVIS W R , JACKSON J. , SHAIKH B.
Published: April 2008

Pedersoli, W.M., Ravis, W.R., Jackson, J., Shaikh, B. Disposition and bioavailability of neomycin in Holstein calves. J. vet. Pharmacol. Therap.17, 5–11.

The disposition and absorption kinetics of neomycin were studied in healthy ruminating dairy calves (n ‐6), approximately 3‐months‐old. The calves were treated with single intravenous (i.v.) (12 mg/kg), intramuscular (i.m.) (24mg/kg), oral (p.o.) (96 mg/kg) and repeated p.o. (96 mg/kg, b.i.d., 15½ days) doses of neomycin. A 3‐week rest period was allowed between treatments A and B and B and C Baseline and serial venous blood samples were collected from each calf plasma concentrations of neomycin were determined by a high performance liquid chromatography procedure. The resulting data were evaluated by using compartmental pharmacokinetic models and nonlinear least squares regression analysis. The mean of some selected parameters were t½λ3 7.48 ± 2.02 h, Clt= 0.25 ± 0.04 L/h/kg, Vd(ss)= 1.17 ± 0.23 L/kg, and MRT = 4.63 ± 0.87 h for the i.v. data and t½= 11.5 ± 3.8 h, MRTabs= 0.960 ± 1.001 h, F = 127 ± 35.2%, and Clt/F= 0.199 ± 0.047 L/h/kg for the i.m. data, respectively. Only one calf absorbed neomycin to any significant degree (F = 0.0042) after a single p.o. dose. Selected mean parameters determined after repeated oral dosing were: F = 0.45 ± 0.45%, Cmax= 0.26 ± 0.37 m̈g/ml, and tmax= 2.6 ± 2.9 h. Terminal half‐lives determined for the i.v. and i.m. treatments were considerably longer than those reported previously in the literature.
Concentration of ceftiofur metabolites in the plasma and lungs of horses following intramuscular treatment
Authors: JAGLAN P. S. , ROOF R. D. , YEIN F. S. , ARNOLD T. S. , GILBERTSON T. J.
Published: April 2008

Jaglan, P.S., Roof, R.D., Yein, F.S., Arnold, T.S., Brown, S.A., Gilbertson. T.J. Concentration of ceftiofur metabolites in the plasma and lungs of horses following intramuscular treatment. J. vet. Pharmacol Therap. 17, 24–30.

Ceftiofur sodium, a broad spectrum cephalosporin antibiotic approved for veterinary use, is metabolized to desfuroylceftiofur which is conjugated to micro as well as macromolecules. Twelve horses, weighing 442–618 kg, were injected intramuscularly with a single dose of 2.2 mg ceftiofur/kg (1.0 mg/lb) body weight. Blood was collected at various intervals over 24 h after treatment. Three groups of four horses each were euthanized and lungs were collected at 1,12, and 24 h after treatment.

The concentration of desfuroylceftiofur and desfuroylceftiofur conjugates in the plasma and lungs was determined by converting them to desfuroylceftiofur acetamide (DCA) and measured DCA by high performance liquid chromatography with UV detection. The average maximum concentration (Cmax) of desfuroylceftiofur and related metabolites in plasma expressed as ceftiofur equivalents was 4.46 ± 0.93 m̈g/ml occurred at 1.25 ± 0.46 h after treatment. These concentrations declined to 0.99 ± 0.16, 0.47 ± 0.15 and 0.17 ± 0.02 m̈g/ml at 8, 12, and 24 h, respectively. The mean residence time of ceftiofur metabolites was 6.10 ± 1.27 h.

Concentration of desfuroylceftiofur and desfuroylceftiofur conjugates in the lungs of horses expressed as ceftiofur equivalents were 1.40 ± 0.36, 0.27 ± 0.07, and 0.15 ± 0.08 m̈g/ml at 1, 12, and 24 h, respectively. These concentrations of the drug at 12 and 24 h in lung homogenate were similar but slightly lower than plasma concentrations in the same horses, and the plasma pharmacokinetic values including half‐life were similar to those observed at the approved dose of 1.1–2.2 mg ceftiofur/kg body weight administered intramuscularly once daily for 3–5 days in cattle.
Single‐dose pharmacokinetics of cefazolin in bovine synovial fluid after intravenous regional injection
Authors: GAGNON H. , FERGUSON I G. , PAPICH M. G. , BAILEY I. V.
Published: April 2008

Gagnon, H., Ferguson, J.G., Papich, M.G., Bailey, J.V. Single‐dose pharmacokinetics of cefazolin in bovine synovial fluid after intravenous regional injection. J. vet. Pharmacol. Therap. 17, 31–37.

The pharmacokinetic properties of cefazolin in the synovial fluid of the tibiotarsal joint were determined in 10 healthy mature cattle after intravenous regional injection of 2 50 mg cefazolin. A pneumatic tourniquet was positioned proximal to the tibiotarsal joint and the intravenous injection was performed distal to the tourniquet. Synovial fluid concentrations of cefazolin increased in the first 30 mm and fluctuated between 54.7 ± 11.0 m̈g/ml (mean ± SEM) and 73.2 ± 13.2 m̈g/ml in the following 90 min while the tourniquet remained inflated. After tourniquet removal, synovial fluid concentration‐time curves followed first‐order one‐compartment model decay in most of the animals with an elimination half‐life of 0.82 h (harmonic mean). Therapeutic concentrations of cefazolin in the synovial fluid of normal joints were reached and this injection technique could be used as an alternative to systemic administration of antibiotics to provide adequate concentrations in a localized area.
Haemodynamic effects of hyoscine‐N‐butylbromide in ponies
Authors: GEIMER T.R. , EKSTRÖM P.M. , LUDDERS J.W. , ERICHSEN D.F. , GLEED R.D.
Published: April 2008

The haemodynamic effects of hyoscine‐N‐butylbromide (0.30 mg/kg, intravenously) were studied in eight adult ponies in a blinded two‐period crossover experiment with repeated measures. Values for heart rate were 63%, 48% and 13% greater than control values at 1, 16 and 46 min, respectively, after administration of hyoscine‐N‐butylbromide. Cardiac output increased by 16% at 16 min after drug injection. Mean right atrial pressure was decreased by 79%, 63%, 45% and 52% at 1, 16, 46 and 61 min, respectively, after drug administration. Stroke volume was decreased by 32% at 1 min and pulmonary arterial wedge pressure was decreased by 44% at 16 min. We detected no significant difference in mean systemic arterial pressure, mean pulmonary arterial pressure, systemic vascular resistance or pulmonary vascular resistance at any time.
Antinociceptive activity of midazolam in sheep
Authors: KYLES A.E. , WATERMAN A.E. , LIVINGSTON A.
Published: April 2008

The purpose of this study was to examine the effects of midazolam on the nociceptive threshold responses in sheep. The intravenous administration of midazolam (0. 1–0.3 mg/kg) produced a significant dose‐dependent elevation of the mechanical and thermal nociceptive thresholds. The intravenous administration of flumazenil (20 μg/kg) markedly attenuated the antinociceptive activity of midazolam in the mechanical nociceptive test, whereas intravenous naloxone (0.2 mg/kg) had no significant effect on midazolam‐mediated analgesia. The intrathecal administration of midazolam (1 mg), via chronically implanted cervical subarachnoid catheters, produced a significant elevation in the mechanical threshold responses. These results indicate that midazolam has antinociceptive actions in the sheep and suggest that this effect is, at least partially, mediated at the spinal level.
Distribution and elimination of clenbuterol in tissues and fluids of calves following prolonged oral administration at a growth‐promoting dose
Authors: SAUER M.J. , PICKETT R.J.H. , LIMER S. , DIXON S.N.
Published: April 2008

A pharmacokinetic study is described in which Friesian calves (n = 30) were treated orally with clenbuterol at 10 times the therapeutic dose. The study was designed to establish the distribution and elimination of clenbuterol from edible tissues, the major compartments of the eye and body fluids. Animals (n= 24) were dosed (10 μg/kg body weight) twice daily with clenbuterol for 21 days and slaughtered in groups of five (one untreated control animal per group) at 6 h and 1, 2, 4, 8 and 16 days after cessation of treatment At slaughter, samples of diaphragm muscle, liver, kidney, bile, urine and both eyes were obtained. One of the eyes was separated into constituent tissues: aqueous humour, vitreous humour, comea, lens, retina (without pigmented epithelium), choroid (with pigmented retinal epithelium; choroid/PRE) and sclera. All samples were stored at ‐20°C. Clenbuterol concentrations were higher in liver than kidney, bile and urine from day 2 of withdrawal onwards. Concentrations in choroid/PRE were at least 10 times higher than in liver at all periods following cessation of treatment and 52 times higher 16 days after treatment The concentrations of clenbuterol in the constituent tissues of the eye were in the order choroid/PRE > comea > sclera > retina > aqueous humour/vitreous humour ≥ lens. Concentrations of clenbuterol in choroid/PRE taken from eyes frozen whole were generally lower than those in choroid/PRE separated before storage. Choroid/PRE stored by either method contained clenbuterol at more than 100 ng/g 16 days following cessation of treatment These data suggest that analysis of choroid taken at the abattoir would provide reliable surveillance information on the use or abuse of clenbuterol within the slaughter population. It is proposed that liver samples taken concurrently could be used in the event of a positive result from choroid/PRE analysis to indicate whether the maximum residue limit for edible tissues has been exceeded.
The influence of cimetidine on the pharmacokinetics of the enantiomers of verapamil in the dog during multiple oral dosing
Authors: JOHNSON L.M. , LANKFORD S.M. , BAI S.A.
Published: April 2008

The disposition of intravenously (0.5 mg/kg) and orally (5 mg/kg) administered verapamil was studied in six dogs after 3 days' pre‐treatment with verapamil alone (5 mg/kg, every 8 h) and during concomitant oral administration of cimetidine (16 mg/kg, every 8 h). Racemic verapamil and norverapamil, an active metabolite of verapamil, were measured by fluorescence high performance liquid chromatography using an achiral phenyl column. The isolated racemic verapamil was rechromatographed on an Ultron‐OVM chiral column, which separated the two verapamil enantiomers. Cimetidine co‐administration significantly reduced the systemic clearance of racemic verapamil as well as that of its enantiomers by 25–29%. The clearance of racemic verapamil administered orally as well as that of its enantiomers was also reduced by 28% during cimetidine coadministration. The decrease in verapamil metabolism by cimetidine appeared to be non‐stereoselective. On the other hand, cimetidine co‐administration had no significant effect on the apparent volume of distribution of racemic verapamil and its enantiomers or the plasma protein binding or the blood to plasma concentration ratio of racemic verapamil. In addition, the ratio of the area under the plasma concentration‐time curve for norverapamil to that of verapamil was unaffected by cimetidine co‐administration. These results suggest that cimetidine alters the disposition of verapamil by decreasing the hepatic blood flow rate and by inhibition of its first‐pass metabolism.
Comparative pharmacokinetics of amoxicillin/clavulanic acid combination after intravenous administration to sheep and goats
Authors: CARCELES C.M. , ESCUDERO E. , BAGGOT J.D.
Published: April 2008

The pharmacokinetic behaviour of an amoxicillin/clavulanic acid combination was studied after intravenous administration of single doses (20 mg/kg per kg body weight) to five sheep and six goats. The objective was to determine whether there are differences between sheep and goats in the disposition of amoxicillin and clavulanic acid. The plasma concentration‐time data were analysed by compartmental pharmacokinetic and non‐compartmental methods. The disposition curves for both drugs were best described by a biexponential equation (two‐compartment open model) in sheep and goats. The elimination half‐lives of amoxicillin were 1.43 ± 0.16 h in sheep and 1.13 ± 0.19 h in goats, and of clavulanic acid were 1.16 ± 0.01 h and 0.85 ± 0.09 h in sheep and goats respectively. The apparent volumes of distribution of amoxicillin and clavulanic acid were similar in the two species. Body clearances of amoxicillin were 0.09 ± 0.01 L/h kg in sheep and 0.11 ± 0.01 L/h kg in goats, and of clavulanic acid were 0.07 ± 0.01 L/h kg and 0.12 ± 0.01 L/h kg in sheep and goats respectively. The half‐lives and body clearances of amoxicillin and clavulanic acid differed significantly between sheep and goats. It was concluded that the disposition of amoxicillin and clavulanic acid administered intravenously as an amoxicillin/clavulanic acid combination to sheep and goats differed between the two ruminant species. Even though the differences in disposition kinetics of both drugs were statistically significant, the same intravenous dosing rate of this antimicrobial combination can generally be used in sheep and goats.