bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative pharmacokinetics of ampicillin‐sulbactam combination in calves and sheep
Authors: MONTESISSA C. , VILLA R. , SONZOGNI O. , BELLOLI C. , CARLI S.
Published: April 2008

The pharmacokinetics of ampicillin and sulbactam administered in combination were studied in calves and sheep. The animals were administered an aqueous solution of ampicillin/sulbactam (2: 1, w/w) intravenously and intramuscularly at doses of 13.2 and 6.6 mg.kg‐1, respectively. A microbiological method was used to detect ampicillin, and HPLC was used to detect sulbactam in serum. Following intravenous (i, v.) administration, the distribution phases were rapid and similar (about 15 min) for both drugs in both species, whereas sulbactam in calves and ampicillin in sheep showed a faster elimination rate. After intramuscular (i.m.) administration both drugs showed peak concentrations higher in calves than in sheep: the peak time of sulbactam was shorter in calves than in sheep. No other significant differences in the pharmacokinetics of the combination were observed between the species after i.m. injection. The mean residence and absorption times, calculated by non‐compartmental analysis, for both calves and sheep suggested that the differences in ampicillin and sulbactam phgrmacokinetics could be attributable to the different molecular structures.
Endothelin and vasoactive peptides: new cardiovascular mediators
Authors: GWATHMEY J. K. , PAIGE J. A.
Published: April 2008

Gwathmey, J.K., Paige, J.A. Endothelin and vasoactive peptides: new cardiovascular mediators. J, vet. Pharmacol. Therap. 17,420–425.

A newly discovered family of vasoactive peptides, endothelins, have strong inotropic and chronotropic effects on the myocardium. Recent studies suggest a possible role for endothelin in pathophysiological states. The ability of these peptides to stimulate mitogenesis in smooth muscle and fibroblasts, coupled with their contribution to the regulation of gene expression and secretion of other neurohumoral mediators, raises the possibility that endothelins may contribute to the development of heart disease. Elevated levels of circulating endothelin have been found in the setting of elevated peak systolic pressure, pulmonary hypertension myocardial infartion, and congestive heart failure. This paper discusses the potential role of endothelin as a regional mediator of pathophysiological states.
Pharmacokinetics of parenteral and oral sustained‐release morphine sulphate in dogs
Authors: DOHOO S. , TASKER R. A. R. , DONALD A.
Published: April 2008

The pharmacokinetics of single‐dose morphine sulphate (MS) administered intravenously (i.v.) and intramuscularly (i.m.) and of oral sustained‐release morphine sulphate (OSRMS) were studied in dogs. Beagles (n = 6) were randomly assigned to six treatment groups using a Latin square design. Treatments included MS 0.5 and 0.8 mg/kg i.v. and i.m. and OSRMS 15 and 30 mg orally (p.o). Serum samples were drawn at intervals up to 420 min following parenteral MS and 720 min following OSRMS. Serum was analysed for morphine concentration using a radioimmunoassay . Pharmacokinetic analysis of the results revealed that MS was eliminated by a first‐order process best described by a two‐compartment model. For i.v. and i.m. data there were no statistically significant differences (P c 0.0 5) between steady‐state volume of distribution, half‐life of elimination and plasma clearance. As expected, area under the concentration vs. time curve (AUC) was significantly greater for the 0.8 mg/kg dosage for i.v. and i.m. routes, and time to maximum serum concentration was significantly longer following i.m. administration. For OSRMS there were no significant differences between dosage for any parameter (AUC, Cmax. tmax t½ F) and prolonged absorption of the drug occurred over approximately 6 h. Bioavailability (F) for both oral dosages was approximately 20%. The i.m. route is an effective method for rapid and complete delivery of MS to dogs. OSRMS may be useful in the provision of long‐term analgesic therapy in dogs, but further work is required to verify the safety and effectiveness of this preparation.
A comparative study of the pharmacokinetics of intravenous and oral trimethoprim/sulfadiazine formulations in the horse
Authors: DUIJKEREN E. VAN , VULTO A. G. , OLDRUITENBORGH‐OOSTERBAAN M. M. SLOET VAN , MEVIUS D. J. , KESSELS B. G. F. , BREUKINK H. J. , MIERTS A. S. J. P. A. M. VAN
Published: April 2008

The biopharmaceutical properties of four fuced trimethoprim/sulfonamide combinations were investigated in the horse. Eight fasted horses were dosed at 1 week intervals in a sequentially designed study with one intravenous (i.v.) and three oral trimethoprim/sulfadiazine (TMP/SDZ) formulations (1, 2 and 3) administered at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulfadiazine (SDZ). Plasma concentrations of each compound were monitored for 48 h. Pharmacokinetic parameters (volume of distribution, bioavailability and total body clearance) for TMP and SDZ were calculated and compared. After oral administration plasma concentrations of TMP and SDZ increased rapidly. With all three paste formulations, TMP peak plasma concentrations were attained within 2 h. SDZ mean peak plasma concentrations were reached at 2.59 ± 0.48 h for a commercial paste (l), and at 1.84 ± 0.66 h and 1.95 ± 0.61 h for the two self‐made formulations (2 and 3). Mean peak plasma TMP concentrations (± SD) were 1.72 ± 0.36 μg/ml, 1.42 ± 0.37 μg/ml and 1.31 ± 0.36 μ g/d, and mean peak plasma SDZ concentrations 12.11 ± 4.5 5 μg/ml, 12.72 ± 3.47 μg/ml and 15.45 ± 4.74 μg/ml for preparations 1, 2 and 3. The bioavailability of TMP was 67.0 ± 20.3%, 57.7 ±21.6% and 60.9 f 18.9% and of SDZ 57.6 ± 14.8%, 59.3 ± 19.5% and 65.9 ± 5.8% for SDZ for 1, 2 and 3, respectively. Following i.v. administration TMP/SDZ plasma concentration ratios approached the optimal 1:20 ratio (It 10%) for about 5 h, but following the oral administrations this ratio was only achieved for a very short time‐span. No adverse effects were seen following i.v. and oral administration. In considering the pharmacokinetic data in combination with in vitro antibacterial sensitivity data, it is concluded that treatment at a dose of 5 mg/kg TMP and 25 mg/kg SDZ with a dosing interval of 12 h can be regarded as therapeutically effective for susceptible bacteria (MIC90 0.25/4.75) for all three oral formulations. It is concluded that neither the formulation nor the addition of different excipients result in significantly different bioavailabilities.
Thiamphenicol pharmacokinetics in sheep
Authors: ABDENNEBI E. H. , KHALES N. , SAWCHUK R. J. , STOWE C M
Published: April 2008

Abdennebi, E.H., Khales, N., Sawchuk, R.J., Stowe, CM. Thiamphenicol pharmacokinetics in sheep. J. vet. Pharmacol. Therap. 17, 12–16.

The pharmacokinetics of thiamphenicol were investigated after intravenous (i‐v.). intramuscular (i.m.) and oral (p.o.) administration to sheep. It was found that the drug is almost completely absorbed following intramuscular injection, with a bioavailability of about 8 7.5%. Thiamphenicol appears to be widely distributed into extravascular compartments, yielding a volume of distribution [V(b)] of approximately 1 1/Kg. Elimination from the blood is relatively rapid, with a biological half‐life of about 1.5 h. Oral treatment showed that thiamphenicol is absorbed from the gastrointestinal tract yielding very low plasma concentrations which were maintained for at least 24 h. Although only 30% of the oral dose was systemically available, in contrast to chloramphenicol, thiamphenicol is truly absorbed when given orally to adult sheep. One possible reason for this observation is that rumen flora do not biotransform this drug as they do for chloramphenicol. Metabolism investigations are, however, needed to confirm this finding.
Comparison of oral erythromycin formulations in the horse using pharmacokinetic profiles
Authors: EWING P. J. , BURROWS G. , MACALLISTER C. , CLARKE C.
Published: April 2008

Ewing, P. J., Burrows, G., MacAllister, C, Clarke, C. Comparison of oral erythromycin formulations in the horse using pharmacokinetic profiles. J. vet. Pharmacol, Therap.17, 17–23.

The pharmacokinetic properties of four erythromycin formulations were compared in six adult horses after administration of single and multiple oral doses. Formulations of erythromycin administered were estolate and phosphate given 37.5 mg/kg every 12 h and 25 mg/kg every 8 h, and stearate and ethylsuccinate given 25 mg/kg every 8 h. Areas under the curve (AUC) and maximum plasma erythromycin concentrations (Cmax) were equal or greater (P ≥ 0.05) following administration of erythromycin phosphate and stearate compared with those values following administration of erythromycin estolate or ethylsuccinate. In comparing an 8 h vs. a 12 h dosage interval for multiple doses of erythromycin phosphate or estolate, there were no significant differences observed in AUC(24–28 h), peak‐trough plasma concentrations or duration that plasma concentrations exceeded the minimal inhibitory concentration (MIC) for Rhodococcus equi. Comparisons of pharmacokinetic parameters between single and multiple doses were made for each formulation. Differences in Cmax, tmax, or t½β between single and multiple doses were demonstrated for erythromycin ethylsuccinate and estolate. Based on equivalent plasma antibiotic concentrations, erythromycin phosphate or stearate could be substituted for estolate in the treatment of Rhodococcus equi pneumonia. Furthermore, there was no advantage of an 8‐h interval, compared with an interval of 12 h.
Probable post‐synaptic α2 adrenergic mediated effect of xylazine on goat uterine motility*
Authors: PEREZ R. , COX T F , ARRUE R.
Published: April 2008

Perez, R., Cox, J.F., Arrue, R. Probable post‐synaptic ot2 adrenergic mediated effect of xylazine on goat uterine motility. J. vet. Pharmacol. Therap. 17, 59–63.

Xylazine has been characterized as a selective α2‐adrenoceptor agonist, which has explained its central nervous system depressant and other pharmacological effects. In order to characterize the effect of xylazine on uterine motility during the oestrus cycle in goats intrauterine pressure changes were recorded in cycling goats using balloon‐tipped catheters placed in the uterine horns and connected to pressure transducers and a recorder. The effect of xylazine on myometrial activity was studied by giving increasing doses of the drug (1.0, 10.0, 100.0 or 500.0 m̈g/kg) intravenously (i.v.) to animals either in the follicular or the luteal phase of the cycle. To establish the subtype of a adrenergic receptor mediating the action of xylazine, goats were pretreated with either prazosin (1.0 mg/kg, i.v.) or yohimbine (1.0 m̈g/kg, i.v.). To establish whether the effect of xylazine was pre‐ or post‐synaptic, xylazine (100 mg/kg, i.v.) was administered to goats pretreated with reserpine (0.8 mg/kg, i.p.) to deplete presynaptic catecholamine stores. Xylazine induced a significant and dose‐dependent increase on uterine motility in cycling goats, apparently mediated by postsynaptic oc2‐adrenoceptors.
Trimethoprim/sulfonamide combinations in the horse: a review
Authors: DUIJKEREN E. VAN. , VULTO A G , MIERT A. S. J. P. A. M. VAN
Published: April 2008

Van Duijkeren, E., Vulto, A.G., van Miert, A.S.J.P.A.M. Trimethoprim/sulfonamide combinations in the horse: a review. J. vet. Pharmacol. Therap.17, 64–73.

The indications for use, side‐effects, and pharmacokinetic parameters of trimethoprim, sulfonamides and their combinations in the horse are reviewed. Trimethoprim/sulfonamide (TMPS) combinations are used for the treatment of various diseases caused by gram‐positive and gram‐negative bacteria, including infections of the respiratory tract, urogenital tract, alimentary tract, skin Joints and wounds‐ TMPS combinations can be administered orally, since absorption from the gastrointestinal tract is relatively good. However, peak serum concentrations can vary significantly between individual horses. Feed intake affects serum concentrations after oral administration. Concentrations of non‐bound trimethoprim (TMP) and sulfadiazine (SDZ) in synovial fluid and peritoneal fluid are equal to serum concentrations after intravenous (i.v.) administration, and high concentrations are found in urine. Concentrations of TMP and sulfamethoxazole (SMX) in cerebrospinal fluid after i.v. administration exceed the minimum inhibitory concentration for common equine pathogens. The volume of distribution is 1.5‐2.71/kg for TMP and 0.3‐0.7 1/kg for various sulfonamides. The plasma half‐life of TMP is 1.9‐4.3 h, whereas the plasma half‐lives of the different sulfonamides vary between 2.7 and 14.0 h. About 50% of total TMP is bound to plasma proteins. The binding of sulfadox‐ine to plasma proteins depends on total plasma concentration and varies between 14% and 72%. The binding of other sulfonamides to plasma proteins may range from 33% for sulfaphenazole (SPZ) to 93% for sulfadimethoxine (SDM). Sulfonamides are metabolized by acetylation of the para‐amino (N4) group and by hydroxylation of the methyl group and the pyrimidine ring. The metabolic pathways of TMP in the horse are not fully known. Bacterial resistance to TMPS combinations is still relatively low. The sensitivity of different micro‐organisms may vary with the relative activity of the sulfonamide used in the combination. The advised oral and i.v. dose rate is 15–30 mg/kg (in a 1:5 TMP/S ratio) with a dose interval of 12 h. The acute toxicity of TMPS is low, but there have been several reports of death after i.v. administration, probably due to vagal stimulation and subsequent bradycardia and vasodilatation caused by the pharmaceutical formulation (excipients, solvents) used. Future research should concentrate on establishing the optimum pyrimidine/sulfonamide combination and its dosing regimen for antimicrobial therapy in horses.
Prolonged‐release hard gelatin capsules of furosemide for the treatment of dogs
Authors: SMAL J. , HAAPALA O. , MARVOLA M. , KUUSELA S. , HAPPONEN I.
Published: April 2008

The object of this study was to examine whether prolonged‐release hard gelatin capsule formulations could be developed for dogs. Different viscosity grades of hydroxypropyl methylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) were used to control drug release. Furosemide was chosen because of its wide use in the management of heart failure in dogs. In vitro, selecting different viscosity grades allowed good control of drug release, whereas in vivo the difference between formulations was clearly smaller. Although all formulations gave prolonged release, both inter‐ and intra‐individual variation in the plasma concentration‐time curves was high. It is difficult to develop prolonged‐release formulations for drugs such as furosemide with highly variable pharmacokinetic properties. However, hard gelatin capsules containing hydrophilic polymers could still be a suitable choice for some drugs.
Pharmacokinetics of trimethoprim/sulphachlorpyridazine in horses after oral, nasogastric and intravenous administration
Authors: DUIJKEREN E. VAN , VULTO A.G. , SLOET M. M. , OOSTERBAAN OLDRUITENBORGH , KESSELS B.G.F. , VAN MIERT A.S.J.P.A.M. , BREUKINK H.J.
Published: April 2008

In the present study, the pharmacokinetic parameters of a trimethoprim/sulphachlorpyridazine preparation following intravenous administration, administration by nasogastric tube and administration with concentrate were determined in the horse. Eight adult horses were dosed at 1 week intervals in a sequentially designed study at a dose of 5 mg/kg trimethoprim (IMP) and 25 mg/kg sulphachlorpyridazine (SCP) on all occasions. Plasma concentrations of both drugs were measured serially for 48 h. Pharmacokinetic parameters of clinical importance (distribution and elimination half‐lives, clearance, bioavail‐ability, volume of distribution) were determined both for TMP and SCP. Following intravenous administration, the volume of distribution at steady‐state (Vd(33)was significantly larger for TMP (1.51 ± 0.25 L/kg than for SCP (0.26 ± 0.05 L/kg. The clearance was 7.73 ± 2.26 mL/min‐kg for TMP and 2.64 ± 0.48 mL/min·kg for SCP. For both TMP and SCP, mean peak plasma concentrations (Cmax) and the bioavailabilities (F) were reduced significantly when the drugs were mixed with concentrate (ct) as compared with those after nasogastric administration (ngt) (Fct= 44.3 ± 10.7% vs.Fngt= 68.3 ± 12.5% for TMP;Fct= 46.3 ± 8.9% vs.Fngt= 67.3 ±13.7% for SCP). Following the administration of TMP and SCP mixed with concentrate, the plasma concentration—time curves showed a biphasic absorption pattern in all horses. The first peak occurred 1–2 h and the second peak 8–10 h after administration of the combination preparation. Based on the pharmacokinetic data obtained and the publishedin vitrosensitivity data, it may be predicted that TMP and SCP given intravenously or by nasogastric tube at a dose of 5 mg/kg and 25 mg/kg respectively and a dosage interval of 8–12 h would result in sufficiently high plasma concentrations for effectiveness against susceptible bacteria. The single oral administration of TMP and SCP mixed with concentrate did not result in effective plasma concentrations. Further studies are needed to investigate whether higher plasma concentrations would be achieved by a multiple dosing scheme for several days.
The disposition of gentamicin in equine plasma, synovial fluid and lymph
Authors: ANDERSON B.H. , FIRTH E.C. , WHITTEM T.
Published: April 2008

Plasma (P), synovial fluid (SF) and lymph (L) concentrations of gentamicin were studied in two trials. A lymph vessel in the hindlimb was cannulated. The day after surgery (trial A), P and L samples were collected for 12 h after intravenous injection of gentamicin sulphate at 2.2 mg/kg dose rate. Approximately 48 h after surgery (trial B), the fetlock joint of the cannulated hindlimb was catheterized and P, SF and L samples collected for 12 h after a similar intravenous injection. The kinetic parameters were similar to those in other reports and did not differ between trials (P< 0.05). The P, L and SF disposition profiles were similar. The 95% confidence interval for P & L concentrations overlapped 2–3 h after injection. Thereafter, parallelism between L and P concentrations was observed, but L concentrations were on average 60% higher than P concentrations, and elimination from L was slower than from P. The mean L/SF and P/SF ratios were 1.54 ± 0.2 and 1.25 ± 0.2, 2–4 h after injection. Gentamicin elimination from SF appeared to be slower than from L and P. Lymph cannulation is a viable technique for antibiotic disposition studies. A sample of any of the fluids 3 h after injection was representative of the others. While SF concentrations were of limited value for predicting tissue fluid (L) concentrations 3–8 after injection, P concentrations were a useful index.
The influence of a heavy infection with sensitive and resistant strains of Ostertagia circumcincta and with Trichostrongylus colubriformis on the pharmacokinetics of febantel in lambs
Authors: LANDUYT J. , DEBACKERE M. , VERCRUYSSE J. , McKELLAR Q.
Published: April 2008

Plasma concentrations of febantel and its major metabolites, fenbendazole, oxfen‐dazole and fenbendazole sulphone, were determined after oral administration of 7.5 mg/kg febantel in lambs before and 28 days after infection with 100 000 L3 larvae of a benzimidazole (BZ)‐ sensitive or BZ‐resistant strain of Ostertagia circumcincta or with 75 000 L3 larvae of a BZ‐ sensitive Trichostrongylus colubriformis strain. The febantel concentrations were always low, and in only a few samples were higher than the limit of detection. A mean decrease in the area under the curve (AUC) for the three metabolites of 10.2%, 16.4% and 4.9% in lambs infected, respectively, with BZ‐sensitive O. circumcincta, BZ‐resistant O. circumcincta and T. colubriformis was observed. The Cmax for all the metabolites was higher in the BZ‐sensitive O. circumcincta group than in the naive sheep, while the Tmax occurred earlier. The Cmax and the Tmax values for all the metabolites were lower in the BZ‐resistant O. circumcincta group than in their own naive controls. In the T. colubriformis group the Cmax values of the metabolites were lower and the Tmax occurred much later.
Pharmacokinetics and tissue residues of norfloxacin and its N‐desethyl‐ and oxo‐metabolites in healthy pigs
Authors: ANADÓN A. , MARTINEZ‐LARRANAGA M.R. , DIAZ M.J. , FERNANDEZ R. , MARTINEZ M.A. , FERNANDEZ M.C.
Published: April 2008

The pharmacokinetic properties of norfloxacin were determined in healthy pigs after single intramuscular (i.m.) and intravenous (i.v.) dosage of 8 mg/kg body weight After i.m. and i.v. administration, the plasma concentration‐time graph was characteristic of a two‐compartment open model. After single i.m. administration, norfloxacin was absorbed rapidly, with atmaxof 1.46 ± 0.06 h. The elimination half‐life (t1/2β) and the mean residence time of norfloxacin in plasma were 4.99 ± 0.28 and 6.05 ± 0.22 h, respectively, after i.m. administration and 3.65 ± 0.16 and 3.34 ± 0.16 h, respectively, after i.v. administration. Intramuscular bioavailability was found to be 53.7 ± 4.4%. Plasma concentrations greater than 0.2 μg/mL were achieved at 20 min and persisted up to 8 h post‐administration. Maximal plasma concentration was 1.11 ± 0.03 μg/mL. Statistically significant differences between the two routes of administration were found for the half‐lives of both distribution and elimination phases (t1/2α,t1/2β) and apparent volume of distribution (Vd(area)). In pigs, norfloxacin was mainly converted to desethylenenorfloxacln and oxonorfloxacin. Considerable tissue concentrations of norfloxacin, desethylenenorfloxacin, and oxonorfloxacin were found when norfloxacin was administered intramuscularly (8 mg/kg on 4 consecutive days). The concentration of the parent fluoroquinolone in liver and kidney ranged between 0.015 and 0.017 μg/g on day 12 after the end of dosing.
Antibacterial activity of marbofloxacin. A new fluoroquinolone for veterinary use against canine and feline isolates
Authors: SPRENG M. , DELEFORGE J. , THOMAS V. , BOISRAMÉ B. , DRUGEON H.
Published: April 2008

Marbofloxacin is a new fluoroquinolone developed exclusively for veterinary use. Minimum inhibitory concentrations of marbofloxacin were assessed for 816 recent isolates associated with canine or feline diseases. Marbofloxacin showed a broad spectrum of activity against gram‐negative and gram‐positive bacteria. In vitro rates of killing of marbofloxacin and enrofloxacin were compared against strains of Staphylococcus intermedius and Pasteurella multocida, and the results showed no marked difference between the two antibiotics. The duration of bactericidal activity was evaluated ex vivo in the urine of dogs and cats treated with marbofloxacin and lasted from 2 to 5 days after a single administration according to the dosages. Post‐antibiotic effect durations were determined with Escherichia colt, PasteureUa multocida, Staphylococcus aureus and Staphylococcus intermedius and were found almost equal to those of enrofloxacin or ciprofloxacin. These results predict a great potential for marbofloxacin in the treatment of a wide range of diseases in dogs and cats.
Disposition kinetics of tylosin tartrate administered intravenously and intramuscularly to normal and water‐deprived camels
Authors: ZIV G. , CREVELD C.V. , BEN‐ZVI Z. , GLICKMAN A. , YAGIL R.
Published: April 2008

The disposition kinetics of tylosin tartrate administered intravenously (i.v.) at 10 mg/kg and intramuscularly (i.m.) at 20 mg/kg were studied in normal camels and in the same camels at the end of a 14 day water‐deprivation period. After i.v. treatment, serum tylosin concentrations in the water‐deprived camels were significantly higher, rate of drug elimination was slower, the volume of distribution was significantly smaller, and total body clearance was significantly slower than in the normal camels. On the other hand, serum drug concentrations were lower in the water deprived camels after i.m. dosing, the mean absorption time was significantly shorter and the i.m. availability was significantly smaller than in the normal camels. Water‐deprivation was thought to cause reduced rate of tylosin elimination by the liver, as was shown for antipyrine—a drug which is eliminated from the body exclusively by the liver. Redistribution of tylosin in tissues concomitant with a greater proportion of drug in blood and extracellular fluid of water‐deprived camels was suggested as a partial explanation for the higher serum drug levels seen after i.v. dosing. The low i.m. availability observed in the water‐deprived camels implies that i.v. is the route of choice for tylosin administration to ill, dehydrated camels.
Effect of water deprivation on the disposition kinetics of enrofloxacin in camels
Authors: GAVRIELLI R. , YAGIL R. , ZIV G. , CREVELD C.V. , GLICKMAN A.
Published: April 2008

Concentrations of enrofloxacin equivalent activity were determined (by microbiological assay) in the serum of normal camels and camels at the end of a 14‐day water‐deprivation period following single intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administrations at 2.5 mg/kg. Also, normal camels were given an oral drench of the drug at 5 mg/kg. Pharmacokinetic variables were determined using compartmental and non‐compartmental analytical methods. Camels lost on average 12.5% of body weight at the end of the water‐deprivation period. The disposition kinetics of i.v. administered drug in normal and water‐deprived camels were very similar. The t1/2β was 3.0–3.5 h; MRT was 4.0–4.5 h; Ve was 0.3 L/kg; V38 was 1.0 L/kg and Cl8 was 4.0–4.6 mL/min/kg. The effect of water deprivation on the rate of drug absorption and elimination after i.m. administration was inconsistent, and there was also a large degree of variability in the normal animals that precluded statistical significance. After s.c. administration, the mean absorption half‐life (t1/2she in the water‐deprived camels was significantly longer than in the normal camels. Systemic availability (F) was similar in both normal and water‐deprived camels after i.m. dosing but was significantly greater (P < 0.05) in normal camels (0.92 compared with 0.65 in water‐deprived camels) after s.c. treatment In normal camels, urinary recovery at 12 h after l.v. and s.c. dosing was 25% and 15%, respectively, and the extent of serum protein binding ranged between 1.7% at 1.8 μg/mL and 24% at 0.33 μg/mL. The drug was not detected in serum after oral administration. Serum and milk enrofloxacin equivalent activities were determined after i.v. (one camel) and i.m. (one camel) drug administration. Serum drug concentrations were consistently higher than in the milk. The AUCmilk/AUCserust ratios were 0.27 and 0.39 after i.v. and i.m. drug administration, respectively. An i.m. or s.c. treatment regimen of 2.5 mg/kg q. 12 h is suggested for clinical and bacteriological efficacy trials with enrofloxacin in normally hydrated and dehydrated camels.
Enrofloxacin‐theophylline interaction: influence of enrofloxacin on theophylline steady‐state pharmacokinetics in the Beagle dog
Authors: INTORRE L. , MENGOZZI G. , MACCHERONI M. , BERTINI S. , SOLDANI G.
Published: April 2008

Enrofloxacin, a quinolone antibiotic developed exclusively for use in animals, was investigated for its effects on the steady‐state pharmacokinetics of theophylline in six healthy Beagle dogs. A sustained‐release theophylline formulation was given alone (20 mg/kg per os twice daily at 12 h intervals) for 9 days and then co‐administered with enrofloxacin (5 mg/kg i.v. once a day) for 5 days. Mean trough theophylline concentrations progressively and significantly increased during the five days of enrofloxacin co‐administration. Theophylline clearance and concentration‐time profile were significantly changed by enrofloxacin co‐administration. No significant change was observed in enrofloxacin pharmacokinetics. The kinetic interaction between theophylline and enrofloxacin could be of clinical significance and may require plasma drug concentration monitoring and adjustment of theophylline dosage.
Plasma and urine disposition and dose proportionality of ceftiofur and metabolites in dogs after subcutaneous administration of ceftiofur sodium
Authors: BROWN S.A. , ARNOLD T.S. , HAMLOW P.J. , SPEEDY A.K. , DELEEUW N.L. , HUBBARD V.L. , CALLAHAN J.K. , FOLZ S.D. , JANOSE R.L. , FLOOK T.F. , COX T.D.
Published: April 2008

Nine male dogs (10.3–13.5 kg body weight) were randomly assigned to three groups of three dogs each and administered ceftiofur sodium subcutaneously as a single dose of 0.22, 2.2, or 4.4 mg ceftiofur free acid equivalents/kg body weight. Plasma and urine samples were collected serially for 72 h and assayed for ceftiofur and metabolites (derivatized to desfuroylceftiofur acetamide) using high‐performance liquid chromatography. Urine concentrations remained above the MIC90 for Escherichia coll (4.0 μg/mL) and Proteus mirabilis (1.0 μg/mL) for over 24 h after doses of 2.2 mg/kg (8.1 μg/mL) and 4.4 mg/kg (29.6 μg/mL), the interval between treatments for ceftiofur sodium in dogs, whereas urine concentrations 24 h after dosing at 0.22 mg/kg (0.1 mg/Ib) were below the MIC90 for E.coli and P. mirabills (0.6 μg/mL). Plasma concentrations were dose‐proportional, with peak concentrations of 1.66 ± 0.0990 μg/mL, 8.91 ± 6.42 μg/mL, and 26.7 ± 1.07 μg/mL after doses of 0.22, 2.2, and 4.4 mg/kg, respectively. The area under the plasma concentration versus time curve, when normalized to dose, was similar across all dosage groups.
Potency of antibacterial drugs in milk as analysed by β‐glucuronidase‐based fluorometry
Authors: FANG W. , VIKERPUUR M.
Published: April 2008

The potency of selected antibacterials on mastitis‐causing Escherichta coli, Streptococcus agalactiae and Streptococcus uberis in milk, whey and Iso‐sensitest broth (ISB) was compared, based on the suppression of bacterial β‐glucuronidase production. The β‐glucuronidase activity in the samples was analysed by substrate‐defined fluorometry where the turbidity of milk does not disturb the assay. In ISB, all four E. coli strains were susceptible to enrofloxacin and gentamicin, sulfadoxintrimethoprim and tetracycline. S. agalactiae and S. uberis strains were susceptible in ISB to most of the antibacterials tested. The antibacterial potency of sulfadoxintrimethoprim, tetracycline, novobiocin, gentamicin and enrofloxacin on E. coli and S. agalactiae were considerably decreased in milk as compared with that in ISB. However, S. uberis seemed to be more susceptible to antibacterials in milk or whey than in ISB. Regression analysis of the sigmoidal dose‐response curves of sulfadoxin‐trimethoprim showed that slopes of the linearized lines seemed to become less steep in milk than in the artificial broth medium, indicating a shift of the bactericidic effect in ISB towards a bacteriostatic effect in milk.
The dose‐related effects of phenylbutazone and a methylprednisolone acetate formulation (Depo‐Medrol®) on cultured explants of equine carpal articular cartilage
Authors: JOLLY W.T. , WHITTEM T. , JOLLY A.C. , FIRTH E.C
Published: April 2008

The dose‐related effects of phenylbutazone and Depo‐Medrol® on chondrocyte viability and chondrocyte‐mediated synthesis and depletion of proteoglycans were investigated using cultured explants of equine middle carpal joint articular cartilage. Explants from 12 horses (941 × 3 mm diameter) were cultured for a total of 5 days, which included 3 days' exposure to either phenylbutazone (0, 2, 20, 200 or 2000 μg/mL) or Depo‐Medrol (0, 20, 200 or 2000 μg/mL). For each explant, amino sugar content was used as a measure of proteoglycan content,35S incorporation as a measure of the rate of proteoglycan synthesis and the number of pyknotic nuclei as a measure of cell death. During culture, control explants remained metabolically active and viable but suffered a net loss of proteoglycans. Proteoglycan loss was reduced by the presence of either phenylbutazone or Depo‐Medrol. This effect was significant at clinically relevant concentrations of phenylbutazone (2–20 μg/mL), but not Depo‐Medrol (20–200 μg/mL). Depo‐Medrol caused a dose‐dependent suppression of proteoglycan synthesis at all concentrations, but chondrocyte viability was affected only at the 2000 μg/mL dose. Phenylbutazone affected proteoglycan synthesis and cell viability only at the 2000 μg/mL concentration. At all concentrations, the anticatabolic effects of each drug influenced the proteoglycan content of the explants far more than did any antianabolic or cytotoxic drug effect. The results suggest that the therapeutic potential of both phenylbutazone and Depo‐Medrol may not be restricted to their anti‐inflammatory effects on the soft tissues of the joint.
Lidocaine elimination and monoethylglycinexylidide formation in the dehydrated camel
Authors: BEN‐ZVI Z. , GOLDIN G. , VAN CREVELD C. , YAGIL R.
Published: April 2008

The elimination kinetics and the formation of the monoethylglycinexylidide (MEGX), a major metabolite of lidocaine, were studied in camels deprived of water for 14 days. The study was conducted on four camels in a crossover design. Lidocaine was administered intravenously at a dose of 1 mg/kg to adult female camels when water was given ad libitum (stage 1) and to the same camels after 14 days of dehydration. Blood samples were taken up to 6 h after dosing. Serum lidocaine and MEGX levels were analysed by polarization fluorescence immunoassay. The elimination profiles of lidocaine and the formation of the metabolite MEGX in the two phases of the study were essentially identical. No difference in any pharmacokinetic parameter was noticed between normally hydrated and water‐deprived camels. It is thus concluded that dehydration does not affect the cytochrome P450 isozymes involved in degradation of lidocaine to MEGX nor does it affect the hepatic blood flow, which is a major determinant in the clearance of lidocaine. The very low clearance of lidocaine in the camel in comparison with other ruminant or monogastric mammals may be associated with the camel's ability to survive drought in the desert.
The pharmacokinetics of oral and intravenous allopurinol and intravenous oxypurinol in the horse
Authors: MILLS P.C. , DUNNETT M. , SMITH N.C.
Published: April 2008

The pharmacokinetics of oral and intravenous allopurinol was studied in five horses and compared with intravenous oxypurinol. The plasma concentration vs. time curves, following intravenous administration of 5 mg/kg, were best described by the biexponential equations Cp = 106.58e‐25.141+ 159.93e‐10.96tfor allopurinol and Cp = 321.09e‐972t+ 82.39e‐0.44tfor oxypurinol. Allopurinol was rapidly removed from the plasma, compared to oxypurinol, with an elimination half‐life (t1/2β) of 0.09 h and an area under the curve (AUC) of 19.8 μmol·h/L after intravenous administration, while the t1/2β and AUC of oxypurinol were 1.09 h and 231 μmol·h/L, respectively. The bioavailability of allopurinol was low (14.3%), although no allopurinol was detected in the plasma of two horses after oral administration. However, the AUC of drug and metabolite after intravenous administration of allopurinol was equivalent to that of intravenously injected oxypurinol. The results suggest that allopurinol is rapidly metabolised in vivo and that the majority of the pharmacological activity of allopurinol in the horse may result from the action of the active metabolite, oxypurinol.
Pharmacokinetics of marbofloxacin in dogs after oral and parenteral administration
Authors: SCHNEIDER M. , THOMAS V. , BOISRAME B. , DELEFORGE J.
Published: April 2008

Six dogs were treated with a single intravenous (i.v.) dose (2 mg/kg) of marbofloxacin, followed by single oral (p.o.) doses of marbofloxacin at 1, 2 and 4 mg/kg, according to a three‐way crossover design. The same experimental design was used for the subcutaneous (s.c.) route. In addition, a long‐term trial involving eight dogs given oral doses of marbofloxacin at 2, 4 and 6 mg/kg/day for thirteen weeks was carried out. Plasma and urine samples were collected during the first two trials, plasma and skin samples were collected after the second of these trials. Plasma, urine and skin concentrations of marbofloxacin were determined by a reverse phase liquid chromatographic method. Mean pharmacokinetic parameters after i.v. administration were the following: t1/2β=12.4h; ClB= 0.10 L/h.kg; Varea= 1.9 L/kg. The oral bioavailability of marbofloxacin was close to 100% for the three doses. At 2 mg/kg, Cmax of 1.4 μg/mL was reached at tmax of 2.5 h. Mean AUC and Cmax values had a statistically significant linear relationship with the doses administered. About 40% of the administered dose was excreted in urine as unchanged parent drug. After s.c. administration, the calculated parameters were close to those obtained after oral administration, except tmax (about 1 h) which was shorter. The mean skin to plasma concentration ratio after the long‐term trial was 1.6, suggesting good tissue penetration of marbofloxacin.
Pharmacokinetics of caffeine in the oestrogen‐implanted ovariectomized ewe
Authors: POLLARD IRINA , WILLIAMSON SUSAN , DOWNING JEFF , SCARAMUZZI REX
Published: April 2008

The disposition kinetics of caffeine and its metabolites theophylline, theobro‐mine and paraxanthine in the oestrogen‐implanted ovariectomized ewe following single intravenous doses of 5, 10, 15 or 20 mg/kg caffeine are described in this paper. Blood was collected at 5, 30 and 60 min, and at 3, 6, 8, 12, 24, 48, 72, 96, 120, 144, 192 and 240 h after dosing. Caffeine concentrations peaked within 30 min of administration but remained in a plateau phase for 3‐6 h before declining over a prolonged period of time. For caffeine the mean elimination half‐life was calculated to be 47 h. Detectable caffeine concentrations remained for 10 days after administration in all groups. The area under the plasma concentration‐time curve (AUC) values were used to compare tissue caffeine exposure and were, approximately, linearly related to dose. Metabolite concentrations were maintained at peak and near peak concentrations for 6‐24 h after caffeine administration followed by prolonged elimination. Because of significant species differences in drug elimination rates, it is concluded that the ewe is not a suitable animal model in the clinical context. However, the sheep may well provide insights into caffeine's mechanism of action of relevance to veterinary drug research.
Contribution of æ1‐acid glycoprotein to plasma protein binding of some basic antimicrobials in pigs
Authors: SON D‐S. , HARIYA S. , SHIMODA M. , KOKUE E.
Published: April 2008

Protein binding kinetics of basic antimicrobials including trimethoprim (TMP), erythromycin (EM), lincomycin (LM) and clindamycin (CM) were studied using porcine plasma, albumin and æ‐acid glycoprotein (AGP). Rosenthal plots of these basic drugs in porcine plasma suggest saturable and non‐saturable binding. Dissociation constants (Kd) and binding capacity (Bmax) for saturable binding were as follows: TMP,Kd= 8.58 μmol/L, Bmax= 5.26 μmol/L; EM,kd= 2.72 μmol/L, Bmax= 3.06 μmol/L; LM,kd= 3.96 μmol/L, Bmax= 6.58 μmol/L and CM,kd= 4.43 μmol/L, Bmax= 21.7 μmol/L. The proportionality constants (Bmax2/kd2) for non‐saturable binding were 0.29 in TMP, 0.52 in EM, 0.17 in LM and 3.2 in CM. Thekds of the drugs in porcine AGP solution were determined by a fluorescence quenching method, using 1‐anilino‐8‐naphthalene sulphonate (ANS) as a fluorescent probe: 9.51 μmol/L in TMP, 1.89 μmol/ L in EM, 4.48 μmol/L in LM and 9.69 μmol/L, in CM. Comparable kd values between porcine plasma and AGP solution indicated that AGP is a major saturable binder in porcine plasma. Binding property to porcine albumin presented linearity, showing the following proportionality constants: 0.23 in TMP, 0.38 in EM, 0.01 in LM and 0.76 in CM. The comparable proportionality constants of TMP and EM between porcine plasma and albumin solution indicate that albumin is a major non‐saturable binder, whereas proportionality constants of LM and CM in albumin solution compared to those in porcine plasma were low, implying another non‐saturable binder, i.e. lipoprotein. Simulation curve of drug‐binding percentage vs. AGP concentrations showed that in pigs under a pathologic state, or during early growth stage with high AGP levels, AGP could be a main contributor to drug‐plasma protein binding for all drugs examined. The increase of AGP from normal to pathological concentrations induced a decrease in the unbound fraction: LM > CM > EM > TMP in order of AGP contribution to drug binding. Therefore, the disposition and efficacy of basic antimicrobials which bind to AGP with high affinity could be markedly influenced by altered AGP levels, implying AGP contribution to pharmacokinetics and pharmacodynamics.
Pharmacokinetics of epidural butorphanol in isoflurane‐anaesthetized dogs
Authors: TRONCY E. , BESNER J.‐G. , CHARBONNEAU R. , CUVELLIEZ S. G. , BLAIS D.
Published: April 2008

Sixteen healthy male dogs were used at random in this protocol. The dogs were anaesthetized with isoflurane in oxygen. Eight of the dogs received 0.25 mg/kg of butorphanol (group B) and the others an equal volume of isotonic saline (group S) administered by a catheter inserted in the lumbosacral epidural space. Butorphanol concentrations in plasma and cerebrospinal fluid (CSF) were measured using high‐performance liquid chromatography with electrochemical detection. Maximum concentration of butorphanol and time to obtain this concentration were 42.28 ng/mL at 13.88 min in blood, and 18.03 ng/mL at 30 min in CSF. Volume of distribution, clearance, mean distribution and elimination half‐lives were respectively 4.39 L/kg, 2.02 L/h.kg, 16.5 min and 189.1 min. Mean isoflurane minimal alveolar concentration values for group B obtained following hind‐ or forelimb stimulation decreased by 31% after epidural butorphanol. Cutaneous analgesia (to pin‐prick test) persisted for 3 h after the end of isoflurane anaesthesia in group B and was in correlation with the plasmatic analgesic dose of butorphanol (9 ng/mL). These results suggested that analgesia was predominantly obtained by action of butorphanol on the supraspinal structures following its vascular systemic absorption.
Stability of ivermectin in rumen fluids
Authors: ANDREW N. W. , HALLEY B. A.
Published: April 2008

To determine whether ivermectin is metabolized in the rumen, in vitro studies were conducted with the tritium‐labelled H2B1a component of ivermectin in rumen fluid from sheep and cattle. No detectable metabolism occurred over 24 h in in vitro incubations at 38°. The viability of the microbes in the rumen fluids was demonstrated by the conversion of 17% and 11% of [14C]cellulose to 14CO2 in 24 h in the incubations with sheep and steer rumen fluids respectively. The results indicate that ivermectin is not metabolized in the rumen. Based on the lack of in vitro metabolism of ivermectin in rumen fluid, the similarity of in vitro liver microsomal metabolism with in vivo metabolism of the avermectins and the physicochemical properties of the avermectins, any disappearance of ivermectin in vitro from rumen fluid is probably a result of binding to solids or surfaces. Apparent discrimination by dung beetles, where observed, between control faeces and faeces from cattle or sheep treated with ivermectin or abamectin therefore must be attributable to chance, to factors unrelated to treatment or to factors such as changes in amino acid composition rather than the production of volatile metabolites of ivermectin.
Bioavailability of ketoprofen in horses after rectal administration
Authors: CORVELEYN S. , DEPREZ P. , WEKEN G. VAN DER , BAEYENS W. , REMON J. P.
Published: April 2008

Six healthy mares ranging in age from 6 to 12 years and weighing from 415 to 540 kg were used to determine the rectal bioavailability of ketoprofen. For the rectal administration, three different formulations, each containing 1 g of ketoprofen, were administered in a fatty and a hydrophilic suppository base and as a liquid suspension. An average elimination half‐life of 1.3 h (±1.2) was found. The average value for the total plasma clearance (ClT) was 131.9 mL/min.kg (range 95‐183.5). The volume of distributionVd(area)was 255 mL/kg and the mean residence time (MRT)P = 0.05; Friedman test). Despite the low rectal bioavailability obtained in this study, there was some evidence for the clinical effectiveness of the rectal formulations.
A lipopolysaccharide‐induced acute phase response in the pig is associated with a decrease in hepatic cytochrome P450‐mediated drug metabolism
Authors: MONSHOUWER M. , WITKAMP R. F. , NIJMEIJER S. M. , van LEENGOED L.A.M.G. , VERNOOY H.C.M. , VERHEIJDEN J.H.M. , MIERT A.S.J.P.A.M. VAN
Published: April 2008

Drug disposition, including hepatic drug metabolism, is markedly affected by infection, inflammation and other conditions that invoke the acute phase response. In the present study, an Escherichia coli lipopolysaccharide (LPS)‐induced acute phase response model was developed in pigs. This model was used to study the effects of the acute phase response on drug disposition and hepatic drug metabolism in vivo and in microsomal preparations. The results obtained were compared with those from Actinobacillus pleuropneumoniae‐infected pigs. Intermittent intravenous administration of LPS induced a mild acute phase response as evidenced by increased rectal body temperatures, anorexia and increased cytokine (TNF‐α and IL‐6) serum levels within 1‐2 h after the first LPS injection. The acute phase response is associated with a pronounced decrease of antipyrine plasma clearance (control 8.5 ± 0.8 vs. LPS 2.2 ± 0.7 mL/min.kg). Furthermore, total cytochrome P450 content and microsomal cytochrome P450‐dependent activities were significantly decreased after 24 h. The decrease in cytochrome P450 activities was accompanied by losses of cytochrome P4501A and P4503A apoproteins. The microsomal glucuronidation rate of 1‐naphthol was not affected in LPS‐treated pigs. Comparing the LPS model with our previous findings in the Actinobacillus pleuropneumoniae model showed a remarkable similarity with regard to the effects on hepatic drug metabolism.
Effect of pharmacological agonists on contractile responses in aortic rings derived from endotoxaemic rats
Authors: DONALDSON L. L. , MYERS A.K.
Published: April 2008

To investigate the vascular smooth muscle dysfunction of septic shock,in vitroisometric responses to phenylephrine (PE) and acetylcholine (ACh) were evaluated in aortic rings, with and without endothelium (± E), removed from male Wistar rats 1.5, 3 and 6 h after intravenous (i.v.) administration of 5 mg/kg lipopolysaccharide (LPS) or vehicle. A reduction in maximum contraction (±E) and sensitivity (‐E) to PE were identified at 6 but not at 1.5 or 3 h. Maximum relaxation to ACh (+ E) was not affected by LPS treatment but sensitivity was increased at 1.5 and 3 h. Having identified 6 h as the time at which the most pronounced changes were observed, further studies at this interval found that maximum contraction to potassium chloride (±E), prostaglandin F2a(+ E) and detomidine (‐E) and relaxation to salbutamol (‐E) were less in aortic rings from endotoxaemic rats. Sensitivity to KCl (±E), PGF2a(‐ E) and detomidine (‐ E) was also reduced. Relaxation to sodium nitroprusside and atrial natriuretic peptide was not changed. These results suggest that attenuated pressor responses to a variety of vasoactive agents may be expected in patients 6 h after systemic exposure to endotoxin and that this vasoplegia may influence the vascular side‐effects of therapeutic agents.