oxytetracycline--anhydrous and carprofen

A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four-period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(-) and S(+) carprofen enantiomers, except for a lower maximum concentration (Cmax ) of S(+) carprofen in serum after co-administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration-time curve (AUC0-96 h were 136.9 and 128.3 μg·h/mL and means for the terminal half-life (T(1/2) k10 ) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC0-96 h in both carprofen treatments and T(1/2) k10 for carprofen alone were lower (P < 0.05) than R(-) carprofen values, indicating a small degree of enantioselectivity in the disposition of the enantiomers. Carprofen inhibition of serum thromboxane B2 ex vivo was small and significant only at a few sampling times, whereas in vivo exudate prostaglandin (PG)E2 synthesis inhibition was greater and achieved overall significance between 36 and 72 h (P < 0.05). Inhibition of PGE2 correlated with mean time to achieve maximum concentrations in exudate of 54 and 42 h for both carprofen treatments for R(-) and S(+) enantiomers, respectively. Carprofen reduction of zymosan-induced intradermal swelling was not statistically significant. These data provide a basis for the rational use of carprofen with oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co-administered.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Carbazoles; Cattle; Cross-Over Studies; Diffusion Chambers, Culture; Dinoprostone; Drug Interactions; Half-Life; Injections, Intramuscular; Injections, Subcutaneous; Male; Oxytetracycline; Thromboxane B2

The aims of this field trial were to describe the clinical-pathologic findings in calves with otitis media (OM) and media-interna (OMI), to evaluate, through the development of a scoring system, the effectiveness of a standardized therapeutic protocol, and to identify the causative pathogens and their possible correlation with concurrent respiratory disease. All animals underwent physical and neurological examinations at three experimental time points: at diagnosis/beginning of treatment (T0), 1 week (T1) and 2 weeks (T2) after therapy was started, respectively. Follow-up telephone interviews with animal owners were conducted 1 month later. The therapeutic protocol consisted of tulathromycin (Draxxin®; Zoetis), oxytetracycline hydrochloride (Terramicina 100®; Zoetis), and carprofen (Rimadyl®; Zoetis).. Twenty-two calves were enrolled. Physical and otoscopic examination at T0 revealed monolateral and bilateral otorrhea in 16 and 6 calves, respectively, with peripheral vestibular system involvement in calves presenting with neurological signs (n = 17; 77 %). A significant improvement of clinical and neurological scores was observed in 20 (90 %) calves, a full recovery in only 1 (5 %). One calf worsened between T0 and T1 and it was removed from the study. None of the other animals showed a worsening of clinical conditions and/or required further treatments at one month follow up. Mycoplasma bovis was isolated in 89 % of the affected ears either alone or together with P. multocida (n = 5), Streptococcus spp. (n = 1), Staphylococcus spp. (n = 1), and Pseudomonas spp. (n = 1). M. bovis either alone or together with these bacteria was also isolated from the upper and/or lower respiratory tract in 19 (86 %) calves.. This is the first prospective study to evaluate the effectiveness of a standardized therapeutic protocol for the treatment of OM/OMI in calves. The therapy led to clinical improvement in the majority of the calves. Persistence of mild clinical-neurological signs did not compromise productive performance. The numerical scoring system for clinical and neurological signs permitted objective evaluation of response to therapy. M. bovis was the pathogen most often isolated. This finding should be considered in the treatment of OM/OMI in calves. Moreover, respiratory tract infection should not be underrated, since it is one of the major risk factors for the development of OM/OMI.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Cattle; Cattle Diseases; Disaccharides; Female; Heterocyclic Compounds; Labyrinthitis; Male; Otitis Media; Oxytetracycline

The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of oxytetracycline were investigated, when administered both alone and in the presence of carprofen, in healthy calves. The study comprised a four treatment, four sequences, and four period cross-over design and used a tissue cage model, which permitted the collection of serum, inflamed tissue cage fluid (exudate) and non-inflamed tissue cage fluid (transudate). There were no clinically relevant differences in the PK profile of oxytetracycline when administered alone and when administered with carprofen. PK-PD integration was undertaken for a pathogenic strain of Mannheimia haemolytic (A1 76/1), by correlating in vitro minimum inhibitory concentration (MIC) and time-kill data with in vivo PK data obtained in the cross-over study. Based on in vitro susceptibility in cation adjusted Mueller Hinton Broth (CAMHB) and in vivo determined PK variables, ratios of maximum concentration (Cmax) and area under curve (AUC) to MIC and time for which concentration exceeded MIC (T>MIC) were determined. The CAMHB MIC data satisfied integrated PK/PD relationships predicted to achieve efficacy for approximately 48 h after dosing; mean values for serum were 5.13 (Cmax/MIC), 49.3 h (T>MIC) and 126.6 h (AUC(96h)/MIC). Similar findings were obtained when oxytetracycline was administered in the presence of carprofen, with PK-PD indices based on MIC determined in CAMHB. However, PK-PD integration of data, based on oxytetracycline MICs determined in the biological fluids, serum, exudate and transudate, suggest that it possesses, at most, limited direct killing activity against the M. haemolytica strain A1 76/1; mean values for serum were 0.277 (Cmax/MIC), 0 h (T>MIC) and 6.84 h (AUC(96h)/MIC). The data suggest that the beneficial therapeutic effects of oxytetracycline may depend, at least in part, on actions other than direct inhibition of bacterial growth.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Cattle; Drug Interactions; Drug Therapy, Combination; Exudates and Transudates; Injections, Intramuscular; Mannheimia haemolytica; Microbial Sensitivity Tests; Oxytetracycline; Pneumonia of Calves, Enzootic

The pharmacodynamics (PD) of oxytetracycline was investigated against a strain of Mannheimia haemolytica. In vitro measurements, comprising minimum inhibitory concentration (MIC), minimum bactericidal concentration and time-kill curves, were conducted in five matrices; Mueller Hinton Broth (MHB), cation-adjusted MHB (CAMHB) and calf serum, exudate and transudate. MICs were much higher in the biological fluids than in MHB and CAMHB. Ratios of MIC were, serum: CAMHB 19 : 1; exudate:CAMHB 16.1; transudate:CAMHB 14 : 1. Ex vivo data, generated in the tissue cage model of inflammation, demonstrated that oxytetracycline, administered to calves intramuscularly at a dose rate of 20 mg/kg, did not inhibit the growth of M haemolytica in serum, exudate and transudate, even at peak concentration. However, using in vitro susceptibility in CAMHB and in vivo-determined pharmacokinetic (PK) variables, average and minimum oxytetracycline concentrations relative to MIC (C(av)/MIC and C(min)/MIC) predicted achievement of efficacy for approximately 48 hours after dosing. Similar C(av)/MIC and C(min)/MIC data were obtained when oxytetracycline was administered in the presence of carprofen. PK-PD integration of data for oxytetracycline, based on MICs determined in the three biological fluids, suggests that it possesses, at most, limited direct killing activity against M haemolytica. These data raise questions concerning the mechanism(s) of action of oxytetracycline, when administered at clinically recommended dose rates.

Topics: Animals; Anti-Infective Agents; Area Under Curve; Carbazoles; Cattle; Colony Count, Microbial; Dose-Response Relationship, Drug; Exudates and Transudates; Injections, Intramuscular; Mannheimia haemolytica; Microbial Sensitivity Tests; Oxytetracycline; Pneumonia of Calves, Enzootic; Tissue Distribution

Rats subjected to hypophysectomy make up one of the largest groups of experimental animals in Europe, since there is a legal demand for batch testing of industrially produced growth hormones. To describe the clinical performance of rats having undergone hypophysectomy, animals were examined postoperatively by monitoring behaviour, body temperature and food intake. Behavioural changes were observed in rats that had only been anaesthetized, as well as in sham-operated rats, while no behavioural deviations could be shown in hypophysectomized rats. On the first day after surgery all rats had declining body temperature and food intake; and this change was not reversed by treatment with carprofen, buprenorphine or oxytetracycline. The mortality rate in rats treated with buprenorphine was increased, as was the mortality rate in rats hypophysectomized when weighing more than 100 g. As there seemed to be no differences whether methohexital or a combination of fentanyl, fluanison and midazolam was used, the latter anaesthesia is recommended due to its analgesic potential. For post-surgical analgesic treatment, carprofen is recommended rather than buprenorphine. At best, the use of hypophysectomized rats should be replaced in industrial batch testing by an existing in vitro method.

Topics: Analgesics, Opioid; Anesthesia, Intravenous; Anesthetics, Intravenous; Animal Welfare; Animals; Behavior, Animal; Body Temperature; Buprenorphine; Butyrophenones; Carbazoles; Eating; Fentanyl; Hypophysectomy; Male; Methohexital; Midazolam; Oxytetracycline; Postoperative Complications; Rats; Rats, Inbred Strains