thromboxane-b2 and oxindanac

A high-performance liquid chromatographic method for the determination of the non-steroidal anti-inflammatory drug, oxindanac, in calf plasma is described. Recoveries over the concentration range 0.375 to 62.5 micrograms/ml were 90.2-107.8% with interassay coefficients of variation of 2.1-22.3%. The limit of detection was estimated as 0.10 micrograms/ml and the limit of quantification calculated to be 0.24 micrograms/ml in a 1 ml plasma sample. This method was used to establish the pharmacokinetics following intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administration to calves of oxindanac at a dose rate of 2 mg/kg. The elimination t1/2 was long (t1/2 21.2 h after i.v. injection) and absorption was rapid (t1/2a 0.072 h) and complete (F > 100%) following i.m. administration. Bioavailability was incomplete (F = 66.6%) following p.o. administration to calves that had been fed on milk, and Wagner-Nelson analysis revealed two absorption phases (t1/2's 0.20 and 1.9 h). Oxindanac produced long-lasting inhibition of serum TxB2 production, with mean Emax values (% inhibition) of 96.8, 94.1 and 81.3 following i.v., i.m. and p.o. administration, respectively. A single i.v. or i.m. injection of 2 mg/kg oxindanac will probably be active in calves for at least 36-48 h.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Cattle; Chromatography, High Pressure Liquid; Drug Administration Routes; Half-Life; Indenes; Injections, Intramuscular; Injections, Intravenous; Male; Reproducibility of Results; Thromboxane B2

The pharmacokinetics and pharmacodynamics of the non-steroidal antiinflammatory drug, oxindanac, were assessed simultaneously in calves after intravenous (i.v.) administration at dose rates of 0.5, 1, 2, 4 and 8 mg/kg. Plasma pharmacokinetic data were fitted to either two or three compartment open models. The elimination t1/2 was constant in the dose range 0.5 to 4 mg/kg (20.2-22.8 h) and shorter at 8 mg/kg (14.7 h). The pharmacodynamics of oxindanac were assessed by its inhibition of serum TxB2, an index of platelet cyclo-oxygenase activity. Plots of total plasma oxindanac concentration vs. inhibition of serum TxB2 fitted in all cases a sigmoidal Emax equation. There were no significant differences in the estimates for ED50 (1.6-1.9 micrograms/ml), Hill constant (1.3-2.7) or Emax between the doses used in the in vivo studies or when blood was spiked with oxindanac in vitro. Plots of inhibition of serum TxB2 vs. time were prepared from the pharmacokinetic model equations in each calf in combination with a single sigmoidal Emax plot generated in vitro. These data were not significantly different from the results produced in vivo. It is concluded that oxindanac causes reversible inhibition of platelet cyclo-oxygenase in calves. Its inhibition of serum TxB2 can be predicted from total plasma drug concentration, as described by a multicompartmental model, and sigmoidal Emax enzyme kinetics. It was not necessary to take into account factors such as drug equilibration between plasma and its target site, free vs. total drug concentration or chirality. This simple model may be useful for predicting the pharmacodynamics of oxindanac in other species.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Chromatography, High Pressure Liquid; Half-Life; Indenes; Injections, Intravenous; Male; Prostaglandin-Endoperoxide Synthases; Thromboxane B2

A simple and humane model of inflammation, induced by the intradermal injection of 0.3 mL of sterile 2% carrageenan, was characterized in calves by measuring the volume of skin swelling plus histological analysis of skin biopsies. Carrageenan produced a biphasic increase in skin swelling, with an early edematous response followed by a more chronic cellular infiltrate. The swelling and sensitivity to pressure observed in the early response were suitable for testing the antiedematous and analgesic activity of a new nonsteroidal anti-inflammatory drug (NSAID), oxindanac. Pretreatment with intravenous oxindanac at doses from 0.5 to 8.0 mg/kg reduced the volume of swelling and this reached statistical significance (p < 0.05) at 2 mg/kg. The ED50 and ED90 values for inhibition of the peak swelling volume (4 h) were estimated to be 1 mg/kg and 2 mg/kg, respectively. These compare with an ED90 of 2.0 mg/kg for inhibition of serum TxB2 production, an index of platelet cyclo-oxygenase activity. The dose of oxindanac required for antiedematous activity correlated, therefore, with maximal inhibition of serum TxB2. The analgesic activity of oxindanac reached no clear maximum response, but statistically significant difference (p < 0.05) from placebo was reached with doses of 2 mg/kg and above. It is concluded that intradermal carrageenan produced a simple, humane and useful model for dose estimation of a new NSAID in calves.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cattle; Cattle Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Indenes; Inflammation; Injections, Intradermal; Male; Pressure; Skin; Thromboxane B2