In vitro effects and in vivo efficacy of a novel cyclooxygenase-2 inhibitor in cats with lipopolysaccharide-induced pyrexia

OBJECTIVE: To determine cyclooxygenase (COX)-2 selectivity, pharmacokinetic properties, and in vivo efficacy of firocoxib (ML-1,785,713) in cats. ANIMALS: 5 healthy male and 14 healthy female domestic shorthair cats. PROCEDURE: Selectivity of firocoxib for inhibiting COX-2 was determined by comparing the potency for inhibiting COX-1 with that of COX-2 in feline blood. Pharmacokinetic properties were determined after i.v. (2 mg/kg) and oral (3 mg/kg) administration in male cats. In vivo efficacy was evaluated in female cats with lipopolysaccharide (LPS)-induced pyrexia with administration of firocoxib 1 or 14 hours before LPS challenge. RESULTS: Blood concentrations resulting in 50% inhibition of COX-1 and COX-2 activity in vitro were 75 +/- 2 microM and 0.13 +/- 0.03 microM, respectively, and selectivity for inhibiting COX-2 relative to COX-1 was 58. Firocoxib had moderate to high oral bioavailability (54% to 70%), low plasma clearance (4.7 to 5.8 mL/min/kg), and an elimination half-life of 8.7 to 12.2 hours. Firocoxib at doses from 0.75 to 3 mg/kg was efficacious in attenuating fever when administered to cats 1 or 14 hours before LPS challenge. CONCLUSIONS AND CLINICAL RELEVANCE: Firocoxib is a potent COX-2 inhibitor and is the only selective COX-2 inhibitor described for use in cats to date. It is effective in attenuating febrile responses in cats when administered 14 hours before LPS challenge, suggesting it would be suitable for once-a-day dosing. Because selective COX-2 inhibitors have an improved therapeutic index relative to nonselective nonsteroidal anti-inflammatory drugs in humans, firocoxib has the potential to be a safe, effective anti-inflammatory agent for cats.     

Obesity induced by force-feeding and accompanying changes in body temperature and fertility in the male domestic fowl.

1. Excessive amounts of food (two-fold more than the ad libitum intake) introduced into the gastro-intestinal tract of three adult male fowls, for 5 weeks, caused a marked increase in body weight resulting mainly from fat deposition. 2. The induced obesity was accompanied by an increase of the rectal temperature (0-2 to 0-3 degrees C) and a decrease of the skin and comb temperatures, a cessation in the growth of the comb, a reduction in the blood packed cell volume, an eight-fold reduction in the number of spermatozoa in the vasa deferentia and a concomitant depression in their motility. 3. A decrease of the testosterone and an increase of luteinising hormone concentrations in the blood plasma was obtained in two of the three treated birds.     

Quantitation of immune response gene expression and cellular localisation of interleukin-1beta mRNA in Atlantic salmon, Salmo salar L., affected by amoebic gill disease (AGD)

The characterisation of selected immune response genes during amoebic gill disease (AGD) in Atlantic salmon, Salmo salar L., was performed using semi-quantitative RT-PCR, quantitative real-time RT-PCR (qRT-PCR), and in situ hybridisation (ISH). The immune response genes of interest were interleukin-1beta (IL-1beta), inducible nitric oxide synthase (iNOS), serum amyloid A (SAA), and serum amyloid P-like pentraxin (SAP). Atlantic salmon were inoculated with the ectoparasite Neoparamoeba sp., the causative agent of AGD, and gill, liver and anterior kidney tissue sampled at 0, 7 and 14 d post-inoculation (p.i.). Semi-quantitative RT-PCR was performed on the tissue samples to identify up/down-regulated mRNA expression relative to uninfected control fish and normalised to the housekeeping gene, beta-actin. Interleukin-1beta (IL-1beta) was the only immune response gene of those investigated whose mRNA was differentially regulated in any of the tissues and was found to be up-regulated in the gills by semi-quantitative RT-PCR. Increased gill IL-1beta mRNA expression was then accurately quantitated and confirmed using probe-based qRT-PCR. The cellular localisation of the IL-1beta mRNA expression in the gills of uninfected and infected fish was then determined by ISH using an IL-1beta-specific biotinylated cRNA probe. Expression of IL-1beta mRNA was localised to filament and lamellar epithelium pavement cells in gills of uninfected and infected Atlantic salmon. These data implicate the involvement of IL-1beta at the site of infection, the gills, of Atlantic salmon during AGD. This work supports previous studies that suggest IL-1beta is important in the regulation of the fish immune response to parasitic infection but additionally shows the cellular localisation of fish IL-1beta mRNA expression during infection.