Development of in vitro assays for the evaluation of cyclooxygenase inhibitors and application for predicting the selectivity of NSAIDs in the cat

Department of Veterinary Basic Sciences, Royal Veterinary College, Hawkshead Campus, North Mymms, Hatfield, Hertfordshire AL9 7TA, UK.
American Journal of Veterinary Research (Impact Factor: 1.21). 05/2005; 66(4):700-9. DOI: 10.2460/ajvr.2005.66.700
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ABSTRACT To develop and validate in cats suitable in vitro assays for screening and ranking nonsteroidal antiinflammatory drugs (NSAIDs) on the basis of their inhibitory potencies for cyclooxygenase (COX)-1 and COX-2.
10 cats.
COX-1 and COX-2 activities in heparinized whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. For the COX-2 assay, blood was pretreated with aspirin. The COX-1 and COX-2 assays were standardized, such that time courses of incubation with the test compounds and conditions of COX expression were as similar as possible in the 2 assays. Inhibition of thromboxane B2 production, measured by use of a radioimmunoassay, was taken as a marker of COX-1 and COX-2 activities. These assays were used to test 10 to 12 concentrations of a COX-1 selective drug (SC-560) and of 2 NSAIDs currently used in feline practice, meloxicam and carprofen. Selectivities of these drugs were compared by use of classic 50% and 80% inhibitory concentration (ie, IC50 and IC80) ratios but also with alternative indices that are more clinically relevant.
These assay conditions provide a convenient and robust method for the determination of NSAID selectivity. The S(+) enantiomeric form of carprofen was found to be COX-2 selective in cats, but meloxicam was only slightly preferential for this isoenzyme.
In vitro pharmacodynamic and in vivo pharmacokinetic data predict that the COX-2 selectivity of both drugs for cats will be limited when used at the recommended doses. This study provides new approaches to the selection of COX inhibitors for subsequent clinical testing.

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Available from: Jerome M Giraudel, Jun 13, 2015
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    • "not yet been fully elucidated (Giraudel et al. 2005, 2009). It is clear that COX-2 inhibitors will be safer than the classic NSAIDs that inhibit both COX-1 and COX-2 (Hazenwinkel et al. 2003; Almansori et al. 2005). "
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    • "concentration, it would seem likely that inhibition at the higher IC 80 level might be achieved for much and possibly all of the 24- h recommended dosing interval. This is suggested by the data of Giraudel et al. (2005). These authors reported a relatively steep whole-blood assay slope for COX-2 inhibition by meloxicam of 3.27:1, so that a low ratio IC 80 COX-2 ⁄ IC 50 COX-2 of 1.53:1 was reported. "
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    ABSTRACT: Lees, P., Cheng, Z., Keefe, T. J., Weich, E., Bryd, J., Cedergren, R., Cozzi, E. Bioequivalence in dogs of a meloxicam formulation administered as a transmucosal oral mist with an orally administered pioneer suspension product. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365-2885.2012.01402.x. A mucosal mist formulation of meloxicam, administered as a spray into the mouth (test article), was compared for bioequivalence to a pioneer meloxicam suspension for oral administration (reference article). Pharmacokinetic profiles and average bioequivalence were investigated in 20 dogs. The study design comprised a two-period, two-sequence, two-treatment cross-over design, with maximum concentration (C(max) ) and area under plasma concentration-time curve to last sampling time (AUC(last) ) used as pivotal bioequivalence variables. Bioequivalence of the products was confirmed, based on relative ratios of geometric mean concentrations (and 90% confidence intervals within the range 0.80-1.25) for C(max) of 101.9 (97.99-106.0) and for AUC(last) of 97.24 (94.44-100.1). The initial absorption of meloxicam was more rapid for the test article, despite virtually identical C(max) values for the two products. Mean elimination half-lives were 29.6 h (test article) and 30.0 h (reference article). The meloxicam plasma concentration-time profiles were considered in relation to published data on the inhibition of the cyclooxygenase-1 (COX-1) and COX-2 isoenzymes by meloxicam.
    Journal of Veterinary Pharmacology and Therapeutics 04/2012; 36(1). DOI:10.1111/j.1365-2885.2012.01402.x · 1.32 Impact Factor
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    • "While the expression of both COX-1 and COX-2 is constitutive and inducible, COX-2 is the isoform which is greatly upregulated in the presence of inflammatory stimuli and is therefore considered to be the desired target of NSAID activity (Lees, 2009). Although the literature is deficient with respect to cattle, meloxicam is considered to preferentially inhibit the inflammatory effects of COX-2 while tending to spare the homeostatic effects of COX-1 in humans (Warner et al., 1999), dogs (Streppa et al., 2002), cats (Giraudel et al., 2005), and horses (Beretta et al., 2005). However, the relative inhibition of the COX isoenzymes by a drug is known to vary between species; therefore, COX preference in one species does not guarantee similar preference in another (Lees, 2009). "
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    ABSTRACT: The pharmacokinetics of oral meloxicam has been studied in ruminant, but not preruminant calves. Oral meloxicam was administered at 0.5 mg/kg to six ruminant calves via gavage (RG); to six preruminant calves via gavage (PRG); and to six preruminant calves via suckling in milk replacer (PRF). Plasma drug concentrations, determined over 120-h postadministration, were analyzed by compartmental and noncompartmental methods. The rate of drug absorption was faster (P<0.01) in PRF (0.237±0.0478/h) than RG calves (0.0815±0.0188/h), while absorption in PRG calves (0.153±0.128/h) was not different from other groups. C(max) was lower (P=0.03) in PRF (1.27±0.430 μg/mL) than in PRG calves (2.20±0.467 μg/mL), while C(max) of RG calves (1.95±0.955 μg/mL) was not different from other groups. V/F was higher in PRF calves (365±57 mL/kg) than either PRG (177±63 mL/kg, P<0.01) or RG (232±83 mL/kg, P=0.01) calves. These observations were likely due to differences in bioavailability, physiological maturity, and timing of the drug delivery into different compartments of the ruminant gastrointestinal tract. Results suggest that an adjustment in meloxicam dose may be necessary when administered with milk replacer.
    Journal of Veterinary Pharmacology and Therapeutics 08/2011; 35(4):373-81. DOI:10.1111/j.1365-2885.2011.01331.x · 1.32 Impact Factor
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