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: 1.34). 05/2005; 66(4):700-9. DOI: 10.2460/ajvr.2005.66.700
Source: PubMed


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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    • "The indicator in healthy animals of g.i.t. toxicity relative to efficacy proposed by Giraudel et al. (2005a, 2009), IC 20 COX-1: IC 80 COX-2, is of interest. It was, for mavacoxib and carprofen, almost identical, 1.92:1 and 1.95:1, respectively (Table 3 "
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    ABSTRACT: Mavacoxib is a novel nonsteroidal anti-inflammatory drug (NSAID), with a preferential action on the cyclooxygenase (COX)-2 isoform of COX and a long duration of action. It is classified chemically as a member of the sulphonamide subgroup of coxibs. Mavacoxib is highly lipid but very poorly water soluble. In the dog, the pharmacokinetic (PK) profile comprises very slow body clearance, long elimination half-life and a relatively large distribution volume. Biotransformation and renal excretion are very limited, and elimination occurs primarily by biliary secretion and excretion of unchanged drug in faeces. The PK profile of mavacoxib differs quantitatively between young healthy dogs (Beagles and mongrels) and clinical cases with osteoarthritis (OA). In OA dogs, mavacoxib exhibits a much longer terminal half-life, associated principally with their greater median body weight compared with dogs used in preclinical studies. There is also some evidence of breed differences and a small effect of age on mavacoxib PK in the OA canine population. The pharmacodynamics (PD) of mavacoxib has been established: (i) in whole blood assays at the molecular level (inhibition of COX-1 and COX-2 isoforms); (ii) in preclinical models of inflammation and pain; and (iii) in clinical OA subjects treated with mavacoxib. The dosage schedule of mavacoxib for clinical use has been determined by owner and veterinary clinical assessments and is supported by integration of PK and PD preclinical data with clinical responses in canine disease models and in dogs with naturally occurring OA. The dosage regimen has been further confirmed by correlating levels of inhibition of COX isoforms in in vitro whole blood assays with plasma concentrations of mavacoxib achieved in OA dogs. In addition to the specific properties of mavacoxib, some general aspects of the PK and PD of other agents of the NSAID group, together with pathophysiological and clinical aspects of OA, are reviewed, as a basis for correlating with the safety and efficacy of mavacoxib in therapeutic use. Integration of PK and PD data suggests that the recommended dosage regimen of 2 mg/kg bw once for 14 days, followed by administration at monthly intervals, is optimal from both efficacy and safety perspectives and is further confirmed by clinical field studies.
    Full-text · Article · Nov 2014 · Journal of Veterinary Pharmacology and Therapeutics
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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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    ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) have been commonly used for the management of chronic pain caused by inflammatory joint disease in dogs. Although effective at relieving pain and inflammation, NSAIDs are associated with a significant risk of serious gastrointestinal side effects. The present study was therefore designed to investigate the effects of carprofen as a poorly-selective COX (cyclooxygenase) inhibitor and robenacoxib as a selective COX-2 inhibitor on the colon mucosa. A biopsy of the gastrointestinal tract was performed before treatment and on the last day of treatment with orally-administered carprofen (Group I), robenacoxib (Group II) and empty gelatine capsule (Group III) for twenty-one days in a randomised study. The most evident microscopic lesions in the colonic mucosa in young beagles were caused by a 21-day treatment with robenacoxib. The infiltration with inflammatory cells in the lamina propria of the colonic mucosa was the most commonly-found histopathological lesion.
    Full-text · Article · Aug 2013 · Veterinární medicína
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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. 36, 78–84. 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 (Cmax) and area under plasma concentration–time curve to last sampling time (AUClast) 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 Cmax of 101.9 (97.99–106.0) and for AUClast of 97.24 (94.44–100.1). The initial absorption of meloxicam was more rapid for the test article, despite virtually identical Cmax 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.
    Full-text · Article · Apr 2012 · Journal of Veterinary Pharmacology and Therapeutics
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