4-(5-(4-fluorophenyl)-3-(trifluoromethyl)-1h-pyrazol-1-yl)benzenesulfonamide and Osteoarthritis

This prospective, multisite, blinded, randomized, non-inferiority clinical study aimed to confirm the efficacy and safety of enflicoxib in the treatment of pain and inflammation associated with canine osteoarthritis. A total of 180 dogs were randomized to receive enflicoxib (n = 78), mavacoxib (n = 80) or placebo (n = 22). Dogs underwent veterinary assessments from day 0 to day 42 using a clinical sum score (CSS). Efficacy was also assessed by the owners using the Canine Brief Pain Inventory (CBPI). The primary efficacy endpoint was the overall CSS from day 0 to day 42.. The overall CSS expressed as area under the curve demonstrated non-inferiority of enflicoxib compared to mavacoxib, and both showed superiority over placebo. At the end of the study, average CSS, and the percentage of CSS responders for enflicoxib (3.64 and 74%) and mavacoxib (4.49 and 68%), was superior to placebo (7.15 and 29%). A faster onset of action was observed for enflicoxib as superiority over placebo was evidenced from the first efficacy assessment (day 7) onwards for both parameters, whereas mavacoxib was only significantly different from day 14 onwards. According to the owner assessment, the percentage of CBPI responders was 90%, 79%, and 43% for dogs treated with enflicoxib, mavacoxib and placebo, respectively, and superiority over placebo was demonstrated for both active treatments. In all secondary parameters, non-inferiority of enflicoxib versus mavacoxib was confirmed. The dog's quality of life improved in all groups, but only enflicoxib showed superiority versus placebo. When assessing severely affected dogs only, results were similar, thus confirming the efficacy of enflicoxib in all stages of canine OA. There were no differences between groups in the frequency of adverse events, which were most frequently mild affecting the gastrointestinal tract and recovered without treatment.. Enflicoxib is efficacious and safe for the treatment of pain and inflammation in any stage of canine osteoarthritis with a faster onset of action compared to mavacoxib.

Topics: Animals; Cyclooxygenase Inhibitors; Dog Diseases; Dogs; Inflammation; Osteoarthritis; Pain; Prospective Studies; Pyrazoles; Quality of Life; Sulfonamides

A multi-site, masked, randomised parallel group study employing a double dummy treatment design was performed in canine veterinary patients to determine the comparative efficacy and safety of mavacoxib and carprofen in the treatment of pain and inflammation associated with osteoarthritis for a period of 134 days. Treatments were administered according to their respective summaries of product characteristics. Of 139 dogs screened, 124 were suitable for study participation: 62 of which were dosed with mavacoxib and 62 with carprofen. Both treatments resulted in a very similar pattern of considerable improvement as indicated in all parameters assessed by both owner and veterinarian. The primary efficacy endpoint 'overall improvement' was a composite score of owner assessments after approximately six weeks of treatment. Both drugs were remarkably effective, with 57/61 (93.4 per cent) of mavacoxib-treated dogs and 49/55 (89.1 per cent) of carprofen-treated dogs demonstrating overall improvement and with mavacoxib's efficacy being non-inferior to carprofen. The treatments had a similar safety profile as evidenced by documented adverse events and summaries of clinical pathology parameters. The positive clinical response to treatment along with the safety and dosing regimen of mavacoxib makes it an attractive therapy for canine osteoarthritis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Dog Diseases; Dogs; Double-Blind Method; Female; Inflammation; Male; Osteoarthritis; Pain; Pyrazoles; Treatment Outcome

NSAIDs are the cornerstone of medical management of canine osteoarthritis (OA). Meloxicam is a daily-administered NSAID widely available in a liquid formulation and manufacturer's summary of product characteristics (SPC) advise that it is given at the lowest effective dose. Mavacoxib is a long-acting NSAID given as a monthly tablet. This study compares these drugs in the management of canine OA. In all, 111 dogs with OA of the elbow, hip or stifle were randomly assigned to receive one of these NSAIDs for a 12-week period, and to administer them as per the manufacturer's SPC. Outcomes, including ground reaction forces and three validated clinical metrology instruments, were measured at baseline, 6 and 12 weeks. Improvements were seen in all outcome measures for both groups to a similar degree, and adverse events occurred at a similar rate. There were significant improvements in outcome measures from week 6 to week 12, as well as from baseline. Long-term meloxicam dose was more important than recent dose. Clinical efficacy and adverse event rates are similar for meloxicam and mavacoxib when administered as per their UK SPC. This is relevant information for veterinary surgeons when prescribing NSAID treatment for canine OA.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dog Diseases; Dogs; Female; Male; Meloxicam; Osteoarthritis; Pyrazoles; Thiazines; Thiazoles; Treatment Outcome

Mavacoxib (Trocoxil™) is an oral long-acting COX-2 inhibitor approved for the treatment of osteoarthritis in dogs. Two field trials were conducted in client-owned dogs suffering from osteoarthritis, with dosages of 4 mg/kg body weight (BW) (Study 1) or 2 mg/kg BW (Study 2). Mavacoxib plasma concentrations were determined from trough blood samples and from blood samples collected at 4-10 months after the last dose. A one-compartment linear model was fitted to the concentration data (1317 concentration records from 286 patients), and parameters for oral clearance (Cl/F), apparent volume of distribution (V(d) /F) and their between-subject variabilities (BSV) were estimated. Covariates were included in the model based on the outcomes of stepwise regression procedures. In the final model, the typical value of Cl/F was a function of BW, age and breed. German shepherds and Labrador retrievers were found to have 31% higher values of Cl/F than patients from different breeds with similar ages and BWs. The typical value of V(d) /F was found to be dependent only on BW. The two field studies appeared to differ similarly with respect to Cl/F and V(d) /F. The explanation for this difference is not known, but the difference was accounted for in the final model as a 23.9% lower bioavailability in Study 2. Mavacoxib exhibited relatively broad BSV in Cl/F and V(d) /F, with coefficients of variation of 47% and 19%, respectively. The typical value for mavacoxib's terminal elimination plasma half-life (t(1/2) ) was 44 days, but a minority of patients (approximately 5%) had empirical Bayes estimates of t(1/2) exceeding 80 days. Simulations with the model indicated that the majority of patients treated with mavacoxib 2 mg/kg will maintain trough plasma mavacoxib concentrations associated with efficacy. Results of the population pharmacokinetic analysis helped to reduce the dose from 4 to 2 mg/kg and thus increased the therapeutic index for this molecule.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Female; Half-Life; Male; Models, Biological; Osteoarthritis; Pyrazoles

Pedobarographic analyses detect pressure redistribution among limbs and within limbs in humans, equids and dogs. The main objective of this study was to assess the usefulness of a set of pedobarographic parameters for the detection of lameness, as well as for its suitability for assessing the effects of therapies against osteoarthritis in dogs. With this purpose, eleven large-breed lame dogs with unilateral osteoarthritis due to elbow dysplasia were evaluated using a pressure platform prior to (D0) and after 3 months (D90) of treatment with mavacoxib, a COX-2 selective NSAID. The obtained parameters were: pressure distribution between lame and sound limbs, as well as paw area, mean pressure, and peak pressure of both lame and sound limbs.. The results showed statistical differences in all these parameters between lame and sound limbs at D0; however, at D90, differences were significantly decreased as result of the treatment, indicating a substantial functional recovery under the study design conditions.. The provided data prove the suitability of this novel technique in canine models for the quantitative and objective assessment of lameness, but also for the evaluation of treatments for lameness caused by articular pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dog Diseases; Dogs; Female; Gait; Joint Diseases; Lameness, Animal; Male; Osteoarthritis; Pressure; Pyrazoles

A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Carrageenan; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Hyperalgesia; Isoenzymes; Magnetic Resonance Spectroscopy; Male; Membrane Proteins; Molecular Structure; Osteoarthritis; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Structure-Activity Relationship; Sulfonamides