Randomized, Double-Blind, Placebo-Controlled Trial of Intraarticular Trans-Capsaicin for Pain Associated With Osteoarthritis of the Knee.

OBJECTIVE: To assess the efficacy and safety of high-purity synthetic trans-capsaicin (CNTX-4975) in patients with chronic moderate-to-severe osteoarthritis (OA)-associated knee pain. METHODS: In this phase II multicenter double-blind study, patients ages 45-80 years who had stable knee OA were randomized in a 2:1:2 ratio to receive a single intraarticular injection of placebo, CNTX-4975 0.5 mg, or CNTX-4975 1.0 mg. The primary efficacy end point was area under the curve (AUC) for change from baseline in daily Western Ontario and McMaster Universities Osteoarthritis Index pain with walking score (range 0-10, 0 = none and 10 = extreme) through week 12. Secondary efficacy end points included a similar AUC analysis of outcomes in patients treated with CNTX-4975 0.5 mg, and evaluations extending to 24 weeks. RESULTS: Efficacy was evaluated in 172 patients (placebo group, n = 69; CNTX-4975 0.5 mg group, n = 33; CNTX-4975 1.0 mg group, n = 70). At week 12, greater decreases in the AUC for the pain score were observed with CNTX-4975 in the 0.5 mg and 1.0 mg groups versus placebo (0.5 mg group least squares mean difference [LSMD] -0.79, P = 0.0740; 1.0 mg group LSMD -1.6, P < 0.0001). Significant improvements were maintained at week 24 in the 1.0 mg group (LSMD -1.4, P = 0.0002). Treatment-emergent adverse events were similar in the placebo and CNTX-4975 1.0 mg groups. CONCLUSION: In this study, CNTX-4975 provided dose-dependent improvement in knee OA-associated pain. CNTX-4975 1.0 mg produced a significant decrease in OA knee pain through 24 weeks; CNTX-4975 0.5 mg significantly improved pain at 12 weeks, but the effect was not evident at 24 weeks.

Benefits of externships with pediatric dentistry programs for potential residents: program directors' and current residents' perceptions.

This study's goal was to understand the extent, framework, and benefits of externships with prospective residency programs undertaken by predoctoral dental students or dentists interested in applying for a residency program. In 2012, a questionnaire was sent to all pediatric dentistry residents and program directors in the United States (63 percent and 74 percent return rate, respectively). Externships were offered by fifty-seven of the seventy-six programs. Most program directors (95 percent) agreed that externships are beneficial and compensate at least partially for the lack of numerical National Board Dental Examination scores or class rankings. Among the responding residents, 61 percent were female. The top reasons given by residents for choosing to extern with a certain program were its location and perceived reputation. Of the 249 respondents who did an externship, 47 percent externed with their current program. The acceptance rate into the number one choice of program was similar among those who did an externship vs. those who did not (73 percent vs. 75 percent). No relationship was found between gender and externships among the 341 respondents who were accepted into their top choice. Most of the residents (98.8 percent) felt that completing an externship was beneficial, and 88 percent got an increased understanding for the differences between university- and non-university-based residency programs.

Pharmacokinetics of firocoxib after administration of multiple consecutive daily doses to horses.

OBJECTIVE: To determine pharmacokinetic parameters and variables, firocoxib concentrations in urine and plasma, urine-to-plasma ratios, and the urine depletion profile of firocoxib and to evaluate whether the pharmacokinetic behavior of firocoxib was governed by linear processes after multiple doses of firocoxib were administered IV and orally. ANIMALS: 6 healthy female horses (5 Paint horses and 1 Quarter Horse) in experiment 1 and 12 healthy male and female horses in experiment 2. PROCEDURES: In experiment 1, 6 horses were orally administered firocoxib paste once daily for 12 consecutive days, and plasma and urine samples were obtained and analyzed. In a second experiment, 12 horses received IV injections of firocoxib solution once daily for 9 consecutive days, and plasma was obtained and analyzed. RESULTS: Mean +/- SD clearance and steady-state volume of distribution of firocoxib were 40.5 +/- 14.7 mL/h/kg and 2.3 +/- 0.7 L/kg, respectively. Mean half-life was 44.2 +/- 21.6 hours and 36.5 +/- 9.5 hours for IV and oral administration, respectively. The urine concentration- time curve decreased in parallel with the plasma concentration-verus-time curve. Renal clearance (0.26 +/- 0.09 mL/kg/h) was low, compared with total body clearance, which indicated that the main route of elimination was hepatic clearance. CONCLUSIONS AND CLINICAL RELEVANCE: The pharmacokinetics of firocoxib during prolonged use were determined. Use of plasma or urine to ascertain drug concentrations in horses is scientifically valid because the plasma-to-urine ratio was consistent over time and among horses.

Comparison of efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis.

OBJECTIVE: To compare efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis. DESIGN: Randomized controlled clinical trial. ANIMALS: 253 client-owned horses with naturally occurring osteoarthritis. PROCEDURES: Horses were treated with firocoxib (0.1 mg/kg [0.045 mg/lb], PO, q 24 h) or phenylbutazone (4.4 mg/kg [2 mg/lb], PO, q 24 h) for 14 days. Physical examinations and lameness evaluations were performed prior to treatment and after 7 and 14 days. Clinical improvement was defined as a reduction of at least 1 lameness grade or a combined reduction of at least 3 points in scores for pain during manipulation or palpation, joint swelling, joint circumference, and range of motion. RESULTS: Proportion of horses clinically improved on day 14 for the firocoxib group (104/123 [84.6%]) was not significantly different from the proportion for the phenylbutazone group (103/119 [86.6%]). Proportion of horses that were improved on day 14 was significantly greater for horses treated with firocoxib than for horses treated with phenylbutazone with regard to score for pain on manipulation or palpation (P = 0.028), joint circumference score (P = 0.026), and range of motion score (P = 0.012), but not for overall lameness score or joint swelling score. No direct treatment-related adverse effects were detected during the study. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that overall clinical efficacy of a paste formulation of firocoxib in horses with naturally occurring osteoarthritis was comparable to efficacy of a paste formulation of phenylbutazone.

Comparison of the effects of firocoxib, carprofen and vedaprofen in a sodium urate crystal induced synovitis model of arthritis in dogs.

A randomized, placebo-controlled, four-period cross-over laboratory study involving eight dogs was conducted to confirm the effective analgesic dose of firocoxib, a selective COX-2 inhibitor, in a synovitis model of arthritis. Firocoxib was compared to vedaprofen and carprofen, and the effect, defined as a change in weight bearing measured via peak ground reaction, was evaluated at treatment dose levels. A lameness score on a five point scale was also assigned to the affected limb. Peak vertical ground reaction force was considered to be the most relevant measurement in this study. The firocoxib treatment group performed significantly better than placebo at the 3 h post-treatment time point and significantly better than placebo and carprofen at the 7 h post-treatment time point. Improvement in lameness score was also significantly better in the dogs treated with firocoxib than placebo and carprofen at both the 3 and 7 h post-treatment time points.

Firocoxib efficacy preventing urate-induced synovitis, pain, and inflammation in dogs.

This positive-control study evaluated the efficacy of firocoxib versus carprofen, deracoxib, and meloxicam for the prevention of pain and inflammation in a urate crystal synovitis model of lameness. Lameness scoring and force plate gait analysis were used to assess efficacy. The resulting lameness scores and force plate ground reaction forces after urate crystal injection were not significantly different among the groups. Relative to each group's baseline (nonlame) score, only the firocoxib group was not significantly lame, based on lameness score, at the model's peak effect.

Efficacy and safety of firocoxib in the management of canine osteoarthritis under field conditions.

A total of 249 client-owned dogs with osteoarthritis were treated with firocoxib (5 mg/kg/day) or a positive control, etodolac (10-15 mg/kg/day), for 30 days. Veterinary examinations were performed on approximately days 0 (visit 1), 14 (visit 2), and 29 (visit 3). Based on defined noninferiority criteria, firocoxib and etodolac were comparable. Based on the magnitude of the change from baseline, improvement with firocoxib was significantly greater than with etodolac for lameness at a trot (visits 2 and 3) and for lameness at a walk, pain on manipulation, and range of motion (visit 3) (P < .05). In weekly owner evaluations, firocoxib provided significantly greater improvement than etodolac (P < .05) at each scoring.

In vitro effects and in vivo efficacy of a novel cyclooxygenase-2 inhibitor in dogs with experimentally induced synovitis.

OBJECTIVE: To determine cyclooxygenase-2 (COX-2) selectivity, pharmacokinetic properties, and in vivo efficacy of ML-1,785,713 in dogs. ANIMALS: 21 healthy male and female mixed-breed dogs and 24 healthy male Beagles. PROCEDURE: Selectivity of ML-1,785,713 for inhibiting COX-2 was determined by comparing the potency for inhibiting cyclooxygenase-1 (COX-1) with that of COX-2 in canine blood. Pharmacokinetic properties were determined after i.v. (2 mg/kg) and oral (8 mg/kg) administration in female mixed-breed dogs. In vivo efficacy was evaluated in male mixed-breed dogs with urate crystal-induced synovitis. Prophylactic efficacy was evaluated by administering ML-1,785,713 two hours before induction of synovitis whereas therapeutic efficacy was determined by administering ML-1,785,713 one hour after induction of synovitis. RESULTS: Blood concentrations that resulted in 50% inhibition of COX-1 and COX-2 activity in vitro were 119.1 microM and 0.31 microM, respectively, and selectivity ratio for inhibiting COX-2 relative to COX-1 was 384. ML-1,785,713 had high oral bioavailability (101%), low systemic clearance (77 mL/min/kg), and an elimination half-life of 5.9 hours. ML-1,785,713 was efficacious when administered prophylactically and therapeutically to dogs with urate crystal-induced synovitis. CONCLUSIONS AND CLINICAL RELEVANCE: ML-1,785,713 is a novel, potent COX-2 inhibitor that is the most selective COX-2 inhibitor described for use in dogs to date. ML-1,785,713 has oral bioavailability and low systemic clearance that is comparable to other non-steroidal anti-inflammatory drugs. It is effective after prophylactic and therapeutic administration in attenuating lameness in dogs with urate crystal-induced synovitis. Drugs that specifically inhibit COX-2 and not COX-1 at therapeutic doses may have an improved tolerability profile, compared with nonselective non-steroidal anti-inflammatory drugs.