Analgesic and anti‐inflammatory actions of robenacoxib in acute joint inflammation in dog

Schmid, V. B., Spreng, D. E., Seewald, W., Jung, M., Lees, P., King, J. N. Analgesic and anti‐inflammatory actions of robenacoxib in acute joint inflammation in dog. J. vet. Pharmacol. Therap. 33 , 118–131. The objectives of this study were to establish dose–response and blood concentration–response relationships for robenacoxib, a novel nonsteroidal anti‐inflammatory drug with selectivity for inhibition of the cyclooxygenase (COX)‐2 isoenzyme, in a canine model of synovitis. Acute synovitis of the stifle joint was induced by intra‐articular injection of sodium urate crystals. Robenacoxib (0.25, 0.5, 1.0, 2.0 and 4.0 mg/kg), placebo and meloxicam (0.2 mg/kg) were administered subcutaneously (s.c.) 3 h after the urate crystals. Pharmacodynamic endpoints included data from forceplate analyses, clinical orthopaedic examinations and time course of inhibition of COX‐1 and COX‐2 in ex vivo whole blood assays. Blood was collected for pharmacokinetics. Robenacoxib produced dose‐related improvement in weight‐bearing, pain and swelling as assessed objectively by forceplate analysis (estimated ED₅₀ was 1.23 mg/kg for z peak force) and subjectively by clinical orthopaedic assessments. The analgesic and anti‐inflammatory effects of robenacoxib were significantly superior to placebo (0.25–4 mg/kg robenacoxib) and were non‐inferior to meloxicam (0.5–4 mg/kg robenacoxib). All dosages of robenacoxib produced significant dose‐related inhibition of COX‐2 (estimated ED₅₀ was 0.52 mg/kg) but no inhibition of COX‐1. At a dosage of 1–2 mg/kg administered s.c., robenacoxib should be at least as effective as 0.2 mg/kg of meloxicam in suppressing acute joint pain and inflammation in dogs.     

Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation

Pelligand, L., King, J. N., Toutain, P. L., Elliott, J., Lees, P. Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation. J. vet. Pharmacol. Therap.  35 , 19–32. Robenacoxib is a novel nonsteroidal anti‐inflammatory drug developed for use in cats. It is a highly selective COX‐2 inhibitor. Results from previous feline studies showed that, despite a short half‐life in blood, the effect of robenacoxib persisted for 24 h in clinical studies. A tissue cage model of acute inflammation was used to determine robenacoxib’s pharmacokinetics and its ex vivo and in vivo selectivity for COX‐1 and COX‐2 using serum TxB₂ and exudate PGE₂ as surrogate markers for enzyme activity, respectively. After intravenous, subcutaneous and oral administration (2 mg/kg), the clearance of robenacoxib from blood was rapid (0.54–0.71 L·h/kg). The mean residence time (MRT) in blood was short (0.4, 1.9 and 3.3 h after intravenous, subcutaneous and oral administration, respectively), but in exudate MRT was approximately 24 h regardless of the route of administration. Robenacoxib inhibition of COX‐1 in blood was transient, occurring only at high concentrations, but inhibition of COX‐2 in exudate persisted to 24 h. The potency ratio (IC₅₀ COX‐1: IC₅₀ COX‐2) was 171:1, and slopes of the concentration–effect relationship were 1.36 and 1.12 for COX‐1 and COX‐2, respectively. These data highlight the enzymatic selectivity and inflamed tissue selectivity of robenacoxib and support the current recommendation of once‐daily administration.     

Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation

Robenacoxib and ketoprofen are acidic nonsteroidal anti‐inflammatory drugs (NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half‐lives. This study reports the pharmacokinetic/pharmacodynamic (PK/PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three‐period cross‐over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B₂ concentrations (measuring COX‐1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin (PG)E₂ concentrations (measuring COX‐2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX‐1 and COX‐2 inhibition were generated by PK/PD modelling. S(+) ketoprofen clearance scaled by bioavailability (CL/F) was 0.114 L/kg/h (elimination half‐life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half‐life = 1.13 h). Exudate elimination half‐lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE₂ concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB₂ between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivoIC₅₀COX‐1/IC₅₀COX‐2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX‐2 inhibition in exudate, despite short half‐lives in blood.     

In vitro and ex vivo inhibition of canine cyclooxygenase isoforms by robenacoxib: A comparative study

In vitro whole blood canine assays were used to quantify the inhibitory actions of the novel non-steroidal anti-inflammatory drug (NSAID) robenacoxib on the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, in comparison with other drugs of the NSAID class. COX-1 activity was determined by measuring serum thromboxane (Tx)B₂ synthesis in blood samples allowed to clot at 37 °C for 1 h. COX-2 activity was determined by measuring prostaglandin (PG)E₂ synthesis in blood samples incubated at 37 °C for 24 h in the presence of lipopolysaccharide. The rank order of selectivity for inhibition of COX-2 versus COX-1 (IC₅₀ COX-1:IC₅₀ COX-2) for veterinary drugs was highest with robenacoxib (128.8) compared to deracoxib (48.5), nimesulide (29.2), S+ carprofen (17.6), meloxicam (7.3), etodolac (6.6), R? carprofen (5.8) and ketoprofen (0.88). Selectivity expressed as the clinically relevant ratio IC₂₀ COX-1:IC₈₀ COX-2 was highest for robenacoxib (19.8) compared to deracoxib (2.3), S+ carprofen (2.5), R? carprofen (2.1), nimesulide (1.8), etodolac (0.76), meloxicam (0.46) and ketoprofen (0.21).An in vivo pharmacokinetic ex vivo pharmacodynamic study in the dog established dosage and concentration–effect relationships for single oral doses of robenacoxib over the dosage range 0.5–8.0 mg/kg. Values of C_max and AUC were linearly related to dosage over the tested range. Robenacoxib did not inhibit serum TxB₂ synthesis (COX-1) ex vivo at dosages of 0.5–4.0 mg/kg and produced only transient inhibition (at the 1 h and 2 h sampling times) at the 8 mg/kg dosage. All dosages of robenacoxib (0.5–8 mg/kg) produced marked, significant and dose related inhibition of PGE₂ synthesis (COX-2) ex vivo.The data demonstrate that in the dog robenacoxib is a highly selective inhibitor of the COX-2 isoform of COX, and significantly inhibits COX-2 and spares COX-1 in vivo when administered orally over the dosage range 0.5–4.0 mg/kg.     

Evaluation of the dose–response relationship of oral robenacoxib in urate crystal‐induced acute stifle synovitis in dogs

The objective of the study was to establish the dose–response relationship for robenacoxib, a selective cyclooxygenase (COX)‐2 inhibitor, in a urate crystal model of acute synovitis. In a randomized partial Latin square design trial, 12 beagle dogs were administered orally single doses of robenacoxib (0.5, 1, 2, 4 and 8 mg/kg), placebo and the positive control meloxicam (0.1 mg/kg), 3 h after injection of sodium urate crystals into a stifle joint. Dogs were assessed for weight bearing on a force plate and by subjective clinical orthopaedic observations. Robenacoxib produced dose‐dependent improvement in weight bearing, and decreased pain on palpation and joint swelling, over the dose range 0.5–2 mg/kg with no further increase in effect over the range 2–8 mg/kg. For weight bearing on the force plate, the ED₅₀ of robenacoxib was 0.6–0.8 mg/kg. The onset of action and time to peak effect of robenacoxib were faster (respectively, 2–2.5 h and 3–5 h) than for meloxicam (respectively, 3 h and 6 h). Robenacoxib significantly inhibited COX‐2 at all doses, with dose‐related activity. Robenacoxib did not inhibit COX‐1 over the dose range 0.5–4 mg/kg, but produced transient inhibition at 8 mg/kg. In conclusion, oral administration of robenacoxib over the dose range 0.5–8 mg/kg demonstrated significant analgesic and anti‐inflammatory efficacy in dogs.     

Serum C-reactive protein and iron levels following gonadectomy are not modified by perioperative administration of robenacoxib to dogs

The aim of this study was to evaluate the perioperative effects of robenacoxib on serum C-reactive protein (CRP) and iron concentrations in dogs undergoing gonadectomy. In a prospective, blinded, controlled clinical trial, 60 healthy dogs were randomly assigned to receive preoperative subcutaneous injection of either robenacoxib [2 mg/kg body weight (BW)], meloxicam (0.2 mg/kg BW), or saline (0.04 mL/kg BW), followed by oral administration over 72 h (robenacoxib: 2 to 4 mg/kg BW; meloxicam: 0.1 mg/kg BW; saline: gelatin capsules). Blood samples were taken before surgery and 12, 24, 48, 72 h, and 7 d after surgery. Pain scores were assessed via the short-form Glasgow Composite Pain Scale over 72 h postoperatively. C-reactive protein (CRP) and iron serum levels increased and decreased (P < 0.01, both), respectively, after surgery and returned to baseline within 1 wk. No differences were observed among treatments (P > 0.05) or based on surgery/gender (P > 0.05). Pain assessment revealed a higher incidence of treatment failure in saline (6 females versus 2 and 1 female in robenacoxib and meloxicam, respectively). In conclusion, robenacoxib and meloxicam had no influence on postoperative CRP or iron in dogs, which suggests that these nonsteroidal anti-inflammatory drugs (NSAIDs) do not have a relevant effect on these biomarkers.     

Comparison of injectable robenacoxib versus meloxicam for peri-operative use in cats: results of a randomised clinical trial

The objective of this study was to evaluate the efficacy and tolerability of robenacoxib, a selective cyclooxygenase-2 inhibitor, for the treatment of post-operative pain and inflammation in cats. The study was a prospective, multi-centre, randomised, blinded, non-inferiority design clinical study to compare robenacoxib to meloxicam. Ninety-six cats undergoing surgery at eight centres in Japan were allocated randomly to receive a single s.c. injection of robenacoxib (2 mg/kg, n=67) or meloxicam (0.3 mg/kg, n=29) shortly before induction of anaesthesia. Most cats underwent soft tissue surgery (n=87), mainly ovariectomy (n=68). Post-operative pain and inflammation were assessed at 3, 8 and 22 h after recovery from anaesthesia using numerical rating scales. For the primary efficacy endpoint (total clinician score), robenacoxib had significantly better efficacy than meloxicam, the relative efficacy ratio being 1.47 (95% confidence interval 1.19-1.78, P=0.0003). For the secondary efficacy endpoints, robenacoxib was superior to meloxicam when assessed on the basis of posture, behaviour, pain on palpation and overall pain control, while meloxicam was superior with respect to wound heat. No cat in either group required rescue analgesia therapy. In tolerability assessments, pain during injection and pain and inflammation at the injection site 22 h after recovery from anaesthesia were rated significantly less with robenacoxib compared to meloxicam. Both treatments were well tolerated on the basis of clinical observations and blood tests, with no significant differences between groups. In conclusion, single pre-operative administration of robenacoxib was well tolerated and had superior efficacy to meloxicam in reducing post-operative pain in cats.     

Subcutaneous meloxicam suspension pharmacokinetics in mice and dose considerations for postoperative analgesia

Meloxicam is a cyclooxygenase (COX) inhibitor with a higher selectivity for cyclooxygenase‐2 (COX‐2) than for cyclooxygenase‐1 (COX‐1). In the laboratory setting, this nonsteroidal anti‐inflammatory drug (NSAID) is commonly selected for analgesia in mice and administered every 24 h. This study characterizes the plasma concentration achieved from a dose of 1.6 mg/kg of meloxicam administered once every 24 h subcutaneously for 72 h in male and female C57BL/6 mice. These values were compared, over time, to reference COX‐2 inhibition constants for meloxicam. No significant differences in trough plasma concentrations were noted between genders. The plasma concentrations were below the COX‐2 IC₅₀ after 12 h. To maintain a plasma concentration at or above the COX‐2 whole blood IC_50, the study results suggest an administration frequency of every 12 h when using a dose of 1.6 mg/kg in C57BL/6 mice.     

Pharmacokinetics and milk secretion of gabapentin and meloxicam co‐administered orally in Holstein‐Friesian cows

Malreddy, P. R., Coetzee, J. F., KuKanich, B., Gehring, R. Pharmacokinetics and milk secretion of gabapentin and meloxicam co‐administered orally in Holstein‐Friesian cows. J. vet. Pharmacol. Therap.  36 , 14–20. Management of neuropathic pain in dairy cattle could be achieved by combination therapy of gabapentin, a GABA analog and meloxicam, an nonsteroidal anti‐inflammatory drug. This study was designed to determine specifically the depletion of these drugs into milk. Six animals received meloxicam at 1 mg/kg and gabapentin at 10 mg/kg, while another group (n = 6) received meloxicam at 1 mg/kg and gabapentin at 20 mg/kg. Plasma and milk drug concentrations were determined over 7 days postadministration by HPLC/MS followed by noncompartmental pharmacokinetic analyses. The mean (±SD) plasma C_max and T_max for meloxicam (2.89 ± 0.48 μg/mL and 11.33 ± 4.12 h) were not much different from gabapentin at 10 mg/kg (2.87 ± 0.2 μg/mL and 8 ± 0 h). The mean (±SD) milk C_max for meloxicam (0.41 ± 80.16 μg/mL) was comparable to gabapentin at 10 mg/kg (0.63 ± 0.13 μg/mL and 12 ± 6.69 h). The mean plasma and milk C_max for gabapentin at 20 mg/kg P.O. were almost double the values at 10 mg/kg. The mean (±SD) milk to plasma ratio for meloxicam (0.14 ± 0.04) was lower than for gabapentin (0.23 ± 0.06). The results of this study suggest that milk from treated cows will have low drug residue concentration soon after plasma drug concentrations have fallen below effective levels.     

Evaluation of cardiovascular effects of intravenous robenacoxib in dogs

The objective of the study was to assess the cardiovascular effects of intravenous (IV) dosing with robenacoxib (Onsior^®) in conscious adult healthy beagle dogs. The study employed a randomized, open, placebo‐controlled, four‐phase Latin square design. A total of eight dogs received a single dose of 2 mg/kg and 4 mg/kg IV robenacoxib (test groups), 2 mg/kg subcutaneous (SC) robenacoxib (reference dose and route), and IV isotonic saline (control). There were no significant differences between groups for clinical observations, buccal mucosal bleeding time or blood hematology, coagulation, and clinical chemistry variables in all eight dogs. In a subset of four dogs, no significant differences between groups were detected using telemetric assessment for arterial blood pressure, heart rate, electrocardiogram, or body temperature over 8 hr postdose. In conclusion, no significant cardiovascular effects were detected after a single IV dose of 2 or 4 mg/kg robenacoxib in conscious healthy dogs.     

Effects of flunixin meglumine and ketoprofen on mediator production in ex vivo and in vitro models of inflammation in healthy dairy cows

Donalisio, C., Barbero, R., Cuniberti, B., Vercelli, C., Casalone, M., Re, G. Effects of flunixin meglumine and ketoprofen on mediator production in ex vivo and in vitro models of inflammation in healthy dairy cows. J. vet. Pharmacol. Therap.  36 , 130–139. In this study, ex vivo assays were carried out in dairy cows to evaluate the anti‐inflammatory effects of two nonsteroidal anti‐inflammatory drugs: ketoprofen (KETO) and flunixin meglumine (FM). Twelve healthy Holstein dairy cattle were randomly allocated to two groups (n=6): group 1 received FM and group 2 received KETO at recommended therapeutic dosages. The anti‐inflammatory effects of both drugs were determined by measuring the production of coagulation‐induced thromboxane B₂ (TXB₂), lipopolysaccharides (LPS) (10 μg/mL)‐induced prostaglandin E₂ (PGE₂), and calcium ionophore (60 μm )‐induced leukotrien B₄ (LTB₄). Cytokine production was assessed by measuring tumor necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ) and interleukin‐8 (CXCL8) concentrations after incubation in the presence of 10 μg/mL LPS. The IC₅₀ of FM and KETO was determined in vitro by determining the concentration of TXB₂ and PGE₂ in the presence of scalar drug concentrations (10^?9–10^?3 m ). Both FM and KETO inhibited the two COX isoforms in vitro, but showed a preference for COX‐1. FM and KETO showed similar anti‐inflammatory effects in the cow.     

Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib

Robenacoxib is a new nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration–time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX-1 and COX-2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B₂ provided a marker of both COX-1 and COX-2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC₅₀ were 28.9 (16.4–51.1) μ m (COX-1) and 0.058 (0.010–0.340) μ m (COX-2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX-1:COX-2) were 502.3 (IC₅₀/IC₅₀), 451.6 (IC₉₅/IC₉₅) and 17.05 (IC₂₀/IC₈₀). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX-1 and 90% inhibition of COX-2.     

The pharmacokinetics and in vitro cyclooxygenase selectivity of deracoxib in horses

Davis, J. L., Marshall, J. F., Papich, M. G., Blikslager, A. T., Campbell, N. B. The pharmacokinetics and in vitro cyclooxygenase selectivity of deracoxib in horses. J. vet. Pharmacol. Therap. 34 , 12–16. The purpose of this study was to determine the pharmacokinetics of deracoxib following oral administration to horses. In addition, in vitro equine whole blood cyclooxygenase (COX) selectivity assays were performed. Six healthy adult horses were administered deracoxib (2 mg/kg) orally. Plasma samples were collected prior to drug administration (time 0), and 10, 20, 40 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after administration for analysis with high pressure liquid chromatography using ultraviolet detection. Following PO administration, deracoxib had a long elimination half‐life (t_1/2k₁₀) of 12.49 ± 1.84 h. The average maximum plasma concentration (C_max) was 0.54 μg/mL, and was reached at 6.33 ± 3.44 h. Bioavailability was not determined because of the lack of an IV formulation. Results of in vitro COX selectivity assays showed that deracoxib was selective for COX‐2 with a COX‐1/COX‐2 ratio of 25.67 and 22.06 for the IC₅₀ and IC₈₀, respectively. Dosing simulations showed that concentrations above the IC₈₀ for COX‐2 would be maintained following 2 mg/kg PO q12h, and above the IC₅₀ following 2 mg/kg PO q24h. This study showed that deracoxib is absorbed in the horse after oral administration, and may offer a useful alternative for anti‐inflammatory treatment of various conditions in the horse.     

Pharmacokinetics of meloxicam in koalas (Phascolarctos cinereus) after intravenous,subcutaneous and oral administration

The pharmacokinetic profile of meloxicam in clinically healthy koalas (n = 15) was investigated. Single doses of meloxicam were administered intravenously (i.v.) (0.4 mg/kg; n = 5), subcutaneously (s.c.) (0.2 mg/kg; n = 1) or orally (0.2 mg/kg; n = 3), and multiple doses were administered to two groups of koalas via the oral or s.c. routes (n = 3 for both routes) with a loading dose of 0.2 mg/kg for day 1 followed by 0.1 mg/kg s.i.d for a further 3 days. Plasma meloxicam concentrations were quantified by high‐performance liquid chromatography. Following i.v. administration, meloxicam exhibited a rapid clearance (CL) of 0.44 ± 0.20 (SD) L/h/kg, a volume of distribution at terminal phase (V_z) of 0.72 ± 0.22 L/kg and a volume of distribution at steady state (V_ss) of 0.22 ± 0.12 L/kg. Median plasma terminal half‐life (t_1/2) was 1.19 h (range 0.71–1.62 h). Following oral administration either from single or repeated doses, only maximum peak plasma concentration (C_max 0.013 ± 0.001 and 0.014 ± 0.001 μg/mL, respectively) was measurable [limit of quantitation (LOQ) >0.01 μg/mL] between 4–8 h. Oral bioavailability was negligible in koalas. Plasma protein binding of meloxicam was ~98%. Three meloxicam metabolites were detected in plasma with one identified as the 5‐hydroxy methyl derivative. This study demonstrated that koalas exhibited rapid CL and extremely poor oral bioavailability compared with other eutherian species. Accordingly, the currently recommended dose regimen of meloxicam for this species appears inadequate.     

Robenacoxib vs. carprofen for the treatment of canine osteoarthritis; a randomized, noninferiority clinical trial

Robenacoxib is a member of the coxib class of nonsteroidal anti-inflammatory drugs (NSAID), with high selectivity for the cyclooxygenase (COX)-2 isoform of COX. In this study, the efficacy and tolerability of robenacoxib were compared with those of carprofen in canine osteoarthritis in a multi-centre, prospective, randomized, blinded, positive-controlled noninferiority clinical trial. Both drugs were administered orally once daily at recommended dosages: robenacoxib at 1-2 mg/kg (n = 125 dogs) and racemic carprofen at 2-4 mg/kg (n = 63 dogs) for a total of 12 weeks. The efficacy of the test compounds was assessed by veterinary investigators and owners using numerical rating scales at baseline and days 7, 14, 28, 56 and 84. In both groups, all scores were significantly (P < 0.0001) improved compared with baseline at all time points (days 7-84). Robenacoxib had noninferior efficacy to carprofen for the primary endpoint, the global functional disability, both for all dogs and for the subgroup of dogs in which robenacoxib was not administered during meals. Noninferiority was also demonstrated for three of six veterinary investigator secondary endpoints and four of six owner efficacy endpoints. For haematology and clinical chemistry variables, there were some significant differences from baseline levels but no differences between groups. There were no differences between groups in the frequencies of adverse events, which were reported in 46% dogs with robenacoxib and 52% with carprofen (P = 0.44), which were most frequently mild events affecting the gastrointestinal tract. In conclusion, noninferior efficacy and tolerability of robenacoxib compared with carprofen was demonstrated in dogs with osteoarthritis.     

In vivo effects of meloxicam on inflammatory mediators,MMP activity and cartilage biomarkers in equine joints with acute synovitis

Reasons for performing study: Meloxicam is a commonly used nonsteroidal anti‐inflammatory drug in equine practice, but little is known about its in vivo effects on joint inflammation and cartilage turnover. Objectives: To study the effects of meloxicam on biomarkers of inflammation, matrix metalloproteinase (MMP) activity, and cartilage biomarkers in joints with experimental synovitis. Methods: In a 2‐period cross‐over study, synovitis was induced at T = 0 h in the L or R intercarpal joint of 6 horses by intraarticular injection of 0.5 ng lipopolysaccharide (LPS). Horses received once daily meloxicam (0.6 mg/kg bwt per os) or placebo starting at post injection hour (PIH) 2, and clinical evaluations as well as blood and synovial fluid (SF) sampling were performed at PIH 0, 8, 24 and 168. Synovial fluid was analysed for prostaglandin E₂, bradykinin, substance P, general MMP activity, glycosaminoglycans (GAG), CS846 epitope, type II collagen cleavage fragments (C2C) and type II collagen carboxypropeptide (CPII). Concentrations in meloxicam‐ vs. placebo‐treated joints over time were compared using a linear mixed model. Results: Lipopolysaccharide injection caused marked transient synovitis without systemic effects. Meloxicam caused a significant reduction in lameness at PIH 8 and 24 and tended to reduce effusion. In addition, meloxicam significantly suppressed SF prostaglandin E₂ and substance P release at PIH 8 and bradykinin at PIH 24 compared to placebo treatment. General MMP activity at PIH 8 and 24 was significantly lower in meloxicam‐ vs. placebo‐treated joints, as were GAG, C2C and CPII concentrations at PIH 24. Conclusions: Acute transient synovitis leads to substantial increases in SF biomarkers of inflammation, MMP activity and cartilage turnover, which can be significantly suppressed by meloxicam. Potential relevance: Early oral treatment with meloxicam ameliorates not only clinical signs and joint inflammation in acute synovitis, but may also limit inflammation‐induced cartilage catabolism.     

Safety of oral robenacoxib in the cat

The safety of robenacoxib, a nonsteroidal anti-inflammatory drug with high selectivity for inhibition of the cyclooxygenase (COX)-2 isoform of COX, was investigated in the cat in two randomized, blinded, placebo-controlled, parallel-group studies. Robenacoxib was administered orally to healthy young domestic short-hair cats at dosages of 0 (placebo), 5 and 10 mg/kg once daily for 28 days (study 1) and at 0 (placebo), 2, 6 and 10 mg/kg twice daily for 42 days (study 2). The recommended minimum dosage for robenacoxib tablets in cats is 1 mg/kg once daily (range 1-2.4 mg/kg). Relative to placebo treatment, no toxicologically significant effects of robenacoxib were recorded in either study, based on general observations of health, haematological and clinical chemistry variables and urinalyses in life, and by post mortem organ weight, gross pathology and histopathology assessments. Pharmacokinetic-pharmacodynamic simulations indicated that all dosages of robenacoxib were associated with marked inhibition of COX-2 at peak effect (median I(max) 97.8-99.4% inhibition) with lesser inhibition of COX-1 (median I(max) 26.8-58.3% inhibition). Inhibition of the COXs was short lasting, with >10% median inhibition persisting for 4.0 h for COX-2 and 1.5 h for COX-1. These levels of inhibition of COX-1 and COX-2 twice daily with robenacoxib were not associated with any detectable toxicity, suggesting that, as previously described in dogs, the high safety index of robenacoxib in cats may be related to a combination of its high COX-2 selectivity and short residence time in the central compartment.     

Bioequivalence in dogs of a meloxicam formulation administered as a transmucosal oral mist with an orally administered pioneer suspension product

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 (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.     

Robenacoxib in the dog: target species safety in relation to extent and duration of inhibition of COX-1 and COX-2

The safety of robenacoxib, a nonsteroidal anti-inflammatory drug with high selectivity for inhibition of the cyclooxygenase (COX)-2 isoform of COX, was investigated in the dog in two randomized, placebo-controlled, parallel group studies. Robenacoxib was administered orally once daily to healthy young beagle dogs at 0 (placebo), 10, 20 and 40 mg/kg for 1 month (Study 1) and at 0 (placebo), 2, 4, 6 and 10 mg/kg for 6 months (Study 2). Relative to placebo treatment, no significant adverse effects of robenacoxib were recorded in either study for clinical observations, haematological and clinical chemistry variables or macroscopic or microscopic lesions at necropsy. In Study 2, additional examinations identified no adverse effects of robenacoxib on buccal bleeding time, electrocardiographic and ophthalmoscopic examinations, urinalysis or stifle joint tissues. Pharmacokinetic-pharmacodynamic simulations indicated that all dosages of robenacoxib were associated with marked inhibition of COX-2 (median Emax 74-99% inhibition). For the highest dosage of robenacoxib (40 mg/kg in Study 1), the upper limit of the 90% tolerance interval was associated with 71% inhibition of COX-1 at Emax, but 50% inhibition persisted for only 3.5 h. This level of inhibition of COX-1 with robenacoxib was not associated with any detectable toxicity, suggesting that the high safety index of robenacoxib in dogs is a function of both its high COX-2 selectivity and short residence time in the central compartment.