Effect of benazepril and pimobendan on serum angiotensin-converting enzyme activity in dogs.

To support their combined use, the objective of the study was to evaluate the effects of benazepril and pimobendan on serum angiotensin-converting enzyme (ACE) activity in dogs. A total of 48 healthy beagle dogs were randomized into four groups (n = 12 per group) in a parallel-group design study: A (control, placebo twice daily (BID)); B (0.5-1.0 mg/kg benazepril once daily (SID) in the morning, placebo in the evening); C (0.25-0.5 mg/kg benazepril BID); D (0.25-0.5 mg/kg benazepril and 0.125-0.25 mg/kg pimobendan, both BID). The test items were administered orally for 15 days. Serum ACE activity was measured on days 1 and 15. Groups B, C and D had significantly lower average serum ACE activity compared to baseline and to the control group, on both days 1 and 15. There were no significant differences in average ACE activity between groups B, C and D. Noninferiority of group C to B was demonstrated. In conclusion, 0.25-0.5 mg/kg benazepril administered BID produced noninferior inhibition of serum ACE activity compared to 0.5-1.0 mg/kg benazepril dosed SID. Pimobendan had no significant effect on benazepril's action on serum ACE activity. The results support the use of benazepril BID in dogs and in combination with pimobendan.

Safety of a benazepril and pimobendan combination tablet in adult healthy dogs.

The objective of the study was to investigate the safety of a combination tablet of benazepril and pimobendan, Fortekor PLUS® , in a randomized, blinded, parallel-group design study in healthy adult beagle dogs. The test article, Fortekor PLUS® tablets, was administered orally twice daily for 6 months at one, two, and four times the highest recommended dosage of 0.5 mg/kg benazepril hydrochloride/0.25 mg/kg pimobendan (four males and four females per group). An additional control group was sham-dosed. Fortekor PLUS® did not induce any treatment-related effects on body weight, food consumption, neurological, ophthalmologic or physical assessments over the 6-month treatment period. The test article was possibly associated with an increased frequency of occasional vomiting. Fortekor PLUS® was associated with small, but significant, increases in heart rate and reductions in PR and QT intervals, which were assessed by electrocardiography. These effects were most probably related to reflex tachycardia secondary to reduced systemic blood pressure. Statistically significant changes in some clinical pathology variables were noted after test article administration, but were considered to be of no clinical relevance as values remained within reference ranges and/or were not dose-dependent. No treatment-related macroscopic or microscopic findings were observed. In conclusion, Fortekor PLUS® tablets were well tolerated in healthy adult dogs when administered at one, two, and four times the highest recommended dosage for 6 months.

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.

Effect of benazepril and robenacoxib and their combination on glomerular filtration rate in dogs.

Combined use of angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs may induce acute kidney injury, especially when combined with diuretics. The objective of this investigation was to evaluate the effect of benazepril, robenacoxib and their combination in healthy dogs. In each of two studies (studies 1 and 2), 32 beagle dogs were randomized into one of four groups in a parallel-group design. Groups received once-daily oral treatment for 7 days with placebo, benazepril, robenacoxib or benazepril plus robenacoxib. In study 2, all dogs received additionally 2 mg/kg furosemide orally twice daily. The primary endpoint was the glomerular filtration rate (GFR) estimated from the plasma clearance of iohexol. Secondary endpoints included standard clinical monitoring and, in study 2, plasma renin activity, urine volume, specific gravity and aldosterone concentration and water intake. Administration of furosemide induced diuresis, reduced GFR and activated the renin-aldosterone-angiotensin system. Benazepril and robenacoxib, administered alone or in combination, were tolerated well, did not decrease GFR with or without co-administration of furosemide and significantly reduced urinary aldosterone concentrations. No increased risk of acute kidney injury was identified with the combination of benazepril and robenacoxib in healthy dogs. Different effects might occur in dogs with heart or renal disease.

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.

Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney.

BACKGROUND: The role of cyclooxygenase(COX)-1 and COX-2 in the saluretic and renin-angiotensin responses to loop diuretics in the cat is unknown. We propose in vivo characterisation of isoform roles in a furosemide model by administering non-steroidal anti-inflammatory drugs (NSAIDs) with differing selectivity profiles: robenacoxib (COX-2 selective) and ketoprofen (COX-1 selective). RESULTS: In this four period crossover study, we compared the effect of four treatments: placebo, robenacoxib once or twice daily and ketoprofen once daily concomitantly with furosemide in seven healthy cats. For each period, urine and blood samples were collected at baseline and within 48 h of treatment starting. Plasma renin activity (PRA), plasma and urinary aldosterone concentrations, glomerular filtration rate (GFR) and 24 h urinary volumes, electrolytes and eicosanoids (PGE2, 6-keto-PGF1α, TxB2), renal injury biomarker excretions [N-acetyl-beta-D-glucosaminidase (NAG) and Gamma-Glutamyltransferase] were measured. Urine volume (24 h) and urinary sodium, chloride and calcium excretions increased from baseline with all treatments. Plasma creatinine increased with all treatments except placebo, whereas GFR was significantly decreased from baseline only with ketoprofen. PRA increased significantly with placebo and once daily robenacoxib and the increase was significantly higher with placebo compared to ketoprofen (10.5 ± 4.4 vs 4.9 ± 5.0 ng ml(-1) h(-1)). Urinary aldosterone excretion increased with all treatments but this increase was inhibited by 75 % with ketoprofen and 65 % with once daily robenacoxib compared to placebo. Urinary PGE2 excretion decreased with all treatments and excretion was significantly lower with ketoprofen compared to placebo. Urinary TxB2 excretion was significantly increased from baseline only with placebo. NAG increased from baseline with all treatments. Immunohistochemistry on post-mortem renal specimens, obtained from a different group of cats that died naturally of non-renal causes, suggested constitutive COX-1 and COX-2 co-localization in many renal structures including the macula densa (MD). CONCLUSIONS: These data suggest that both COX-1 and COX-2 could generate the signal from the MD to the renin secreting cells in cats exposed to furosemide. Co-localization of COX isoenzymes in MD cells supports the functional data reported here.

Efficacy and acceptability of the new oral phosphate binder Lenziaren(®) in healthy cats fed a renal diet.

The efficacy and acceptability of the new oral phosphate binder Lenziaren(®) (SBR759) were evaluated in healthy cats fed with a commercial diet containing low amounts of phosphate ('renal diet'). Lenziaren(®) at 0.125, 0.25, 0.5 and 1 g/day was compared to a reference product Lantharenol(®) (3.0 g/day) and a placebo in a masked, randomized, parallel-group design study in 36 cats (n = 6 per group). All products were mixed with the ration which was fed once daily for 28 days. Lenziaren(®) produced significant dose-related reductions in serum and urine phosphate concentrations, faecal apparent phosphorus digestibility and fractional urinary phosphate excretion. Cats administered Lenziaren(®) consumed significantly less food than the placebo group, but this had no negative impact on body weight or acceptability assessments. When compared to the positive control, Lantharenol(®) , Lenziaren(®) was significantly more acceptable (0.125, 0.5 and 1.0 g/day doses), was associated with higher food consumption (0.125, 0.5 and 1.0 g/day doses) and had greater efficacy in reducing serum phosphate (0.5 and 1.0 g/day) and urine phosphate concentrations (1.0 g/day). In conclusion, Lenziaren(®) was an effective oral phosphate binder in healthy cats fed with a renal diet. Lenziaren(®) was well accepted and tolerated. Dosages of 0.25-1.0 g/cat per day are recommended for clinical testing.

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 vivo IC50 COX-1/IC50 COX-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.

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.

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

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 TxB(2) and exudate PGE(2) 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 (IC(50) COX-1: IC(50) 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.

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.

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.

In vitro and ex vivo inhibition of COX isoforms by robenacoxib in the cat: a comparative study.

Robenacoxib is a novel nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animals. Whole blood assays were used to characterize in the cat the pharmacodynamics of robenacoxib for inhibition of the cyclooxygenase (COX) isoforms, COX-1 and COX-2, in comparison with other NSAIDs. Based on in vitro IC(50) COX-1:IC(50) COX-2 ratios, robenacoxib was COX-2 selective (ratio = 32.2), diclofenac (ratio = 3.9) and meloxicam (ratio = 2.7) were only weakly COX-2 preferential, and ketoprofen (ratio = 0.049) was COX-1 selective. In an in vivo pharmacokinetic ex vivo pharmacodynamic study, after both p.o. (1-2 mg/kg) and subcutaneous (2 mg/kg) dosing, robenacoxib achieved peak blood concentrations rapidly (T(max) = 1 h for both administration routes) and was cleared from blood relatively rapidly (mean residence time was 1.70 h after p.o. and 1.79 h after subcutaneous dosing). In ex vivo COX isoform inhibition assays, orally (1-2 mg/kg) or subcutaneously (2 mg/kg) administered robenacoxib significantly inhibited COX-2, with a relatively short duration of action in the central compartment, and had no effect on COX-1. Therefore robenacoxib was COX-2 selective and spared COX-1 in vivo. In contrast, meloxicam (0.3 mg/kg via subcutaneous injection) inhibited both COX-1 and COX-2 isoforms significantly for at least 24 h, indicating nonselectivity in vivo.

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

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 ED(50) 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 ED(50) 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.

Analytical determination and pharmacokinetics of robenacoxib in the dog.

An analytical method was developed and validated for the measurement of the novel analgesic and anti-inflammatory drug robenacoxib in blood and plasma of dogs and cats. To prevent nonreproducible carry-over effects, an initial solid phase extraction procedure was followed by high pressure liquid chromatography analysis for samples with concentrations in the range 500 to 20,000 ng/mL. To improve accuracy, samples of concentration 3 to 100 ng/mL were analyzed by liquid chromatography-mass spectrometry. Applying these methods, blood concentration-time profiles and pharmacokinetic variables of robenacoxib in dogs were determined in a four-phase cross-over study, which compared different routes of administration of the drug, including intravenous (i.v.) injection, oral application with and without feed, and subcutaneous (s.c.) application. After i.v. administration the mean clearance from blood was 0.81 L/kg/h, the volume of distribution was 0.77 L/kg for the elimination phase and 0.24 L/kg for steady-state, and the terminal half-life in blood was 0.63 h. Maximum blood concentrations were obtained in less than 1 h following oral or s.c. application. Absolute bioavailability was 88% after s.c. injection, 84% after oral administration to fasted dogs, but was reduced to 62% when applied orally to fed dogs. In canine and feline plasma the degree of binding of robenacoxib to plasma protein in vitro was greater than 98%. The blood:plasma concentration ratio was 0.44:1 in the dog and 0.65:1 in the cat. In conclusion analytical methods for the quantification of robenacoxib in blood and plasma in the dog and cat were developed and validated. In dogs, robenacoxib has good bioavailability after oral (84%) and subcutaneous (88%) administration.

Use of a pharmacokinetic/pharmacodynamic approach in the cat to determine a dosage regimen for the COX-2 selective drug robenacoxib.

This study investigated the analgesic, anti-inflammatory and antipyretic efficacy of the new COX-2 selective inhibitor robenacoxib in the cat and established pharmacodynamic (PD) parameters for these effects. Robenacoxib, at a dosage of 2 mg/kg administered subcutaneously, was evaluated in a kaolin-induced paw inflammation model in 10 cats, using both clinically relevant endpoints (lameness scoring, locomotion tests) and other indicators of inflammation (body and skin temperature, thermal pain threshold) to establish its pharmacological profile. A pharmacokinetic/pharmacodynamic (PK/PD) modelling approach, based on indirect response models, was used to describe the time course and magnitude of the responses to robenacoxib. All endpoints demonstrated good responsiveness to robenacoxib administration and both the magnitude and time courses of responses were well described by the indirect pharmacodynamic response models. Pharmacokinetic and clinically relevant pharmacodynamic parameters were used to simulate dosage regimens that will assist the planning of clinical trials and the selection of an optimal dosage regimen for robenacoxib in the cat.

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) microM (COX-1) and 0.058 (0.010-0.340) microM (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.

Preclinical pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase-2.

This manuscript reports the results of preclinical studies in the rat with robenacoxib, a novel selective cyclooxygenase (COX)-2 inhibitor. Robenacoxib selectively inhibited COX-2 in vitro as evidenced from COX-1:COX-2 IC50 ratios of 27:1 in purified enzyme preparations and >967:1 in isolated cell assays. Binding to COX-1 was rapid and readily reversible (dissociation t(1/2) << 1 min), whilst COX-2 binding was slowly reversible (t(1/2) = 25 min). In vivo, robenacoxib inhibited PGE2 production (an index of COX-2 inhibition) in lipopolysaccharide (LPS)-stimulated air pouches (ID50 0.3 mg/kg) and for at least 24 h in zymosan-induced inflammatory exudate (at 2 mg/kg). Robenacoxib was COX-1 sparing, as it inhibited serum TxB2 synthesis ex vivo (an index of COX-1 inhibition) only at very high doses (100 mg/kg but not at 2-30 mg/kg). Robenacoxib inhibited carrageenan-induced paw oedema (ID50 0.40-0.48 mg/kg), LPS-induced fever (ID50 1.1 mg/kg) and Randall-Selitto pain (10 mg/kg). Robenacoxib was highly bound to plasma protein (99.9% at 50 ng/mL in vitro). After intravenous dosing, clearance was 2.4 mL/min/kg and volume of distribution at steady-state was 306 mL/kg. Robenacoxib was preferentially distributed into inflammatory exudate; the AUC for exudate was 2.9 times higher than for blood and the MRT in exudate (15.9 h) was three times longer than in blood (5.3 h). Robenacoxib produced significantly less gastric ulceration and intestinal permeability as compared with the reference nonsteroidal anti-inflammatory drug (NSAID), diclofenac, and did not inhibit PGE2 or 6-keto PGF(1alpha) concentrations in the stomach and ileum at 30 mg/kg. Robenacoxib also had no relevant effects on kidney function at 30 mg/kg. In summary, results of preclinical studies in rats studies suggest that robenacoxib has an attractive pharmacological profile for potential use in the intended target species, cats and dogs.

Efficacy and Safety of Injectable Robenacoxib for the Treatment of Pain Associated With Soft Tissue Surgery in Dogs.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are used routinely to control pain and inflammation after surgery in dogs. Robenacoxib is a cyclooxygenase-2 selective NSAID. HYPOTHESIS/OBJECTIVE: Assess the clinical efficacy and safety of an injectable formulation of robenacoxib in dogs undergoing surgery. ANIMALS: Three hundred and seventeen client-owned dogs (N = 159 robenacoxib or N = 158 placebo). METHODS: In this prospective, multicenter, randomized, masked, placebo-controlled, parallel-group study, dogs received a SC injection of either robenacoxib, at a target dose of 2.0 mg/kg, or placebo once prior to surgery and for 2 additional days postoperatively. Pain assessments were performed using the short form of the Glasgow Composite Measure Pain Scale (CMPS-SF). The primary efficacy variable was treatment success/failure, with failure defined as the need for rescue therapy to control pain or withdrawal of the dog from the study due to an adverse event. RESULTS: Significantly (P = .006) more dogs administered robenacoxib were considered treatment successes (108 of 151, 73.7%) compared to dogs given placebo (85 of 152, 58.1%). Total pain scores (P < .01), pain at the surgery sites (response to touch, P < .01), and posture/activity (P < .05) were significantly improved at 3, 5, and 8 hours postextubation in dogs receiving robenacoxib versus placebo. CONCLUSIONS AND CLINICAL IMPORTANCE: Robenacoxib administered by SC injection prior to surgery and for 2 additional days postoperatively was effective and well tolerated in the control of postoperative pain and inflammation associated with soft tissue surgery in dogs.

Effects of Benazepril on Survival of Dogs with Chronic Kidney Disease: A Multicenter, Randomized, Blinded, Placebo-Controlled Clinical Trial.

BACKGROUND: Chronic kidney disease (CKD) is an important cause of morbidity and mortality in dogs. OBJECTIVE: To evaluate the efficacy in prolonging survival and safety of benazepril administration to dogs with CKD. ANIMALS: Forty-nine client-owned dogs with CKD. METHODS: Dogs were randomized to benazepril (0.25 to <0.5 mg/kg) or placebo once daily for up to 2 years in a prospective, multicenter, blinded clinical trial. The primary endpoint variable was the renal survival time, defined as the time from inclusion in the study to the treatment failure endpoint of death or euthanasia or need for administration of parenteral fluids related to renal failure. RESULTS: No benefit of benazepril versus placebo was detected for renal survival time in all dogs; median (95% confidence interval (CI)) survival times were 305 (53-575) days in the benazepril group and 287 (152-not available) in the placebo group (P = .53). Renal survival times were not significantly longer with benazepril compared to placebo for subgroups: hazard ratios (95% CI) were 0.50 (0.21-1.22) with P = .12 for initial urine protein-to-creatinine ratio (UPC) >0.5, and 0.38 (0.12-1.19) with P = .080 for initial UPC >0.5 plus plasma creatinine ≤440 µmol/L. Proteinuria, assessed from the UPC, was significantly (P = .0032) lower after treatment with benazepril compared to placebo. There were no significant differences between groups for clinical signs or frequencies of adverse events. CONCLUSIONS AND CLINICAL RELEVANCE: Benazepril significantly reduced proteinuria in dogs with CKD. Insufficient numbers of dogs were recruited to allow conclusions on survival time.