Population pharmacokinetic analysis of blood concentrations of robenacoxib in dogs with osteoarthritis.

The purpose of this analysis was to investigate whether the recommended daily dosage of 1-2mg/kg robenacoxib provides consistent exposure when administered to dogs with chronic osteoarthritis (OA), and the need for dose adjustment in special patient populations. Data from three prospective, multi-center field studies in 208 OA dogs were analyzed using non-linear mixed effects modeling. A model based assessment was performed with stepwise inclusion and exclusion of population characteristics to explain between-subject variability, and assess the according necessity for dose adjustment. Only the influence of bodyweight on both apparent clearance and volume were found to be significant (p<0.01). No significant influence of sex, age and breed, or kidney and liver variables was identified in this representative sample of OA dogs. The population pharmacokinetic analysis performed showed that the 1-2mg/kg dosage chosen provided consistent robenacoxib exposure in a wide range of canine patients. No other dose adjustment seems necessary.

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.

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.

Remission of the clinical signs of atopic dermatitis in dogs after cessation of treatment with cyclosporin A or methylprednisolone.

Seventy-eight dogs with atopic dermatitis were treated for four months with either cyclosporin A or methylprednisolone. During the two months after the treatment ceased, 87 per cent of the dogs treated with methylprednisolone relapsed after a mean period of 27.9 days, whereas only 62 per cent of the dogs treated with cyclosporin A relapsed after a mean period of 40.7 days (P < .0.001). The clinical condition of the dogs was evaluated either when they relapsed, or two months after the treatment ceased if they had not relapsed. Both the skin lesions and pruritus increased significantly more markedly in the dogs treated with methylprednisolone than in those treated with cyclosporin A. At the end of the study the skin lesions were markedly less severe than before the therapy; in the dogs in both groups that did not relapse, the lesion score was improved by 77 per cent two months after the treatment had stopped, and in the dogs that did relapse the lesion scores had improved by 45 per cent and 35 per cent in the dogs treated with cyclosporin A and methylprednisolone, respectively. Pruritus remained well controlled in the dogs that did not relapse, but increased to baseline levels or close to baseline in the dogs that relapsed.

Bovine mastitis and intramammary drug delivery: review and perspectives.

Intramammary infections (IMIs) represent a major feature in bovine pathology. The treatment of IMIs concern antimicrobial substances. Therapeutic strategies involve administration of immediate release formulations during lactation with or without long-acting formulations during the dry period. Current treatments are not very successful and cure rates are poor, especially towards Staphylococcus aureus which is responsible for chronic infections and huge economic losses. New strategies have recently been investigated. These include particular immunomodulators like lysostaphin or cytokines, and novel formulations (e.g. liposomes, microparticles or nanoparticles) that allow uptake of the active component by phagocytes and thus prolong an enhanced antibacterial activity.

Comparison of the effects of adrafinil, propentofylline, and nicergoline on behavior in aged dogs.

OBJECTIVE: To compare the efficacy of adrafinil, propentofylline, and nicergoline for enhancing behavior of aged dogs. ANIMALS: 36 Beagles between 9 and 16 years old. PROCEDURE: Dogs were randomly assigned to receive adrafinil (20 mg/kg of body weight, PO, q 24 h; n = 12), propentofylline (5 mg/kg, PO, q 12 h; 12), or nicergoline (0.5 mg/kg, PO, q 24 h; 12) for 33 days. Baseline behaviors in an open field and in kennels (home cage) were recorded before treatment. After treatment, behaviors in the open field were recorded 2 hours after drug administration on days 2, 15, and 28, and 10 hours after administration on days 7, 20, and 33. Behaviors in the home cage were recorded 2 and 7 hours after drug administration on days 4, 17, and 30. RESULTS: Treatment with adrafinil resulted in a significant increase in locomotion in each of the open-field tests and an increase in locomotion in the home cage. This latter increase was smaller and more variable than that in the open field. Locomotion was not affected by treatment with propentofylline or nicergoline. In the open field, sniffing decreased over time in all 3 groups, but the largest decline was observed in the propentofylline group. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with adrafinil may improve the quality of life of aged dogs by increasing exploratory behavior and alertness.

Behavioral activating effects of adrafinil in aged canines.

Adrafinil, a vigilance enhancing pharmaceutical, was administered to aged dogs for 14 consecutive days at doses of 10, 20, 30, or 40 mg/kg using a crossover design. The effects on spontaneous behavior in a 10-min canine open-field test were systematically recorded every fourth day, starting with day 1 of treatment. The open field tests were given 2 or 10 h following oral administration of capsules containing either adrafinil or lactose, the placebo control. Adrafinil caused an increase in locomotor activity at the three highest doses at both the 2- and 10-h intervals and during both the first (days 1 and 5) and second treatment week (days 9 and 13). Adrafinil also caused a transient increase in directed sniffing. At the highest dose level, adrafinil caused a decrease in urination frequency. The increased locomotion was generally unaccompanied by stereotypical behavior in the test session. There was some variability; a subpopulation of animals showed either no effect, or decreased locomotion. The individual differences were correlated with changes in serum levels of adrafinil 10 h following treatment.

Oral administration of adrafinil improves discrimination learning in aged beagle dogs.

Aged beagle dogs were trained on either a size or intensity discrimination task 2 h following treatment with either 20 mg/kg of adrafinil or a placebo control. Training continued until the dogs reached a predetermined criterion level of performance, or failed to acquire the task after 40 sessions. The treatments and tasks were then reversed, with both the test order and treatment order counterbalanced. Thus, half of the animals were first tested on the intensity discrimination, and half of these were first tested under adrafinil. Treatment with adrafinil produced significant improvement in learning, as indicated by a decrease in both errors and trials to criterion. An effect of adrafinil on motivation may partially account for these findings; however, adrafinil did not significantly affect response latency. Adrafinil is believed to serve as an alpha-1 adrenoceptor agonist. The improved learning may also result from enhancement of vigilance due to facilitation of noradrenergic transmission in the central nervous system.

Comparative field evaluation of marbofloxacin tablets in the treatment of feline upper respiratory infections.

One hundred and three cats presenting with clinical signs of feline acute upper respiratory infection were selected from Belgium, France and the Netherlands in a randomised comparative field trial. Each cat underwent a bacteriological examination before treatment (day 0) and received either marbofloxacin, at a dosage of 2 mg/kg once daily for five days, or amoxycillin-clavulanic acid (ACA) at a dosage of 12.5 mg/kg twice daily for five days. Clinical examinations were performed on days 2, 5 and 14. Pasteurella species were cultured in one-third of the samples. The other main bacteria isolated were Streptococcaceae, Enterobacteriaceae and Staphylococcaceae. Response rates (cures + improvements) to treatment on day 5 were 87.8 vs 77.8 per cent for marbofloxacin and ACA, respectively. A few mild side-effects (diarrhoea, vomiting) were recorded with both drugs.

Prevention of surgical infections in dogs with a single intravenous injection of marbofloxacin: an experimental model.

Eighteen healthy beagle dogs of both sexes were each given 0, 2 or 4 mg/kg marbofloxacin intravenously before the subcutaneous implantation of a silicon tissue cage. Two millilitres of a suspension containing 1.3 x 10(4) colony forming units (CFU)/ml of Staphylococcus intermedius were then injected into the cage 15 minutes after the intravenous injection. The dogs were clinically assessed immediately, and then two, four, eight and 24 hours after the challenge. Samples of inflammatory fluid were harvested at the same times in order to count staphylococci and to assay marbofloxacin concentrations. Blood samples were taken in order to assay plasma marbofloxacin levels. The staphylococcal counts were lower in both treated groups than in untreated dogs (P < 0.01). All the clinical criteria were similar in the three groups. The concentration of marbofloxacin was similar in plasma and inflammatory fluid. Both doses were well tolerated and no adverse reactions were observed.

Use of an oral antiseptic bioadhesive tablet in dogs.

V3703 (Stomadhex) is a tablet with bioadhesive properties enabling it to remain in place for several hours after it has been placed on the oral mucosa. It continuously releases chlorhexidine and niacinamide. In a study conducted in 15 dogs, the tablets were well tolerated by the animals. The product significantly reduced (p < 0.05): dental plaque; quantitative periodontopathogen and total anaerobic bacterial counts; spirochetes; and halitosis when used daily over a 14 day period. Gingivitis was also reduced, though not significantly (p = 0.07). Stomadhex treatment can provide a carry-over effect following dental scaling by reducing oral microflora and retarding the reappearance of dental plaque.

Comparative study of marbofloxacin and amoxicillin-clavulanic acid in the treatment of urinary tract infections in dogs.

One hundred and four dogs with clinical signs of urinary tract infection were selected by 15 practitioners in a multicentric, controlled and randomised study. The clinical diagnosis was confirmed by urinalysis and imaging. Each dog received either marbofloxacin (2 mg/kg orally once daily or 4 mg/kg by subcutaneous injection every four days) or amoxicillin-clavulanic acid tablets (12.5 mg/kg twice daily) for 10 or 28 days, depending on the clinical diagnosis. Rectal temperature, general condition, appetite, urinary signs, defecation disorders and pain on abdominal palpation were monitored at each visit, the timetable depending on diagnosis: three urinalyses and at least three examinations per case were performed. Side effects were also thoroughly sought at each examination. Marbofloxacin and amoxicillin-clavulanic acid both yielded good bacteriological cure rates (96.2 per cent versus 85.0 per cent, respectively) and clinical cure rates (83.3 per cent versus 69.7 per cent). Fewer relapses were observed in those dogs that received marbofloxacin. Few mild side effects were recorded with both products.

Coffin-Lowry syndrome: a multicenter study.

The Coffin-Lowry syndrome is an inherited syndrome of mental retardation, characteristic facies and skeletal anomalies. The occurrence of severe manifestations in males, with no instance of male-to-male transmission, suggests an X-linked inheritance. The paper describes seven families from five European Centers.