Linda M. Roycroft

Efficacy and safety of deracoxib for control of postoperative pain and inflammation associated with soft tissue surgery in dogs.

OBJECTIVE To investigate the effectiveness and safety of deracoxib (Deramaxx®) administered at a dose of 1-2 mg/kg/day for 3 days for control of postoperative pain and inflammation associated with soft tissue surgery in dogs. STUDY DESIGN Prospective, randomized, blinded, placebo-controlled, multi-center clinical study. ANIMALS Dogs (n = 34). METHODS Dogs undergoing soft tissue surgeries were randomly assigned to receive either deracoxib (n = 18) or placebo (n = 16) as a preoperative treatment and again once daily for 2 additional days after surgery unless removed from the study. Dogs were evaluated before surgery and again postsurgically at predetermined times using the Glasgow Composite Pain Scale (GCPS). All dogs were allowed to receive another pain medication (except nonsteroidal anti-inflammatory drugs [NSAIDs] or corticosteroids) as postsurgical pain intervention if the dog scored ≥6 on the GCPS or was in obvious discomfort. Dogs receiving pain intervention were considered treatment failures and were removed from the study. RESULTS Two of 16 dogs treated with deracoxib were rescued compared with 9 of 16 dogs receiving placebo (P = .0091). In addition, deracoxib treated dogs had numerically lower GCPS scores. CONCLUSIONS Results suggest perioperative administration of deracoxib to dogs at 1-2 mg/kg/day for 3 days significantly improves analgesia in the postoperative surgical period after soft tissue surgery. Placebo dogs not rescued after painful procedures highlight the need for refinement of current pain assessment tools.

Clinical safety of robenacoxib in feline osteoarthritis: results of a randomized, blinded, placebo- controlled clinical trial

Objectives The objective of this study was to evaluate the clinical safety of the non-steroidal anti-inflammatory drug (NSAID) robenacoxib in cats with osteoarthritis. Degenerative joint disease, including osteoarthritis, is highly prevalent in cats and many cases have associated pain and impaired mobility. Although NSAIDs are used routinely to control pain and inflammation in cats with osteoarthritis, there are safety concerns because of the high concurrent prevalence of chronic kidney disease (CKD) and the paucity of data on the safety of these drugs in target clinical populations. Methods A total of 194 cats with osteoarthritis were recruited and randomly allocated to receive either robenacoxib at a dosage of 1.0–2.4 mg/kg (n = 95) or placebo (n = 99) tablets PO q24h for 28 days. Safety was assessed in 193 cats, including a subgroup of 40 animals with concurrent CKD, defined as serum creatinine concentration ⩾1.6 mg/dl and urine specific gravity <1.030. Safety endpoints included reports of adverse events, results of clinical examinations, including body weight, and clinical chemistry and hematology variables. Results In all 193 cats and the subgroup of 40 animals with concurrent CKD, there were no differences between groups in frequencies of reported adverse events, body weight change or results of serum or urine chemistry or hematology variables. Conclusions and relevance Robenacoxib was well tolerated when administered daily for 1 month in cats with osteoarthritis, including cats with evidence of concurrent CKD. There was no clinical indication of damage to the gastrointestinal tract, kidney or liver.

Safety, tolerability, and pharmacokinetics of 6-month daily dosing of an oral formulation of cyclosporine (ATOPICA for cats) in cats

Cyclosporine was proven efficacious in the treatment of feline hypersensitivity dermatitis. This target animal study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ATOPICA for Cats® (cyclosporine oral solution, USP) MODIFIED following 6-month daily dosing in cats. Forty healthy cats (four cats/sex/group) received 0, 8 (1×), 16 (2×), 24 (3×), or 40 (5×) mg/kg cyclosporine once daily for 6 months (183 days). Body weight, food consumption, ophthalmoscopic, physical examinations including neurological assessments, blood pressure, electrocardiography, clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), organ weights, and macroscopic and microscopic examinations were performed and assessed. In addition, blood concentrations of cyclosporine were measured at the pretreatment trough on Days 1, 2, 7, 14, 31, 91, 154, and 182, and post-treatment on Days 1, 31, and 182. Adverse effects possibly related to treatment included prolonged APTT and one report each of bone marrow hypocellularity and lymphoma; all occurred in cats treated with doses more than 16 mg/kg. There was no significant accumulation of cyclosporine beyond the first week of treatment. Results confirm that ATOPICA for Cats is safe and well tolerated in cats without unexpected accumulation beyond the first week of treatment when administered as directed.

Effect of oral administration of cyclosporine on Toxoplasma gondii infection status of cats

OBJECTIVE To evaluate whether anti-inflammatory doses of cyclosporine activate Toxoplasma gondii in chronically infected cats or potentiate infection in cats exposed for the first time. ANIMALS 30 T gondii-negative cats. PROCEDURES Cats were assigned to 1 of 3 groups (10 cats/group). Group 1 (control) cats were administered a placebo for 126 days; group 2 cats were administered a placebo for 84 days, followed by cyclosporine at 7.5 mg/kg/d, PO, for 42 days; and group 3 cats were administered cyclosporine at 7.5 mg/kg/d, PO, for 126 days. Cats were orally inoculated with T gondii on day 42. Results for fecal flotations, PCR assays, and histologic examinations and IgM and IgG titers were analyzed. Cyclosporine concentrations were measured on selected days. RESULTS All cats were infected by T gondii and developed signs of self-limiting gastrointestinal tract infection. Group 3 had the highest incidence and severity of CNS and pulmonary histopathologic findings typical of toxoplasmosis. One cat in group 3 died of systemic toxoplasmosis; that cat had a cyclosporine concentration of 1,690 ng/mL. Group 2 cats infected with T gondii before cyclosporine administration did not have repeated oocyst shedding. Group 3 cats shed fewer oocysts for a shorter time than did control cats of group 1. CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of cyclosporine in accordance with the protocol for this study did not potentiate the enteroepithelial phase of T gondii infection. Cats with high cyclosporine blood concentrations at the time of primary T gondii infection may be at risk of developing systemic toxoplasmosis.

Efficacy of a single oral administration of milbemycin oxime against natural infections of Ancylostoma braziliense in dogs.

The objective of this randomized, blinded, placebo controlled laboratory study was to confirm the efficacy of a single oral administration of two marketed formulations of milbemycin oxime (Interceptor(®) Flavor Tabs(®) and Sentinel(®) Flavor Tabs(®)) at a minimum dose of 0.5 mg/kg (0.23 mg/lb) against natural infections of Ancylostoma braziliense in dogs. Thirty-six hookworm infected dogs, a minimum of 10 weeks of age and of various breeds and genders were used. Fecal egg counts were done on three separate days prior to treatment for randomization purposes. Dogs were ranked by descending order of the fecal egg count arithmetic means and randomly assigned to either the two milbemycin treatment groups or the placebo control group in blocks of three dogs each, 12 dogs per group. Dogs were dosed according to the product label with blinding maintained by separation of function. Worm counts were done at necropsy 7 days after treatment. Reduction in A. braziliense worm counts in the milbemycin groups were compared to the placebo control group using analysis of variance of the A. braziliense logarithmic mean worm counts and percent efficacy was based on geometric means. Efficacy was defined as the ability of the test products to significantly (p≤0.05) reduce parasite load by 90% or greater in treated dogs when compared to adequately infected placebo control dogs. The placebo control group had a geometric mean worm count of 19.2. The Interceptor treated group had a geometric mean worm count of 0.38 representing a 98% reduction in parasite load and the Sentinel treated group had a geometric mean worm count of 0.98 representing a 95% reduction in parasite load. Both reductions were highly significant (p<0.0001). In this study, milbemycin oxime, when administered as two marketed formulations at a minimum dose of 0.5 mg/kg (0.23 mg/lb), was efficacious for removing adult A. braziliense in naturally infected dogs.

Evaluation of Oral Robenacoxib for the Treatment of Postoperative Pain and Inflammation in Cats: Results of a Randomized Clinical Trial

The efficacy and safety of robenacoxib were assessed for the control of postoperative pain and inflammation in cats. The study was a multicenter, prospective, randomized, blinded, and parallel group clinical trial. A total of 249 client-owned cats scheduled for forelimb onychectomy plus either ovariohysterectomy or castration surgeries were included. All cats received butorphanol prior to anesthesia and forelimb four-point regional nerve blocks with bupivacaine after induction of general anesthesia. Cats were randomized to receive daily oral tablet robenacoxib, at a mean (range) dosage of 1.84 (1.03–2.40) mg/kg (n = 167), or placebo (n = 82), once prior to surgery and for two days postoperatively. Significantly (P < 0.05) fewer robenacoxib cats received additional analgesia rescue therapy (16.5%) than placebo cats (46.3%). Pain elicited on palpation of the soft tissue incision site, behavior following social interaction, and posture assessed during the first 8 hours after extubation were significantly (P < 0.05) improved in cats receiving robenacoxib. Frequency of reported adverse clinical signs, hematology, serum chemistry and urinalysis variables, and body weight changes weresimilar between groups. In conclusion, robenacoxib was effective and well tolerated in the control of postoperative pain and inflammation in cats undergoing onychectomy with ovariohysterectomy or castration.

Clinical efficacy and safety following dose tapering of ciclosporin in cats with hypersensitivity dermatitis

Objectives This study was designed to evaluate the efficacy and safety of reducing ciclosporin (CsA) dosing frequency from daily to every other day (EOD) or twice a week (TW) according to clinical response in cats with hypersensitivity dermatitis (HD) and treated with CsA. Methods One hundred and ninety-one cats with HD were given 7 mg/kg CsA daily for at least 4 weeks. Depending on clinical response, the dosing frequency was tapered from daily to EOD over the next 4 weeks and further to TW for an additional 4 weeks. Safety was evaluated through physical examinations, clinical pathology and the monitoring of adverse events (AEs). Results The majority of cats were able to have their dose of CsA tapered to either EOD (15.5%) or TW (62.9%) according to the clinical response. Observed AEs were most frequently mild and self-limiting vomiting and diarrhea. A higher percentage of AEs occurred with daily administration (73%) compared with other dosing regimens (27%). Conclusions and relevance Following 4 weeks of daily dosing at 7 mg/kg, CsA may be tapered to EOD or TW while maintaining the desired therapeutic response in cats with HD. Additionally, CsA appears to be well tolerated with fewer AEs at EOD or TW dosing. Establishing the lowest effective dosing frequency of CsA improves the drug’s safety profile.

Confirmatory field study for the evaluation of ciclosporin at a target dose of 7.0 mg/kg (3.2 mg/lb) in the control of feline hypersensitivity dermatitides

Objectives This study was designed to confirm the efficacy and tolerability of a daily dose of 7.0 mg/kg (3.2 mg/lb) ciclosporin (CsA) in the treatment of feline hypersensitivity dermatitis (HD), as this includes some of the most frequently suspected skin diseases in cats and recent publications have reported the successful use of CsA in the treatment of feline HD. Methods In total, 217 cats with feline HD were treated daily for 42 days with a target dose of 7 mg/kg CsA (n = 144) or a placebo control (n = 73) administered either in the food or directly in the mouth following feeding. Clinical and dermatological evaluations were conducted on days 0, 21 and 42, or study exit. Safety was evaluated through physical examinations, clinical pathology and the monitoring of adverse events (AEs). Results Administration of CsA at 7.0 mg/kg produced a significant improvement in the total lesion score (P <0.0001). The average reduction from visit 1 to visit 3 was 65.1% in the CsA group (9.2% for the placebo). In addition, owners assessed 78.3% of the cases in the CsA group as a success. Statistically significant recoveries were also seen in extent of lesions, investigator assessment of overall improvement, and mean improvement in both the investigators’ and owners’ assessment of pruritus. Mild gastrointestinal disorders were the most common AEs but did not require cessation of therapy. Conclusions and relevance Results confirm that 7.0 mg/kg CsA dosed daily in food or orally for up to 6 weeks is effective and well tolerated by cats with feline HD.

Effect of high-dose ciclosporin on the immune response to primary and booster vaccination in immunocompetent cats

Ciclosporin (Atopica oral solution for cats 100 mg/ml; Novartis Animal Health) was recently approved for use in cats with feline hypersensitivity dermatitis. The immunosuppressant effect of ciclosporin on the ability of cats to mount an immune response following vaccination was determined. Thirty-two healthy, immunocompetent adult cats (16 cats/group) were treated with either ciclosporin for 56 days at a dose of 24 mg/kg once daily or sham dosed. Prior to treatment, cats had an adequate antibody response to primary vaccination against feline calicivirus (FCV), feline herpesvirus-1 (FHV-1), feline panleukopenia virus (FPV), feline leukemia virus (FeLV) and rabies. Booster vaccination or novel vaccination with feline immunodeficiency virus (FIV) was administered 28 days after initiation of treatment with ciclosporin. There were no differences between the ciclosporin-treated and control cats for FCV and FPV antibody titers following booster vaccination. There were delays/reductions in antibody response to FHV-1, FeLV and rabies in treated cats; however, adequate protection was achieved in response to all booster vaccinations. Following primary vaccination with FIV, control cats showed a response, but treated cats showed no antibody production. Adverse events commonly associated with ciclosporin treatment, including diarrhea/loose stool, vomiting, salivation and regurgitation, were reported. In adult cats treated with 24 mg/kg/day of ciclosporin (more than three times the therapeutic dose), vaccine titer levels were adequate for protection following booster vaccination. In contrast, treated cats failed to mount a humoral response to a novel (FIV) vaccination, suggesting that memory B-cell immune responses remain intact during repeated high-dose ciclosporin administration in cats, but that primary immune responses are impaired.

Zinc-carnosine and vitamin E supplementation does not ameliorate gastrointestinal side effects associated with ciclosporin therapy of canine atopic dermatitis.

Chelated zinc-carnosine and vitamin E [GastriCalm(®) (GCM); Teva Animal Health] is marketed as an anti-emetic supplement for dogs to assist the repair of damaged stomach and intestinal mucosa. The purpose of this prospective, double-blinded, placebo-controlled trial was to determine whether GCM reduced the frequency of vomiting, diarrhoea and appetite changes during initiation of ciclosporin (Atopica(®); Novartis Animal Health) therapy for the treatment of canine atopic dermatitis. Sixty privately owned dogs diagnosed with atopic dermatitis were randomly assigned to GCM (n=30) or placebo (n=30) groups. All dogs received ∼ 5 mg/kg ciclosporin (range, 3.5-5.8 mg/kg) once daily. Dogs <13.6 kg received half a tablet of GCM or placebo; dogs ≥ 13.6 kg received one tablet once daily. GastriCalm(®) or placebo was administered 30 min prior to eating, and the ciclosporin was administered 2 h after feeding. Owners recorded episodes of vomiting, diarrhoea and appetite changes. Dogs were examined on days 0 and 14. Forty-one of 60 dogs (68.3%) had at least one episode of vomiting, diarrhoea or appetite change, leaving nine placebo dogs (30%) and ten GCM dogs (33.3%) free of adverse events (AE). Twenty-seven of 60 dogs (45%) vomited, and 15 of 60 (25%) had diarrhoea. There was no significant difference in episodes of individual AEs, but the placebo group had a significantly lower total AE score (summation of episodes of appetite change, vomiting and diarrhoea; P=0.022). Small dogs (<6.82 kg) had significantly fewer total AEs in both treatment groups and tolerated ciclosporin better than larger dogs (P<0.05).