Expert opinion on the identification, risk assessment, and mitigation of microorganisms and parasites relevant to xenotransplantation products from pigs.

Xenotransplantation has the potential to address shortages of organs available for clinical transplantation, but concerns exist regarding potential risks posed by porcine microorganisms and parasites (MP) to the health of human recipients. In this study, a risk-based framework was developed, and expert opinion was elicited to evaluate porcine MP based on swine exposure and risk to human health. Experts identified 255 MP to include in the risk assessment. These were rated by experts for five criteria regarding potential swine exposure in the USA and human health risks. MP were subsequently categorized into three risk mitigation groups according to pre-defined rules: disqualifying porcine MP (due to their pathogenic potential, n = 130); non-disqualifying porcine MP (still relevant to consider for biosecurity or monitoring efforts, n = 40); and alert/watch list (not reported in the USA or MP not in swine, n = 85). Most disqualifying (n = 126) and non-disqualifying (n = 36) porcine MP can effectively be eliminated with high biosecurity programs. This approach supports surveillance and risk mitigation strategies for porcine MP in swine produced for xenotransplantation, such as documentation of freedom from porcine MP, or use of porcine MP screening, monitoring, or elimination options. To the authors' knowledge, this is the first effort to comprehensively identify all relevant porcine MP systematically and transparently evaluate the risk of infection of both donor animals and immunosuppressed human recipients, and the potential health impacts for immunosuppressed human recipients from infected xenotransplantation products from pigs.

Fuzapladib in a randomized controlled multicenter masked study in dogs with presumptive acute onset pancreatitis.

BACKGROUND: Currently, no specific treatment is available for acute onset pancreatitis (AP), and management relies on symptomatic and supportive standard of care (SOC). Fuzapladib is a novel leukocyte function-associated antigen type-1 (LFA-1) activation inhibitor, blocking activation and subsequent adhesion and migration of neutrophils, potentially decreasing the risk of pancreatitis progression and systemic inflammation. OBJECTIVE: Evaluate the safety and clinical response of dogs with AP after 3 days of administration of fuzapladib. ANIMALS: Sixty-one client-owned dogs with presumptive AP. METHODS: Randomized, masked, and placebo controlled multicenter study. Sixty-one dogs with AP were included for safety assessment, whereas 35 evaluable cases (fuzapladib, n = 16; placebo, n = 19) were included for clinical evaluation. Clinical improvement was assessed based on the change in the modified clinical activity index (MCAI) score on Day 3 compared to Day 0. Secondary variables included canine acute pancreatitis clinical severity index (CAPCSI) scores and serum concentrations of canine pancreatic lipase immunoreactivity, cytokines, and C-reactive protein. RESULTS: Fuzapladib was well tolerated by all treated dogs. Mean change in MCAI scores was significantly higher in the fuzapladib-treated (-7.75) than the placebo group (-5.68; P = .02, 95% confidence interval [CI] for the difference, -4.33, -0.35), suggesting clinical improvement in fuzapladib-treated dogs. No significant difference was found in any of the secondary variables between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of fuzapladib to dogs was safe, and a favorable response was detected in 2 clinical activity scores. Effects of fuzapladib on survival and duration of hospitalization were not studied.

Safety and effectiveness of the sodium-glucose cotransporter inhibitor bexagliflozin in cats newly diagnosed with diabetes mellitus.

BACKGROUND: Bexagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. A pilot study has shown that bexagliflozin can decrease dependence on exogenous insulin in cats with diabetes mellitus (DM). OBJECTIVE: To evaluate the safety and effectiveness of bexagliflozin as a monotherapy for DM in previously untreated cats. ANIMALS: Eighty-four client-owned cats. METHODS: Historically controlled prospective open-label clinical trial. Cats were dosed PO with 15 mg bexagliflozin once daily for 56 days, with a 124-day extension to evaluate safety and treatment effect durability. The primary endpoint was the proportion of cats experiencing a decrease in hyperglycemia and improvement in clinical signs of hyperglycemia from baseline on day 56. RESULTS: Of 84 enrolled cats, 81 were evaluable on day 56, and 68 (84.0%) were treatment successes. Decreases in mean serum glucose, fructosamine, and ß-hydroxybutyrate (ß-OHB) concentrations were observed, and investigator assessments of cat neurological status, musculature, and hair coat quality improved. Owner evaluations of both cat and owner quality of life were favorable. The fructosamine half-life in diabetic cats was found to be 6.8 days. Commonly observed adverse events included emesis, diarrhea, anorexia, lethargy, and dehydration. Eight cats experienced serious adverse events, 3 of which led to death or euthanasia. The most important adverse event was euglycemic diabetic ketoacidosis, diagnosed in 3 cats and presumed present in a fourth. CONCLUSION AND CLINICAL IMPORTANCE: Bexagliflozin decreased hyperglycemia and observed clinical signs in cats newly diagnosed with DM. As a once-daily PO medication, bexagliflozin may simplify management of DM in cats.

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.

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.

Prevalence of Ancylostoma braziliense in dogs from Alachua and Marion Counties, Florida, United States.

A convenience collection of fecal samples from 148 dogs in northern Florida was examined for the presence of Ancylostoma braziliense eggs by using centrifugal sugar flotation and polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Of the 148 samples, 64 (43.2%) contained hookworm eggs. DNA from 42 samples was successfully amplified using PCR; using RFLP, 2 samples were identified as containing DNA of A. braziliense (4.8% of the 42 successfully amplified samples).

Obtaining an isolate of Ancylostoma braziliense from dogs without the need for necropsy.

Isolation of a specific Ancylostoma species typically requires death of the source animal, or holding an animal long enough to collect feces after treatment, for worm recovery and identification. The reason for collecting worms is that the eggs are not easy to distinguish morphologically. In keeping with the 3 Rs of laboratory animal research (reduction, refinement, replacement), the objective of this study was to obtain an isolate of Ancylostoma braziliense from 1-time field-collected samples of canine feces without the need for killing the host. During a collection trip to Florida, fecal samples (n  =  148) were collected and identified as containing eggs of Ancylostoma species (n  =  64) using centrifugal sugar flotation. Eggs from hookworm-positive slides were washed into tubes, DNA was extracted, and 2 samples were identified as A. braziliense using restriction fragment length polymorphism (RFLP) with Hinf1. Larval cultures were initiated from these samples, and larvae from the cultures were returned to New York and used to inoculate a purpose-bred kitten with the goal of inhibiting the growth of any contaminating Ancylostoma caninum that might be present in the culture. The infection was patent at 15 days, and eggs were identified as A. braziliense by RFLP and DNA sequencing. Using forceps during endoscopy, 2 adult worms (1 male, 1 female) were recovered from the cat and identified morphologically as A. braziliense . Larvae were cultured from the feces of this cat and used to infect a laboratory-reared beagle dog. Additionally, worms recovered from the feces of the cat post-treatment were confirmed to be A. braziliense , except for 1 female A. caninum containing infertile eggs. The dog (patent 14 days post-infection) was also infected with A. braziliense as determined by RFLP and DNA sequencing of eggs and cultured larvae. Both the cat and dog were treated, verified to be no longer shedding eggs, and then placed into adoptive homes.

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

The efficacy and safety of deracoxib administered at 1-2 mg/kg/day for 3 days was assessed for the control of postoperative pain and inflammation associated with dental surgery in dogs. Client-owned dogs scheduled for dental extractions were premedicated with butorphanol and randomly assigned to receive either deracoxib (n = 31) or placebo (n = 31) preoperatively and again once daily for 2 additional days. Dogs were evaluated prior to and after surgery using a modified Glasgow Composite Pain Scale (mGCPS). Dogs could be rescued at any time if they scored ≥4 on the mGCPS or in cases of obvious discomfort. Rescued dogs were considered treatment failures for determining treatment response and were removed from the study. Of the 62 dogs enrolled, 57 were usable for the efficacy analyses and all were assessed for safety. Four of 27 deracoxib-treated dogs (14.8%) were rescued compared to 20 of 30 placebo dogs (66.7%) (P = 0.0006). Deracoxib-treated dogs also had numerically lower mGCPS scores. Eight of 31 deracoxib dogs (26%) had adverse events reported compared to 6 of 31 placebo dogs (19%). Results indicate perioperative administration of deracoxib to dogs at 1-2 mg/kg/day for 3 days significantly improves analgesia after dental surgery.