BackgroundThis study evaluated the effectiveness and safety of grapiprant for treatment of pain in dogs with osteoarthritis (OA).Hypothesis/ObjectivesGrapiprant will relieve pain as measured by the owner's and veterinarian's evaluation of pain in dogs with OA. Another objective was evaluation of the safety of grapiprant.AnimalsTwo hundred and eighty‐five client‐owned dogs with OA were enrolled and treated with grapiprant or placebo with 262 cases (N = 131 in each group) evaluable for the effectiveness analysis.MethodsIn this prospective, randomized, masked, placebo‐controlled study dogs were treated daily with grapiprant (2 mg/kg) per OS or placebo. Owners completed an evaluation using the Canine Brief Pain Inventory (CBPI) on days 0, 7, 14, 21, and 28. Success was defined as improvement in the CBPI. Veterinary assessments were made on screening and days 14 and 28. Safety was evaluated by physical examination, evaluation of clinical pathology results, and owner observations.ResultsGrapiprant treatment improved pain compared to placebo on day 28 (48.1 and 31.3% treatment successes respectively; P = .0315). The pain interference score (PIS) and pain severity score (PSS) improved in the grapiprant group compared to placebo (P = .0029 and 0.0022, respectively). Veterinary assessments were significantly better in the grapiprant‐treated dogs (P = .0086). Grapiprant generally was well tolerated, but a higher percentage of treated dogs (17.02%) had occasional vomiting as compared to the placebo group (6.25%).Conclusions and Clinical ImportanceGrapiprant is an effective treatment for alleviation of pain in dogs with OA, and represents a modality of treatment that may be better tolerated than current options.

The organic anion transporting polypeptides, Oatp1 (Slc21a1) and Oatp2 (Slc21a5), mediate hepatic uptake of cardiac glycosides. Previously, we demonstrated that chemicals that increase cytochrome P450s differentially affect hepatic uptake of cardiac glycosides. We postulated that increased uptake of cardiac glycosides observed after pretreatment of animals with phenobarbital (PB) and pregnenolone-16␣-carbonitrile ( Hepatic clearance and biliary excretion of drugs and their metabolites can occur through passive transport or through active transport (carrier-mediated) systems. Previous studies from this laboratory described a phenomenon in which pretreatment of animals with chemicals known to differentially increase specific microsomal cytochrome P450 enzymes also enhanced both hepatic plasma clearance and biliary excretion of a number of choleophiles, including cardiac glycosides. [1][2][3][4] Specifically, pretreatment of rats with two compounds known classically to activate CYP2B and CYP3A transcription, the barbiturate phenobarbital (PB) and the synthetic steroid pregenenolone-16␣-carbonitrile (PCN), respectively, resulted in the decreased plasma half-life, increased hepatic clearance, and decreased toxicity of cardiac glycosides. In contrast, pretreatment of rats with chemicals known to act through the aryl hydrocarbon receptor resulted in a slight suppression of cardiac glycoside plasma clearance by the liver. 2 Further studies demonstrated that PCN increased the maximal velocity and affinity of ouabain uptake into hepatocytes, 3 suggesting that this chemical altered the hepatocellular capacity and affinity for choleophilic substrates. In subsequent studies, an energydependent, Na ϩ -independent carrier-mediated transport system for ouabain was identified. This Na ϩ -independent transport system was sensitive to inhibition by neutral (e.g., digoxin), acidic (e.g., taurocholate), and basic (e.g., quinine) compounds. 4 Together, these findings suggested that a multispecific, Na ϩ -independent hepatic transport system existed, which could be positively modulated by microsomal enzymeinducing chemicals, specifically PB and PCN.Since these earlier reports, 1-4 specific mediators of this hepatic Na ϩ -independent transport system have been cloned and characterized, and consist of several members of the rat organic anion transporting polypeptide (Oatp) family. The primary forms expressed in rat liver include, Oatp1 (gene symbol: Slc21a1), Oatp2 (Slc21a5), and liver-specific transporter 1 (rlst-1) or Oatp4 (Slc21a10). In rat liver, the organic anion transporting polypeptides, Oatp1, 5 Oatp2, 6,7 and rlst-1/ Oatp4, 8-10 transport a number of conjugated and unconjugated xenobiotics and endobiotics in a charge-independent manner. The substrates for this family of transporters include: the cardiac glycosides, the statin class of lipid-lowering drugs, human immunodeficiency virus-protease inhibitors, bile acids, eicosanoids, thyroid hormone and thyroid hormone conjugates, steroid hormone conjugates, and numerous peptidede...

Results suggested the safety of long-term oral administration of grapiprant to dogs. Efficacy of grapiprant in the treatment of dogs with osteoarthritis needs to be evaluated in other studies.

BackgroundLocal anesthetics are an important component of perioperative pain management, but the duration of action of available products is limited. We hypothesized that a single local infiltration of a novel bupivacaine liposome injectable suspension (AT-003) would provide clinically effective analgesia over a 72-h period.In a masked, randomized, placebo-controlled, multi-center pilot field study, dogs undergoing lateral retinacular suture placement for cranial cruciate insufficiency were randomly assigned to surgical site infiltration with AT-003 (5.3 mg/kg) or an equivalent volume of saline. Infiltration of the surgical site was done prior to closure. Primary outcome measure was the Glasgow Composite Measure Pain Scale (CMPS-SF) assessed prior to surgery and at 2, 4, 8, 12, 24, 30, 36, 48, 54, 60 and 72 h following surgery by trained individuals. Provision for rescue analgesia was employed. Repeated measures analysis of variance were utilized to test for possible differences between treatment groups and a success/failure analysis was also employed, based on the need for rescue analgesia.ResultsForty-six dogs were enrolled and evaluated. For CMPS-SF scores there was a significant overall treatment effect (p = 0.0027) in favor of AT-003. There were significantly more successes in the AT-003 group compared to placebo over each time period (p = 0.0001 for 0–24 h, p = 0.0349 for 0–48 h, and p = 0.0240 for 0-72 h). No significant adverse events were seen.ConclusionsAT-003 (bupivacaine liposome injectable suspension) provided measurable local analgesia over a 72-h period following post-stifle surgery surgical site tissue infiltration. Further work is indicated to develop this product for clinical use.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-016-0798-1) contains supplementary material, which is available to authorized users.

A new anti-inflammatory drug for pain (grapiprant) was recently shown to have minimal side effects following chronic (9-month) daily oral dose of 6 or 50 mg/kg suspension. The current study compares the pharmacokinetics of the formulation used in the chronic safety study to those of the tablet formulation that will be marketed upon FDA approval. Sixteen Beagle dogs were randomized to receive single doses of either 6 or 50 mg/kg grapiprant as both suspension and table formulations within a cross-over design with a 15-day washout. Clinical observations were vomiting in one high-dose suspension dog and loose stools in two dogs, one in each 6 mg/kg formulation group. For both formulations, grapiprant reached a maximum concentration within two hours. The tablet formulation had better bioavailability, with AUC values 34% higher at 6 mg/kg and 64% higher at 50 mg/kg compared to the suspension. Results on Day 0 were similar to those reported on Day 15, suggesting little to no accumulation. Using conversion factors of 1.34 and 1.64, these findings suggest that the 6 and 50 mg/kg suspension doses are equivalent to 4.5 and 30 mg/kg tableted doses, respectively. Combining these findings with the 9-month safety study demonstrates that safety was evaluated at doses approximately 15-fold above the demonstrated therapeutic dose of 2 mg/kg and 10-fold over the 'safety dose', defined as the maximum dose a dog of any body weight could receive when dosed at 2 mg/kg with whole or half-tablets.