Pilot, randomized, placebo-controlled clinical field study to evaluate the effectiveness of bupivacaine liposome injectable suspension for the provision of post-surgical analgesia in dogs undergoing stifle surgery.

BACKGROUND: Local 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. RESULTS: Forty-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. CONCLUSIONS: AT-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.

Safety and toxicokinetic profiles associated with daily oral administration of grapiprant, a selective antagonist of the prostaglandin E2 EP4 receptor, to cats.

OBJECTIVE To evaluate safety and toxicokinetic profiles associated with daily oral administration of grapiprant, a new analgesic that selectively blocks the prostaglandin E2 EP4 receptor, to cats. ANIMALS 24 healthy domestic shorthair cats (12 males and 12 females). PROCEDURES Cats were randomly assigned (3 of each sex/group) to receive a placebo capsule or grapiprant at 3, 9, or 15 mg/kg, administered PO once daily for 28 days, beginning on day 0. Food consumption and behavior were observed daily, body weight was measured weekly, and clinicopathologic tests were performed on blood and urine samples collected on days -7, 14, and 25. Blood samples for toxicokinetic analyses were collected after treatment on days 0 and 27. Cats were euthanized on day 28, and full necropsies and histologic evaluations were performed. RESULTS Grapiprant rapidly reached peak serum concentrations and maintained substantial concentrations throughout the 28-day period. By day 27, maximum serum concentrations ranged from 683 ng/mL to 4,950 ng/mL, which were attained by 1 to 4 hours after administration. Serum half-lives on day 27 ranged from approximately 2 to 14 hours (median, approx 5 to 6 hours). Grapiprant was well tolerated, and no adverse effects were detected at doses ≤ 15 mg/kg. No significant effects of grapiprant were identified on body weight, food consumption, clinicopathologic variables, or gross or histologic necropsy findings. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested the safety of daily oral administration of grapiprant to cats. Additional studies are needed to evaluate the efficacy of grapiprant for treatment of cats with osteoarthritis.

Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation.

There are five active prostanoid metabolites of arachidonic acid (AA) that have widespread and varied physiologic functions throughout the body, including regulation of gastrointestinal mucosal blood flow, renal haemodynamics and primary haemostasis. Each prostanoid has at least one distinct receptor that mediates its action. Prostaglandin E2 (PGE 2) is a prostanoid that serves important homeostatic functions, yet is also responsible for regulating pain and inflammation. PGE 2 binds to four receptors, of which one, the EP4 receptor, is primarily responsible for the pain and inflammation associated with osteoarthritis (OA). The deleterious and pathologic actions of PGE 2 are inhibited in varying degrees by steroids, aspirin and cyclo-oxygenase inhibiting NSAIDs; however, administration of these drugs causes decreased production of PGE 2, thereby decreasing or eliminating the homeostatic functions of the molecule. By inhibiting just the EP4 receptor, the homeostatic function of PGE 2 is better maintained. This manuscript will introduce a new class of pharmaceuticals known as the piprant class. Piprants are prostaglandin receptor antagonists (PRA). This article will include basic physiology of AA, prostanoids and piprants, will review available evidence for the relevance of EP4 PRAs in rodent models of pain and inflammation, and will reference available data for an EP4 PRA in dogs and cats. Piprants are currently in development for veterinary patients and the purpose of this manuscript is to introduce veterinarians to the class of drugs, with emphasis on an EP4 PRA and its potential role in the control of pain and inflammation associated with OA in dogs and cats.

Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs.

OBJECTIVE: To investigate the safety of daily oral administration of grapiprant to dogs. ANIMALS: Thirty-six 9-month-old Beagles of both sexes. PROCEDURES: Dogs were randomly assigned to groups that received grapiprant via oral gavage at 0, 1, 6, or 50 mg/kg (total volume, 5 mL/kg), q 24 h for 9 months. Each group contained 4 dogs of each sex (ie, 8 dogs/group), except for the 50 mg/kg group, which included 4 additional dogs that were monitored for an additional 30 days after treatment concluded (recovery period). All dogs received ophthalmologic, ECG, and laboratory evaluations before treatment began (baseline) and periodically afterward. All dogs were observed daily. Dogs were euthanized at the end of the study for necropsy and histologic evaluation. RESULTS: All dogs remained clinically normal during treatment, with no apparent changes in appetite or demeanor. Emesis and soft or mucoid feces that occasionally contained blood were observed in all groups, although these findings were more common in dogs that received grapiprant. In general, clinicopathologic findings remained within baseline ranges. Drug-related changes in serum total protein and albumin concentrations were detected, but differences were small and resolved during recovery. No drug-related gross or microscopic pathological changes were detected in tissue samples except mild mucosal regeneration in the ileum of 1 dog in the 50 mg/kg group. CONCLUSIONS AND CLINICAL RELEVANCE: 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.