Abstract
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.
Highlights
Prostanoids are metabolites of arachidonic acid (AA) and have been the target of medicinal therapies for centuries (Appelboom 2002)
This manuscript reviews the mechanism of action of anti-inflammatory drugs for use in animals and introduce the first-in-class drug for managing pain and inflammation associated with osteoarthritis (OA) in veterinary patients: grapiprant, an EP4 prostaglandin receptor antagonist (PRA)
In a series of experiments reported by Chen et al (2010), an EP4 PRA, ER819762, suppressed inflammatory cytokine production, suppressed disease and slowed disease progression in collagen and GPI-induced arthritis in mice. These data support the anti-inflammatory role of EP4 receptor antagonism in rodents. These results demonstrated that EP4 PRAs can reduce inflammation as effectively as COX-2 inhibitors
Summary
Prostanoids are metabolites of arachidonic acid (AA) and have been the target of medicinal therapies for centuries (Appelboom 2002). Pain and inflammation are mediated by prostanoids, in particular PGE2, and therapeutic drugs are often used to decrease the production and activity of this molecule (Curry et al 2005; KuKanich et al 2012). This suggests that administration of a selective COX-2 inhibitor drug in the face of gastrointestinal ulceration, such as due to stress or administration of corticosteroids or a non-selective cyclo-oxygenaseinhibiting NSAID such as aspirin, may reduce healing and potentiate ulceration and perforation (Lascelles et al 2005) Another potential mechanism for gastrointestinal injury secondary to cyclo-oxygenase inhibiting NSAID administration is the increased production of inflammatory leukotrienes (Curry et al 2005). Grapiprant is a targeted approach to pain management – it selectively blocks the EP4 receptor, does not interfere with the production of prostanoids, and does not affect the other PG receptor pathways that are affected in animals treated with COX inhibitor NSAIDs
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