Phenylbutazone induces equine glandular gastric disease without decreasing prostaglandin E₂concentrations

Abstract

In equids, phenylbutazone at high doses induces gastric disease, primarily in the glandular portion of the stomach. However, the mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric disease in horses has yet to be determined. While phenylbutazone-associated ulceration is often attributed to a decrease in basal gastric prostaglandins, this has not been demonstrated in the horse. Twelve horses were randomly assigned to treatment (n = 6; 4.4 mg/kg phenylbutazone PO in 20 ml molasses q 12 hr for 7 days) or placebo (n = 6; 20 ml molasses PO q 12 hr for 7 days) groups. Before treatment and 3 and 7 days after initiation of treatment, gastroscopy was performed and glandular gastric biopsies were collected and frozen at -80°C. Glandular disease was assessed on a scale of 0-4. Prostaglandin E concentrations in biopsies were measured using a commercially available enzyme-linked immunosorbent assay. All phenylbutazone-treated horses developed grade ≥2 glandular disease. Prostaglandin concentrations increased over time (p = .0017), but there was no effect of treatment (p = .49). These findings indicate that despite induction of glandular disease grade ≥2, phenylbutazone did not decrease basal glandular gastric prostaglandin E concentration.

<p>Equine glandular gastric disease: prevalence, impact and management strategies</p>

“…Prostaglandins are considered a critical part of the mucosal barrier, contributing to mucous secretion, blood flow, bicarbonate secretion, and inhibition of acid secretion 23. However, in two studies using an experimental (nonsteroidal anti-inflammatory drug-induced) model of EGGD, glandular mucosal prostaglandins (PGE and/or PGI) did not decrease following treatment with 1–7 days of phenylbutazone 24,25. Furthermore, there was no association between NSAID use and glandular ulcers in racehorses in training 14.…”

Impact of concurrent treatment with omeprazole on phenylbutazone‐induced equine gastric ulcer syndrome (EGUS)

“…Phenylbutazone, a non‐selective inhibitor of cyclo‐oxygenase (cyclo‐oxygenase‐1, COX‐1; and cyclo‐oxygenase 2, COX‐2), is the most commonly prescribed NSAID for equine orthopaedic pain in the US 1 . Adverse effects of non‐selective COX inhibitors (such as phenylbutazone) in horses include renal medullary necrosis and ulceration of the gastrointestinal tract, primarily the glandular gastric mucosa and right dorsal colon 2‐9 …”

“…However, prostaglandins appear to play a lesser role in NSAID‐induced enteropathy 11,12 . In horses, decreases in neither glandular gastric nor colonic prostaglandin concentration (PGE ± PGI) were observed despite induction of glandular ulceration or clinical (hypoalbuminemia and neutropenia) or pathological findings consistent with right dorsal colitis 4,13‐15 . Other mechanisms contributing to GI damage include increased reactive oxygen species formation through mitochondrial uncoupling, decreased hydrophobicity of the mucosa and topical irritation from luminal factors, including acid (stomach) or bile (intestine) and bacteria 16 .…”

Serum protein expression in Equine Glandular Gastric Disease (EGGD) induced by phenylbutazone

“…Although it is quite clear that high doses of NSAIDs can cause EGGD, the potential of NSAIDs to cause EGGD under a clinical dose regimen is unclear. Andrew et al [3] reported that a clinical dose of phenylbutazone (approximately 2.6 mg/kg/day) did not induce gastric ulceration when administered for 2 weeks whereas Pedersen et al [32] used a higher recommended dose (4.4 mg/kg twice a day) for a week and caused EGGD in all horses.…”

“…Unlike ESGD, EGGD appears to be an emerging disease (specifically in sport horses) about with little is known and that has had limited research. The possible risk factors for EGGD include breed, management, stress [29], and non-steroid anti-inflammatory drugs (NSAIDs) [32]. It is believed that NSAIDs can induce gastric damage by inhibition of COX enzymes leading to decreased concentration of mucosal prostaglandins (PGs), which play an important role in gastric mucosa protection [20, 28].…”