Acute gastrointestinal permeability responses to different non-steroidal anti-inflammatory drugs

Abstract

Background and aims-Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage both in the upper and lower gastrointestinal tract. New antiinflammatory drugs have been developed in an attempt to improve their gastrointestinal side eVect profile. Our objective was to compare the eVect on gastrointestinal permeability of acute equieVective doses of four diVerent NSAIDs; three were designed to reduce gastrointestinal mucosal injury. Materials-Healthy volunteers underwent sugar tests in a randomised fashion, 15 days apart, at: (1) baseline; (2) after two days of 75 mg slow release (microspheres) indomethacin; (3) after two days of 7.5 mg oral meloxicam which preferentially inhibits cyclooxygenase 2; and (4) after two days of 750 mg naproxen. A subgroup of subjects was tested after two days of 200 mg celecoxib. In each test, subjects ingested a solution containing sucrose, lactulose, and mannitol and sucralose, to evaluate gastroduodenal, intestinal, and colonic permeability, respectively. Results-Gastric permeability was significantly aVected by naproxen (p<0.05) but not by slow release indomethacin, meloxicam, or celecoxib. Intestinal permeability was significantly increased by the first three NSAIDs (p<0.05) but not by celecoxib. Abnormal lactulose/mannitol ratios were observed in 42% of meloxicam treatments, in 62% during indomethacin, and in 75% of subjects treated with naproxen. Finally, colonic permeability, as measured by sucralose, was not significantly increased by any of the four drugs. Conclusion-Our study provides evidence that the newly developed NSAIDs reduce gastric mucosal permeability significantly. However, most produced significant alteration of small intestinal permeability. In contrast, our results suggest that celecoxib seems to exhibit the most desirable gastrointestinal side eVect profile. (Gut 2001;49:650-655)

Intestinal Permeability and Absorption in Dogs with Traumatic Injury

“…In humans, NSAIDS have increased intestinal permeability, but the effect of carprofen in dogs is not yet known. 21,22 Future studies should attempt to standardize medications that could have effects on intestinal permeability. Finally, severity of trauma scores are not routinely used in veterinary medicine.…”

Acute Effects of Carprofen and Meloxicam on Canine Gastrointestinal Permeability and Mucosal Absorptive Capacity

“…Permeability and mucosal function testing has the advantage of enabling a quantitative measure of damage, and is therefore a far less subjective assessment of mucosal integrity. Fluctuations in permeability not only parallel endoscopic damage scores 1,8,12 but may also enable earlier detection of damage. 30 The technique is, however, less sensitive than endoscopy for the presence of discrete ulcers, evidenced in 1 study by the more rapid reduction in sucrose permeability than the disappearance of gastric ulcers.…”

“…Of interest, in contrast to the findings reported here, meloxicam caused a significant increase in gastroduodenal permeability (lactulose/mannitol urinary recovery ratio) in 8/19 human patients after only 2 days of treatment. 12 Meloxicam is also a preferential COX-2 inhibitor in humans, 46 and although the mechanisms involved were uncertain, a topical effect was suggested in view of the drug's acidic nature. 46,47 It is also an interesting observation that COX-1 knockout mice (that produce virtually no intestinal prostaglandins) do not develop GI lesions spontaneously, 48 implying that COX-1 inhibition is in fact an oversimplified model of damage.…”

“…12,38,39 The pharmacokinetics of sucralose metabolism and excretion have been explored in the dog, 36 and unchanged sucralose is maximally excreted in urine 3-6 hours after oral dosing. However, there currently exists no established test protocol or reference interval for sucralose permeability in the dog; hence it is unknown whether or not these dogs had abnormal baseline values.…”

“…[2][3][4][5] There are numerous accounts of NSAID-induced GI toxicosis in dogs [4][5][6][7] and humans, 8,9 and there is strong evidence that the pathophysiology involves altered integrity of the GI mucosal barrier. [9][10][11][12] Focal disruption of the mucosal barrier can result in penetration of potentially damaging compounds such as antigens, proteases, hydrogen ions, and bacteria, and other factors that stimulate the recruitment of chemotactic inflammatory cells. [13][14][15][16][17] In humans, the prevalence of NSAID-associated gastric damage described by different authors varies from 26 to 45%, 18,19 and the incidence of acute toxicity in dogs is so far unreported.…”