Gastrointestinal mucosal injury following repeated daily oral administration of conventional formulations of indometacin and other non-steroidal anti-inflammatory drugs to pigs: a model for human gastrointestinal disease
Bibliographic record
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) vary in their propensity to cause damage in different regions of the gastrointestinal (GI) tract in laboratory animals and humans. This may depend on the type of drug formulation as well as the intrinsic pharmacological properties of the drugs. The purpose of this study was to determine the effects of NSAIDs, with cyclooxygenase 1 and 2 inhibitory activity but with different potency as inhibitors of prostaglandin production, when given orally as tablet/capsule formulations of NSAIDs for 10 days to pigs, a species that has close resemblance in structure and function of the tract to that in humans. Three capsule or tablet formulations of NSAIDs were given orally to pigs for 10 days. GI bleeding was measured by determination of radioactive iron in the faeces from (59)Fe-pre-labelled red blood cells. The blood loss was compared with the pathological changes in the GI mucosa observed at autopsy, mucosal myeloperoxidase (MPO) activity as an index of leucocyte infiltration, and plasma and mucosal concentrations of the drugs at termination assayed by high-performance liquid chromatography. Mucosal damage and bleeding varied according to the type of NSAID. Gastroduodenal ulcers and lesions occurred with the cyclooxygenase inhibitors indometacin (indomethacin) (Indocid capsules 10 or 5 mg kg(-1) day(-1) b.i.d.), aspirin (USP tablets 150 mg kg(-1) day(-1) b.i.d) and naproxen (Apotex tablets 50 or 75 mg kg(-1) day(-1) b.i.d.), and there was an increase in the cumulative (i.e. 10-day) blood loss at higher doses of indometacin and naproxen, and with aspirin. There was no statistically significant increase in gastric or intestinal mucosal MPO activity in the non-damaged mucosa with these drugs and this was confirmed by histological observations in non-lesioned areas of the mucosa. Indometacin produced focal ulcers in the caecum but this was not observed with the other drugs. All the NSAIDs produced significant blood loss coincident with gastric ulceration but no increase in gastric or intestinal MPO activity. Plasma concentrations of the non-aspirin NSAIDs were within the range encountered therapeutically in humans. The mucosal concentrations of indometacin in the gastric and intestinal mucosa correlated with mucosal injury. These findings show that: (i) NSAIDs vary in their propensity to produce mucosal injury in different regions of the GI tract according to their pharmacological properties and formulation; (ii) mucosal injury from some NSAIDs may not directly relate to blood loss at low doses of NSAIDs and this may depend on inhibition of platelet aggregation; and (iii) the occurrence of caecal ulcers uniquely observed with indometacin treatment may be relevant to the development of intestinal pathology (e.g. diaphragm-like structures) seen occasionally in humans. These results suggest that the pig model employed in the present studies may be useful for investigations of GI damage from NSAID tablets/capsules, especially in regions that are generally inaccessible to routine endoscopic investigations in humans (e.g. the proximal regions of the large intestine).
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".