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Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability
G R Davies1, M E Wilkie, D S Rampton
1Gastrointestinal Science Research Unit, London Hospital Medical College, UK.
Abstract:
In previous open studies, misoprostol and metronidazole reduced nonsteroidal anti-inflammatory drug-induced intestinal permeability changes and inflammation respectively. We assessed the effects of indomethacin treatment (50 mg three times a day) for one week with either coadministered metronidazole (400 mg twice a day, group 1, N = 9) or misoprostol (200 micrograms four times a day, group 2, N = 7) on intestinal permeability to [51Cr]EDTA and mannitol in healthy volunteers, using double-blind, placebo-controlled, randomized techniques. Given alone, neither metronidazole nor misoprostol affected [51Cr]EDTA permeation, whereas indomethacin alone increased it from 1.20 (0.40) [mean percent urinary recovery (SD) groups 1 and 2] to 2.43 (0.72), P < 0.002. Coadministered metronidazole (group 1) prevented this increase [1.10 (0.39) before, 1.55 (0.54) after, P > 0.05], whereas misoprostol (group 2) did not [1.31 (0.51) before, 3.26 (1.10) after, P = 0.005]. No drug regimen altered mannitol permeation. Indomethacin and misoprostol did not affect urinary recovery of intravenously administered probes. The results with metronidazole, if related to its antibacterial effects, support evidence from animal models that bacteria contribute to NSAID-induced intestinal damage. The previously reported reduction of indomethacin-induced increased permeability by misoprostol during a one-day study is not seen when the drugs are used in standard clinical doses for one week.
Insights
Metronidazole, but not misoprostol, prevented nonsteroidal anti-inflammatory drug-induced intestinal permeability increases in healthy volunteers over one week. This suggests bacteria may contribute to NSAID-induced intestinal damage.
Area of Science:
- Gastroenterology
- Pharmacology
- Clinical Research
Background:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) can increase intestinal permeability.
- Previous studies suggested misoprostol and metronidazole may mitigate NSAID effects.
Purpose of the Study:
- To assess the effects of coadministered metronidazole or misoprostol with indomethacin on intestinal permeability in healthy volunteers.
- To evaluate the impact of a one-week treatment course on intestinal permeability.
Main Methods:
- Double-blind, placebo-controlled, randomized study in healthy volunteers.
- Indomethacin treatment with either metronidazole or misoprostol for one week.
- Intestinal permeability assessed using [51Cr]EDTA and mannitol.
Main Results:
- Indomethacin alone significantly increased [51Cr]EDTA intestinal permeability.
- Coadministered metronidazole prevented the indomethacin-induced increase in permeability.
- Misoprostol did not prevent the increased permeability when used for one week at clinical doses.
- Neither drug regimen altered mannitol permeation.
Conclusions:
- Metronidazole's protective effect on intestinal permeability suggests a role for bacteria in NSAID-induced intestinal damage.
- Misoprostol did not show the same protective effect as previously reported, potentially due to duration or dosage.
- Findings highlight differential effects of coadministered drugs on NSAID-induced intestinal changes.