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Effects of oral adenosine 5'-triphosphate and adenosine in enteric-coated capsules on indomethacin-induced permeability changes in the human small intestine: a randomized cross-over study.

Bours MJ, Bos HJ, Meddings JB, Brummer RJ, van den Brandt PA, Dagnelie PC - BMC Gastroenterol (2007)

Bottom Line: The indomethacin-induced increase was neither affected by administration of encapsulated ATP (0.047 (0.033-0.065)) nor adenosine (0.050 (0.030-0.067)).The observed lack of effect of encapsulated ATP/adenosine may have been caused by opening of the enteric-coated supplement at a site distal from the indomethacin-inflicted site.Further studies on site-specific effectiveness of ATP/adenosine on intestinal permeability changes are warranted.

View Article: PubMed Central - HTML - PubMed

Affiliation: Maastricht University, Department of Epidemiology, Nutrition and Toxicology Research Institute Maastricht, Maastricht, The Netherlands. M.Bours@epid.unimaas.nl

ABSTRACT

Background: It is well-known that nonsteroidal anti-inflammatory drugs (NSAIDs) can cause damage to the small bowel associated with disruption of mucosal barrier function. In healthy human volunteers, we showed previously that topical administration of adenosine 5'-triphosphate (ATP) by naso-intestinal tube attenuated a rise in small intestinal permeability induced by short-term challenge with the NSAID indomethacin. This finding suggested that ATP may be involved in the preservation of intestinal barrier function. Our current objective was to corroborate the favourable effect of ATP on indomethacin-induced permeability changes in healthy human volunteers when ATP is administered via enteric-coated capsules, which is a more practically feasible mode of administration. Since ATP effects may have been partly mediated through its breakdown to adenosine, effects of encapsulated adenosine were tested also.

Methods: By ingesting a test drink containing 5 g lactulose and 0.5 g L-rhamnose followed by five-hour collection of total urine, small intestinal permeability was assessed in 33 healthy human volunteers by measuring the urinary lactulose/rhamnose excretion ratio. Urinary excretion of lactulose and L-rhamnose was determined by fluorescent detection high-pressure liquid chromatography (HPLC). Basal permeability of the small intestine was assessed as a control condition (no indomethacin, no ATP/adenosine). As a model of increased small intestinal permeability, two dosages of indomethacin were ingested at 10 h (75 mg) and 1 h (50 mg) before ingesting the lactulose/rhamnose test drink. At 1.5 h before indomethacin ingestion, two dosages of placebo, ATP (2 g per dosage) or adenosine (1 g per dosage) were administered via enteric-coated hydroxypropyl methylcellulose (HPMC) capsules with Eudragit L30D-55.

Results: Median urinary lactulose/rhamnose excretion ratio (g/g) in the control condition was 0.032 (interquartile range: 0.022-0.044). Compared to the control condition, lactulose/rhamnose ratio after ingestion of indomethacin plus placebo was significantly increased to 0.039 (0.035-0.068); P < 0.01). The indomethacin-induced increase was neither affected by administration of encapsulated ATP (0.047 (0.033-0.065)) nor adenosine (0.050 (0.030-0.067)). Differences in L/R ratios between the conditions with indomethacin plus placebo, ATP or adenosine were not significant.

Conclusion: In this study, either ATP or adenosine administered via enteric-coated capsules had no effect on indomethacin-induced small intestinal permeability changes in healthy human volunteers. The observed lack of effect of encapsulated ATP/adenosine may have been caused by opening of the enteric-coated supplement at a site distal from the indomethacin-inflicted site. Further studies on site-specific effectiveness of ATP/adenosine on intestinal permeability changes are warranted.

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Box Whisker plot of urinary lactulose/rhamnose (L/R) excretion ratios (g/g) observed in four experimental conditions. The control condition represents basal permeability of the small intestine, as indicated by the urinary L/R ratio after ingestion of a test drink containing 5 g lactulose and 0.5 g L-rhamnose with no prior indomethacin ingestion and no placebo/ATP/adenosine challenge. The other conditions represent urinary L/R ratios after ingestion of two subsequent indomethacin dosages at 10 h (75 mg) and 1 h (50 mg) before ingestion of the test drink; at 1.5 h prior to the indomethacin dosages, two dosages of placebo (indomethacin + placebo), ATP (indomethacin + ATP, 2 g ATP per dosage) or adenosine (indomethacin + adenosine, 1 g adenosine per dosage) were administered via enteric-coated capsules (*P < 0.01 vs. control; n = 33, Wilcoxon signed ranks test). Differences in L/R ratios between the conditions with indomethacin plus placebo, ATP or adenosine were not significant.
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Figure 1: Box Whisker plot of urinary lactulose/rhamnose (L/R) excretion ratios (g/g) observed in four experimental conditions. The control condition represents basal permeability of the small intestine, as indicated by the urinary L/R ratio after ingestion of a test drink containing 5 g lactulose and 0.5 g L-rhamnose with no prior indomethacin ingestion and no placebo/ATP/adenosine challenge. The other conditions represent urinary L/R ratios after ingestion of two subsequent indomethacin dosages at 10 h (75 mg) and 1 h (50 mg) before ingestion of the test drink; at 1.5 h prior to the indomethacin dosages, two dosages of placebo (indomethacin + placebo), ATP (indomethacin + ATP, 2 g ATP per dosage) or adenosine (indomethacin + adenosine, 1 g adenosine per dosage) were administered via enteric-coated capsules (*P < 0.01 vs. control; n = 33, Wilcoxon signed ranks test). Differences in L/R ratios between the conditions with indomethacin plus placebo, ATP or adenosine were not significant.

Mentions: Figure 1 shows L/R ratios of the four experimental conditions. Median L/R ratio (g/g) in the control condition (no indomethacin, no ATP/adenosine) was 0.032 (interquartile range: 0.022–0.044). After ingestion of indomethacin plus placebo, the median L/R ratio was significantly increased to 0.039 (0.035–0.068; P < 0.01 vs. control). Intake of enteric-coated capsules with either ATP or adenosine at 1.5 h prior to indomethacin ingestion had no effect on the indomethacin-induced increase in L/R ratio. Median L/R ratio after ingestion of indomethacin plus ATP was 0.047 (0.033–0.065; P = 0.22 vs. placebo), and median L/R ratio after ingestion of indomethacin plus adenosine was 0.050 (0.030–0.067; P = 0.49 vs. placebo). Median L/R ratios after indomethacin ingestion with administration of ATP or adenosine remained significantly increased compared to the L/R ratio in the control condition (P < 0.01, Fig. 1).


Effects of oral adenosine 5'-triphosphate and adenosine in enteric-coated capsules on indomethacin-induced permeability changes in the human small intestine: a randomized cross-over study.

Bours MJ, Bos HJ, Meddings JB, Brummer RJ, van den Brandt PA, Dagnelie PC - BMC Gastroenterol (2007)

Box Whisker plot of urinary lactulose/rhamnose (L/R) excretion ratios (g/g) observed in four experimental conditions. The control condition represents basal permeability of the small intestine, as indicated by the urinary L/R ratio after ingestion of a test drink containing 5 g lactulose and 0.5 g L-rhamnose with no prior indomethacin ingestion and no placebo/ATP/adenosine challenge. The other conditions represent urinary L/R ratios after ingestion of two subsequent indomethacin dosages at 10 h (75 mg) and 1 h (50 mg) before ingestion of the test drink; at 1.5 h prior to the indomethacin dosages, two dosages of placebo (indomethacin + placebo), ATP (indomethacin + ATP, 2 g ATP per dosage) or adenosine (indomethacin + adenosine, 1 g adenosine per dosage) were administered via enteric-coated capsules (*P < 0.01 vs. control; n = 33, Wilcoxon signed ranks test). Differences in L/R ratios between the conditions with indomethacin plus placebo, ATP or adenosine were not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1913056&req=5

Figure 1: Box Whisker plot of urinary lactulose/rhamnose (L/R) excretion ratios (g/g) observed in four experimental conditions. The control condition represents basal permeability of the small intestine, as indicated by the urinary L/R ratio after ingestion of a test drink containing 5 g lactulose and 0.5 g L-rhamnose with no prior indomethacin ingestion and no placebo/ATP/adenosine challenge. The other conditions represent urinary L/R ratios after ingestion of two subsequent indomethacin dosages at 10 h (75 mg) and 1 h (50 mg) before ingestion of the test drink; at 1.5 h prior to the indomethacin dosages, two dosages of placebo (indomethacin + placebo), ATP (indomethacin + ATP, 2 g ATP per dosage) or adenosine (indomethacin + adenosine, 1 g adenosine per dosage) were administered via enteric-coated capsules (*P < 0.01 vs. control; n = 33, Wilcoxon signed ranks test). Differences in L/R ratios between the conditions with indomethacin plus placebo, ATP or adenosine were not significant.
Mentions: Figure 1 shows L/R ratios of the four experimental conditions. Median L/R ratio (g/g) in the control condition (no indomethacin, no ATP/adenosine) was 0.032 (interquartile range: 0.022–0.044). After ingestion of indomethacin plus placebo, the median L/R ratio was significantly increased to 0.039 (0.035–0.068; P < 0.01 vs. control). Intake of enteric-coated capsules with either ATP or adenosine at 1.5 h prior to indomethacin ingestion had no effect on the indomethacin-induced increase in L/R ratio. Median L/R ratio after ingestion of indomethacin plus ATP was 0.047 (0.033–0.065; P = 0.22 vs. placebo), and median L/R ratio after ingestion of indomethacin plus adenosine was 0.050 (0.030–0.067; P = 0.49 vs. placebo). Median L/R ratios after indomethacin ingestion with administration of ATP or adenosine remained significantly increased compared to the L/R ratio in the control condition (P < 0.01, Fig. 1).

Bottom Line: The indomethacin-induced increase was neither affected by administration of encapsulated ATP (0.047 (0.033-0.065)) nor adenosine (0.050 (0.030-0.067)).The observed lack of effect of encapsulated ATP/adenosine may have been caused by opening of the enteric-coated supplement at a site distal from the indomethacin-inflicted site.Further studies on site-specific effectiveness of ATP/adenosine on intestinal permeability changes are warranted.

View Article: PubMed Central - HTML - PubMed

Affiliation: Maastricht University, Department of Epidemiology, Nutrition and Toxicology Research Institute Maastricht, Maastricht, The Netherlands. M.Bours@epid.unimaas.nl

ABSTRACT

Background: It is well-known that nonsteroidal anti-inflammatory drugs (NSAIDs) can cause damage to the small bowel associated with disruption of mucosal barrier function. In healthy human volunteers, we showed previously that topical administration of adenosine 5'-triphosphate (ATP) by naso-intestinal tube attenuated a rise in small intestinal permeability induced by short-term challenge with the NSAID indomethacin. This finding suggested that ATP may be involved in the preservation of intestinal barrier function. Our current objective was to corroborate the favourable effect of ATP on indomethacin-induced permeability changes in healthy human volunteers when ATP is administered via enteric-coated capsules, which is a more practically feasible mode of administration. Since ATP effects may have been partly mediated through its breakdown to adenosine, effects of encapsulated adenosine were tested also.

Methods: By ingesting a test drink containing 5 g lactulose and 0.5 g L-rhamnose followed by five-hour collection of total urine, small intestinal permeability was assessed in 33 healthy human volunteers by measuring the urinary lactulose/rhamnose excretion ratio. Urinary excretion of lactulose and L-rhamnose was determined by fluorescent detection high-pressure liquid chromatography (HPLC). Basal permeability of the small intestine was assessed as a control condition (no indomethacin, no ATP/adenosine). As a model of increased small intestinal permeability, two dosages of indomethacin were ingested at 10 h (75 mg) and 1 h (50 mg) before ingesting the lactulose/rhamnose test drink. At 1.5 h before indomethacin ingestion, two dosages of placebo, ATP (2 g per dosage) or adenosine (1 g per dosage) were administered via enteric-coated hydroxypropyl methylcellulose (HPMC) capsules with Eudragit L30D-55.

Results: Median urinary lactulose/rhamnose excretion ratio (g/g) in the control condition was 0.032 (interquartile range: 0.022-0.044). Compared to the control condition, lactulose/rhamnose ratio after ingestion of indomethacin plus placebo was significantly increased to 0.039 (0.035-0.068); P < 0.01). The indomethacin-induced increase was neither affected by administration of encapsulated ATP (0.047 (0.033-0.065)) nor adenosine (0.050 (0.030-0.067)). Differences in L/R ratios between the conditions with indomethacin plus placebo, ATP or adenosine were not significant.

Conclusion: In this study, either ATP or adenosine administered via enteric-coated capsules had no effect on indomethacin-induced small intestinal permeability changes in healthy human volunteers. The observed lack of effect of encapsulated ATP/adenosine may have been caused by opening of the enteric-coated supplement at a site distal from the indomethacin-inflicted site. Further studies on site-specific effectiveness of ATP/adenosine on intestinal permeability changes are warranted.

Show MeSH
Related in: MedlinePlus