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

Abstract

Email: Martijn JL Bours* -M.Bours@epid.unimaas.nl; Hilde J Bos -H.Bos@student.unimaas.nl; Jon B Meddings -Jon.Meddings@ualberta.ca; Robert-Jan M Brummer -RJ.Brummer@INTMED.unimaas.nl; Piet A van den Brandt -PA.vandenBrandt@epid.unimaas.nl; Pieter C Dagnelie -Dagnelie@epid.unimaas.nl * Corresponding author 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.

Polyethylene glycol versus dual sugar assay for gastrointestinal permeability analysis: is it time to choose?

“…Single PEG 400 excretion, the PEG 3350/PEG 400 ratio, and the L/R ratio determined in 0–2-hour urine after probe intake all provided accurate detection of indomethacin-induced increases in gastrointestinal permeability. The L/R cutoff point of 0.18 in 0–5-hour urine is in line with data from previous studies using the dual sugar test after short-term indomethacin consumption 33 , 34 and prolonged indomethacin intake. 35 – 37 Unfortunately, no cutoff points were reported in previous studies using PEG for permeability analysis in healthy individuals after indomethacin.…”

Human Intestinal Barrier Function in Health and Disease

“… 162 Enteric-coated capsules containing ATP however showed no effect. 163 Also, the intake of recombinant human lactoferrin reduced the NSAID-mediated increase in small intestinal permeability from 0.036 to 0.028 (lactulose/rhamnose ratio, P <0.05). 164 …”

Intestinal permeability in the pathogenesis of NSAID-induced enteropathy

“…56 On similar grounds, Bours et al have shown that coadministration of ATP with indomethacin abolishes its effect to increase intestinal permeability, 56 but the compounds need to be given together for the effect. 86 This line of research although very encouraging has not been followed up, presumably because of lack of interest from the pharmaceutical industry as these measures seem too simple. Finally, one study suggests that the potential benefi cial effects of metronidazole may result from the effect of reducing the degree of uncoupling caused by the NSAIDs.…”