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Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen
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  1. A A Shaha,
  2. B Thjodleifssonb,
  3. F E Murraya,
  4. E Kaya,
  5. M Barrya,
  6. G Sigthorssonc,
  7. H Gudjonssonb,
  8. E Oddssonb,
  9. A B Pricec,
  10. D J Fitzgeralda,
  11. I Bjarnasonc
  1. aBeaumont Hospital Dublin and Royal College of Surgeons in Ireland, Dublin, Ireland, bNational University Hospital, Reykjavik, Iceland, cGuy's, King's, and St Thomas' Medical School, London, UK
  1. Professor D Fitzgerald, Centre of Cardiovascular Science, Royal College of Surgeons in Ireland, St Stephen's Green, Dublin, Ireland.dfitzgerald{at}rcsi.ie

Abstract

BACKGROUND Selective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs.

AIMS We compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity.

SUBJECTS Thirty six healthy volunteers were randomised to nimesulide 100 mg or naproxen 500 mg twice daily for two weeks in a double blind, crossover study with a washout between treatments.

METHODS Gastrointestinal side effects were assessed by endoscopy, and by estimation of small intestinal absorption-permeability and inflammation. Comparisons were made between variables at the end of each treatment phase.

RESULTS Nimesulide caused significantly less gastric injury using the modified Lanza score (p<0.001) as well as reduced duodenum injury (p=0.039). Nimesulide had lower visual analogue scores (VAS) for haemorrhage and erosive lesions in the stomach (p<0.001) and for mucosal injection in the duodenum (p=0.039). Naproxen increased excretion of calprotectin, a marker of intestinal inflammation (5.5 (1.2) to 12.1 (2.1) mg/l) while nimesulide had no effect (treatment difference p=0.03). Naproxen abolished platelet aggregation to arachidonic acid and suppressed serum thromboxane B2 (TXB2) by 98%, indices of COX-1 activity. In contrast, nimesulide had no significant effect on platelet aggregation, although it reduced serum TXB2 by 29%. Production of prostaglandin E2 and prostacyclin by gastric biopsies, also COX-1 dependent, was inhibited by naproxen, but not by nimesulide. COX-2 activity, determined as endotoxin induced prostaglandin E2 formation in plasma, was markedly suppressed by both treatments.

INTERPRETATION Nimesulide has preferential selectivity for COX-2 over COX-1 in vivo at full therapeutic doses and induces less gastrointestinal damage than that seen with naproxen in the short term.

  • cyclooxygenase
  • prostaglandins
  • platelet aggregation
  • non-steroidal anti-inflammatory drug enteropathy

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Footnotes

  • Abbreviations used in this paper:
    NSAID
    non-steroidal anti-inflammatory drug
    COX
    cyclooxygenase
    PG
    prostaglandin
    TX
    thromboxane
    VAS
    visual analogue score
    LPS
    lipopolysaccharide
    PGI2
    prostacyclin
    ADP
    adenosine diphosphate
    TRAP
    thrombin receptor activator peptide

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