title: [Preferential COX-2 inhibition: its clinical relevance for gastrointestinal non-steroidal anti-inflammatory rheumatic drug toxicity].
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of arthritis and pain. These drugs tend to cause significant side effects, however, including gastric and intestinal toxicity. The mechanism of action of NSAIDs is through their inhibition of the key enzyme of prostaglandin biosynthesis, the cyclooxygenase. Recently, two forms of cyclooxygenase have been found to exist: COX-1 and COX-2, the constitutive and inducible forms, respectively. COX-1 exists in the stomach, intestine, kidneys and platelets, while COX-2, the inducible form, is expressed during inflammation. The therapeutic effects of NSAIDs are largely the result of inhibition of the enzyme cyclooxygenase-2 (COX-2), whereas the toxic effects (e.g., gastrointestinal, renal and platelet effects) are primarily due to the inhibition of COX-1. Individual NSAIDs show different potencies against COX-1 compared with COX-2 and this explains the variations in the side effects of NSAIDs at their anti-inflammatory doses. Drugs with high potency against COX-2 and a better COX-2-/COX-1 activity ratio will have anti-inflammatory activity with fewer gastrointestinal side effects. In contrast piroxicam and indomethacin, which drugs have a much higher potency against COX-1 than against COX-2, are amongst those with the highest gastrointestinal toxicity. Based on these findings, COX-2 seems to be an ideal target for the development of new anti-inflammatory drugs. Several compounds with preferential or specific COX-2 inhibiting properties have been synthesized and evaluated in pre-clinical and clinical studies i.e. Meloxicam, Celecoxib, MK-966, Flusolid and L-745, 337. The COX-2 selectivity of these novel NSAIDs relate well to their favorable gastrointestinal tolerability profile. Clinical trials have shown meloxicam and celecoxib to be as effective as currently available NSAIDs, but with an improved gastrointestinal tolerability profile. Further clinical trials and large-scale postmarketing surveillance programs are needed, however, to confirm the potential therapeutic benefits of these novel preferential or specific COX-2 inhibitors.
authors: Klinische Forschung Hamburg, Wissenschaftliches Institut, Hamburg.
authors: H G
authors: HG
authors: Dammann
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology; D002986:Clinical Trials as Topic; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D008565:Membrane Proteins; D010437:Peptic Ulcer / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D012307:Risk Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases