Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs

Byron Cryer, Mark Feldman

Research output: Contribution to journalArticle

563 Citations (Scopus)

Abstract

PURPOSE: Both isoforms of cyclo-oxygenase, COX-1 and COX-2, are inhibited to varying degrees by all of the available nonsteroidal anti- inflammatory drugs (NSAIDs). Because inhibition of COX-1 by NSAIDs is linked to gastrointestinal ulcer formation, those drugs that selectively inhibit COX-2 may have less gastrointestinal toxicity. We measured the extent to which NSAIDs and other anti-inflammatory or analgesic drugs inhibit COX-1 and COX-2 in humans. SUBJECTS AND METHODS: Aliquots of whole blood from 16 healthy volunteers were incubated ex vivo with 25 antiinflammatory or analgesic drugs at six concentrations ranging from 0 (control) to 100 μM (n = 5 for each). Blood was assayed for serum-generated thromboxane B2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E2 synthesis measured. RESULTS: Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others (eg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX-1 inhibitory potency in blood (P <0.001) and with COX-1 selectivity (P <0.01), but not with COX-2 inhibitory potency. Even COX-2 'selective' NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. CONCLUSION: No currently marketed NSAID, even those that are COX-2 selective, spare gastric COX activity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.

Original languageEnglish (US)
Pages (from-to)413-421
Number of pages9
JournalAmerican Journal of Medicine
Volume104
Issue number5
DOIs
StatePublished - May 1998

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Cyclooxygenase 1
Cyclooxygenase 2
Anti-Inflammatory Agents
Pharmaceutical Preparations
Dinoprostone
Stomach
Analgesics
Mefenamic Acid
Flurbiprofen
Gastrointestinal Agents
Ketoprofen
Thromboxane B2
Naproxen
Diclofenac
Ibuprofen
Non-Steroidal Anti-Inflammatory Agents
Prostaglandin-Endoperoxide Synthases
Ulcer
Lipopolysaccharides
Volunteers

ASJC Scopus subject areas

  • Nursing(all)

Cite this

Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. / Cryer, Byron; Feldman, Mark.

In: American Journal of Medicine, Vol. 104, No. 5, 05.1998, p. 413-421.

Research output: Contribution to journalArticle

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abstract = "PURPOSE: Both isoforms of cyclo-oxygenase, COX-1 and COX-2, are inhibited to varying degrees by all of the available nonsteroidal anti- inflammatory drugs (NSAIDs). Because inhibition of COX-1 by NSAIDs is linked to gastrointestinal ulcer formation, those drugs that selectively inhibit COX-2 may have less gastrointestinal toxicity. We measured the extent to which NSAIDs and other anti-inflammatory or analgesic drugs inhibit COX-1 and COX-2 in humans. SUBJECTS AND METHODS: Aliquots of whole blood from 16 healthy volunteers were incubated ex vivo with 25 antiinflammatory or analgesic drugs at six concentrations ranging from 0 (control) to 100 μM (n = 5 for each). Blood was assayed for serum-generated thromboxane B2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E2 synthesis measured. RESULTS: Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others (eg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX-1 inhibitory potency in blood (P <0.001) and with COX-1 selectivity (P <0.01), but not with COX-2 inhibitory potency. Even COX-2 'selective' NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. CONCLUSION: No currently marketed NSAID, even those that are COX-2 selective, spare gastric COX activity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.",
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N2 - PURPOSE: Both isoforms of cyclo-oxygenase, COX-1 and COX-2, are inhibited to varying degrees by all of the available nonsteroidal anti- inflammatory drugs (NSAIDs). Because inhibition of COX-1 by NSAIDs is linked to gastrointestinal ulcer formation, those drugs that selectively inhibit COX-2 may have less gastrointestinal toxicity. We measured the extent to which NSAIDs and other anti-inflammatory or analgesic drugs inhibit COX-1 and COX-2 in humans. SUBJECTS AND METHODS: Aliquots of whole blood from 16 healthy volunteers were incubated ex vivo with 25 antiinflammatory or analgesic drugs at six concentrations ranging from 0 (control) to 100 μM (n = 5 for each). Blood was assayed for serum-generated thromboxane B2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E2 synthesis measured. RESULTS: Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others (eg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX-1 inhibitory potency in blood (P <0.001) and with COX-1 selectivity (P <0.01), but not with COX-2 inhibitory potency. Even COX-2 'selective' NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. CONCLUSION: No currently marketed NSAID, even those that are COX-2 selective, spare gastric COX activity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.

AB - PURPOSE: Both isoforms of cyclo-oxygenase, COX-1 and COX-2, are inhibited to varying degrees by all of the available nonsteroidal anti- inflammatory drugs (NSAIDs). Because inhibition of COX-1 by NSAIDs is linked to gastrointestinal ulcer formation, those drugs that selectively inhibit COX-2 may have less gastrointestinal toxicity. We measured the extent to which NSAIDs and other anti-inflammatory or analgesic drugs inhibit COX-1 and COX-2 in humans. SUBJECTS AND METHODS: Aliquots of whole blood from 16 healthy volunteers were incubated ex vivo with 25 antiinflammatory or analgesic drugs at six concentrations ranging from 0 (control) to 100 μM (n = 5 for each). Blood was assayed for serum-generated thromboxane B2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E2 synthesis measured. RESULTS: Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others (eg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX-1 inhibitory potency in blood (P <0.001) and with COX-1 selectivity (P <0.01), but not with COX-2 inhibitory potency. Even COX-2 'selective' NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. CONCLUSION: No currently marketed NSAID, even those that are COX-2 selective, spare gastric COX activity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.

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