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  • Review Article
  • Published:

COX-2 and beyond: approaches to prostaglandin inhibition in human disease

A Correction to this article was published on 01 December 2003

Key Points

  • A plausible mechanism has emerged which suggests that cyclooxygenase-2 (COX-2) inhibitors might expose otherwise predisposed individuals to thrombotic or systemic hypertensive complications. There is no evidence that COX-2 inhibitors represent an independent risk of myocardial infarction or stroke in patients at low demographic risk of cardiovascular disease.

  • Arachidonic acid is metabolized by prostaglandin G2/H2 synthase (colloquially known as COX) to form prostaglandins, which have diverse and conflicting effects on inflammation, gastric epithelial integrity and cardiovascular function.

  • COX-1 is widely expressed and generates predominantly prostaglandins to subserve housekeeping functions, such as gastroprotection and haemostatic integrity. COX-2 is readily induced by cytokines and mitogens and accounts largely for prostaglandin formation in inflammation and cancer. A COX-1 variant, termed COX-3, has recently been described.

  • Selective inhibitors of COX-2 — for example, celecoxib, rofecoxib, valdecoxib, its prodrug, parecoxib, etoricoxib and lumiracoxib — cause less endoscopically visualized gastric ulceration in arthritis patients than equi-efficacious doses of traditional nonsteroidal anti-inflammatory drugs (NSAIDs), which coincidentally inhibit COX-1 and COX-2. Rofecoxib halved the incidence of clinically important gastrointestinal events when compared with naproxen in the VIGOR trial, whereas gastrointestinal events did not differ significantly between celecoxib, diclofenac and ibuprofen in the CLASS study.

  • COX-2 inhibitors suppress substantially platelet inhibitory, vasodilator prostaglandins, such as prostacyclin (PGI2), without coincidental inhibition of the platelet agonist vasoconstrictor thromboxane (TxA2). As PGI2 counters the cardiovascular effects of TxA2 and augments the response to thrombotic stimuli in vivo, this affords a plausible mechanism by which COX-2 inhibitors might enhance the risk of thrombosis in otherwise predisposed individuals. The incidence of clinically important cardiovascular events has diverged significantly between patients receiving either rofecoxib or etoricoxib versus naproxen. This might reflect, in part, a cardioprotective effect of naproxen. A cluster of cardiovascular and cerebrovascular events occurred in coronary artery bypass patients receiving parecoxib/valdecoxib.

  • Systemic hypertensive adverse events have been reported on all COX-2 inhibitors. It is presently unclear whether their incidence differs from what is observed on traditional NSAIDs. Studies in mice indicate that the likelihood that such events might relate to the degree of COX-2 inhibition and the selectivity with which it is attained. The role of COX-2 inhibitors in atherogenesis is complex, reflecting the diverse biology of its products, which differ in predominance amongst the distinct cell types implicated in this condition.

  • Selective inhibitors of COX-2 are as effective as traditional NSAIDs in the treatment of pain and inflammation, but are less prone to cause gastric ulceration. There is no evidence that they present a hazard to patients otherwise at low risk of cardiovascular disease. Plausible mechanisms have emerged which suggest a potential risk of thrombosis or renovascular hypertension from COX-2 inhibitors in individuals otherwise predisposed to these conditions.

  • As the potential of the further clinical efficacy of COX-2 inhibitors in cancer and brain disease develops, interest is shifting downstream in the biosynthetic/response cascade with the emergence of drugs targeted at individual prostaglandin synthases and receptors.

Abstract

Selective inhibitors of cyclooxygenase (COX)-2 afford relief from pain and inflammation. They could also prove useful in the chemoprevention of cancer and are being investigated in a range of neurological diseases. This novel class of drug is less likely to cause gastric ulceration than traditional nonsteroidal anti-inflammatory drugs (tNSAIDs). However, plausible mechanisms have been proposed whereby COX-2 inhibitors could cause thrombosis or renovascular hypertension in patients predisposed to these conditions. The limited data available with structurally distinct inhibitors in relevant populations are consistent with this possibility, although these might be partly explained by a cardioprotective effect of the tNSAID naproxen. This article will review the role of COX-2 inhibitors in a number of indications, including cardiovascular disease, hypertension and atherosclerosis.

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Figure 1: Structural distinction between hydrophobic channels in PGG/H synthase isozymes.
Figure 2: Prostaglandin biosynthetic cascade.
Figure 3: Selective inhibitors of COX-2.
Figure 4: Prostacyclin modifies the cardiovascular response to thromboxane in vivo.
Figure 5: Posthoc depiction of cardiovascular events in non-aspirin users in the CLASS study.
Figure 6: Dose-related increase in reports of hypertension as a serious adverse event in trials of celecoxib and rofecoxib.
Figure 7: Distinct effects of COX-1 and COX-2 inhibition on the systemic pressor response to infused angiotensin II.

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DATABASES

LocusLink

AGTR1

COX-1

COX-2

EP1

EP2

EP3

EP4

FP

IP

MRP4

PGE synthase-1

Ptgs1

Ptgs2

TP

Online Mendelian Inheritance in Man

Alzheimer disease

familial adenomatous polyposis

Parkinson disease

Glossary

PGG2/H2S

Prostaglandin (PG) G2/H2 synthase catalyses the conversion of arachidonic acid to the prostaglandin endoperoxide intermediates PGG2 and PGH2. This bifunctional protein possesses both cyclooxygenase (COX) and hydroperoxidase activities, but is colloquially known as the COX enzyme. Drugs such as aspirin and traditional nonsteroidal anti-inflammatories inhibit only the COX activities of PGG2/H2 synthases-1 and -2. Similarly, COX-2 inhibitors only inhibit the COX function of PGG2/H2 synthase-2.

ANKYLOSING SPONDYLITIS

An arthritic condition of the spine.

GOUT

A form of arthritis caused by accumulation of monosodium urate crystals in joint cavities.

AMPHIPHILIC MOLECULES

Contain both hydrophilic and hydrophobic groups.

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FitzGerald, G. COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2, 879–890 (2003). https://doi.org/10.1038/nrd1225

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