Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.

In your April 20 news item,1Prankish H Why do COX-2 inhibitors increase risk of cardiovascular events?.Lancet. 2002; 359: 1410Summary Full Text Full Text PDF Scopus (13) Google Scholar you question why cyclo-oxygenase-2 (COX-2) inhibitors increase the risk of cardiovascular events. We ask, however, despite the worldwide interest in this question, what actual evidence supports such a concern? In the UK, the National Institute for Clinical Excellence (NICE) has classified four drugs as COX-2-selective inhibitors: etodolac, meloxicam, celecoxib, and rofecoxib. Etodolac and meloxicam have been in use in many countries since the early to mid 1990s and there is no indication from clinical trials or from postmarketing surveillance that either drug increases thrombotic events.2Jick SS The risk of gastrointestinal bleed, myocardial infarction, and newly diagnosed hypertension in users of meloxicam, diclofenac, naproxen, and piroxicam.Pharmacotherapy. 2000; 20: 741-744Crossref PubMed Scopus (30) Google Scholar Similarly, there is no evidence from clinical use or controlled trials of a link between administration of celecoxib and an increase in thrombotic events. For example, although in the CLASS trial3White WB Faich G Whelton A et al.Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac.Am J Cardiol. 2002; 89: 425-430Summary Full Text Full Text PDF PubMed Scopus (212) Google Scholar there were more fatal acute myocardial infarctions among individuals taking celecoxib than those taking diclofenac or ibuprofen, this finding was balanced by a lower rate of cerebrovascular events and cardiac arrests or sudden cardiac deaths among celecoxib takers. This conclusion is much more convincing than the suggestion that celecoxib increases thrombotic events after the simple comparison of data between trials without meta-analysis.4Mukherjee D Nissen SE Topol EJ Risk of cardiovascular events associated with selective COX-2 inhibitors.JAMA. 2001; 286: 954-959Crossref PubMed Scopus (1659) Google Scholar Thus, there is no evidence of a relation between thrombotic events and the use of three of these four COX-2 inhibitors. The only evidence for such a link comes from the VIGOR trial, in which high-dose rofecoxib (50 mg) was compared with naproxen (500 mg twice daily) for 12 months in patients with rheumatoid arthritis. Significantly more thrombotic events were recorded in the rofecoxib group than in the naproxen group. That trial, however, had no placebo group and was not powered to test for cardiovascular outcomes. It also excluded individuals who had a history of cerebrovascular events in the previous 2 years or a history of myocardial infarction or coronary bypass in the previous year, as well as those taking aspirin, ticlodipine, or anticoagulants. Meta-analysis of VIGOR and other trials, none of which was powered for cardiovascular outcomes, suggests that rofecoxib does not increase thrombotic events. Other evidence suggests that naproxen may itself be anti-thrombotic.5Dalen JE Selective COX-2 inhibitors, NSAIDs, aspirin and myocardial infarction.Arch Intern Med. 2002; 162: 1091-1092Crossref PubMed Scopus (46) Google Scholar Therefore, even for rofecoxib there is no clear evidence of a link between use and thrombotic events. Because of current concerns, trials of up-coming COX-2 inhibitors should study cardiovascular side-effects as predefined endpoints. Although this may not happen for etoricoxib, since it has already been approved in the UK, Mexico, Brazil, and Peru, such an endpoint will be included in the gastrointestinal safety study of lumiracoxib (COX189) compared with ibuprofen and naproxen for 12 months. Cardiovascular safety will be a prespecified secondary endpoint and the study will permit the inclusion of patients taking low-dose aspirin for cardioprotection. The outcomes of such trials may provide definitive answers to questions on the safety of this class of drug. In the meantime, we hope that a clear understanding of the presented facts will offer a large measure of reassurance. JRV has received payment from Boehringer Ingelheim, Merck, and Shire Pharmaceuticals to act as a consultant, to speak at conferences, or both, in the past 3 years. TDW has received payment for Almirall Prodesfarma, Boehringer Ingelheim Pharma KG, Merck and subsidiaries, and Shire Pharmaceuticals to act as a speaker, consultant, or both.

Prostaglandins formed by cyclooxygenase-1 (COX-1) or COX-2 produce hyperalgesia in sensory nerve endings. To assess the relative roles of the two enzymes in pain processing, we compared responses of COX-1- or COX-2-deficient homozygous and heterozygous mice with wild-type controls in the hot plate and stretching tests for analgesia. Preliminary observational studies determined that there were no differences in gross parameters of behavior between the different groups. Surprisingly, on the hot plate (55 degrees C), the COX-1-deficient heterozygous groups showed less nociception, because mean reaction time was longer than that for controls. All other groups showed similar reaction times. In the stretching test, there was less nociception in COX-1-null and COX-1-deficient heterozygotes and also, unexpectedly, in female COX-2-deficient heterozygotes, as shown by a decreased number of writhes. Measurements of mRNA levels by reverse transcription-PCR demonstrated a compensatory increase of COX-1 mRNA in spinal cords of COX-2-null mice but no increase in COX-2 mRNA in spinal cords of COX-1-null animals. Thus, compensation for the absence of COX-1 may not involve increased expression of COX-2, whereas up-regulation of COX-1 in the spinal cord may compensate for the absence of COX-2. The longer reaction times on the hot plate of COX-1-deficient heterozygotes are difficult to explain, because nonsteroid anti-inflammatory drugs have no analgesic action in this test. Reduction in the number of writhes of the COX-1-null and COX-1-deficient heterozygotes may be due to low levels of COX-1 at the site of stimulation with acetic acid. Thus, prostaglandins made by COX-1 mainly are involved in pain transmission in the stretching test in both male and female mice, whereas those made by COX-2 also may play a role in the stretching response in female mice.

The discovery of a second cyclooxygenase (COX) enzyme 10 years ago is changing the multimillion dollar market for non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of arthritis. Two drugs, rofecoxib (Vioxx) and celecoxib (Celebrex), developed by new screening methods using COX-1 and COX-2 enzymes, have had spectacular launches in many countries as “selective” or “specific” COX-2 inhibitors. Others, such as meloxicam (Mobic), etodolac (Lodine), and nimesulide (eg, Aulin), were developed by classic pharmacological testing before COX-2 was discovered. Compounds were chosen that were, for instance, active against inflammation in rats but had little or no damaging effect on the rat stomach. They have been on the market for several years and turn out also to be selective COX-2 inhibitors.

In 1971, Vane showed that nonsteroid antiinflammatory drugs (NSAIDs) inhibited the biosynthesis of prostaglandins and proposed this as their mechanism of action. Much work around the world has followed. The aspirin-like drugs inhibit the binding of the prostaglandin substrate, arachidonic acid, to the active site of the enzyme. After characterization of the COX-1 enzyme in 1976, a second COX gene was discovered in 1991 encoding for the inducible COX-2. The constitutive isoform of COX, COX-1, has clear physiological functions. The inducible isoform, COX-2, is induced by pro-inflammatory stimuli in migratory cells and inflamed tissues. The range of activities of NSAIDs against COX-1 compared to COX-2 explains the variations in the side effects of NSAIDs at their antiinflammatory doses. Drugs which have the highest potency on COX-2 and less effect on COX-1 will have potent antiinflammatory activity with fewer side effects. All the results published so far support the hypothesis that the unwanted side effects of NSAIDs, such as damage to the gastric mucosa and kidneys, are due to their ability to inhibit COX-1, while their antiinflammatory (therapeutic effects) are due to inhibition of COX-2. Other roles for COX-2 inhibitors will surely be found in the next few years, for prostaglandin formation is under strong control in organs such as the kidney, lungs and uterus. COX-2 is also potently expressed in human colon cancer cells, and NSAIDs delay the progress of colon tumors possibly by causing apoptosis of the tumor cells. The risk of developing Alzheimer's disease, which may involve an inflammatory component, is lessened by chronic ingestion of NSAIDs. The new highly selective inhibitors of COX-2 will not only provide a means of delaying premature labor but will also lead to advances in cancer therapy and protection against Alzheimer's disease.

Heneka, M. T.; Ruetten, H.; Millar, C.; Thiemermann, C.; Vane, J. R. Author Information

The effect of the nitric oxide (NO) donor SIN-1 on energy metabolism was examined in three murine transplantable tumours in vivo using 31P MRS. SIN-1 at 2 mg kg-1 i.v. reduced Pi/total by 40-50% in SCCVII/Ha and KHT tumours within 5 min of injection, returning to control levels by 20 min. However, this dose of SIN-1 did not consistently alter Pi/total in RIF-1 tumours. Reduction in Pi/total in SCCVII/Ha tumours 10 min after 5 mg kg-1 i.v. SIN-1 was similar to that for 2 mg kg-1. SIN-1 at 10 mg kg-1 had no effect on Pi/total at 10 min after injection, but increased this ratio 2-fold over control at 60 min, at which time no effect of the lower doses of SIN-1 were observed. SIN-1 effects on SCCVII/Ha tumour response to X-rays were also examined, using an in vivo/in vitro clonogenic assay 24 h after treatment. SIN-1 at 0.5-2 mg kg-1 i.v. given immediately before irradiation increased tumour cell killing 2-4-fold over that for 15 Gy X-rays alone, while higher SIN-1 doses were ineffective. The results indicate that NO donors can alter tumour energy metabolism and X-ray response in a manner consistent with increased oxygenation. However, these responses are dependent upon dose, timing and tumour type.