Nomenclature for COX-2 Inhibitors

COMMENTARY

community. Pope and colleagues have developed a computerised instrument, the somatomorphic matrix, as a measure of body-image misperception.7 Among collegeage men in Austria, France, and the USA, they found that most men believed they would be more attractive to women if they were14 kg more muscular than they really were, whereas women rejected this brawny monstrosity in favour of a fairly average male body image. This finding is highly reminiscent of Fallon and Rozin’s observation that women routinely believed that their most attractive weight was lower than their current weight, and that their ideal weight was lower still, whereas men’s preference for female weight was significantly higher than women’s.9 What is to be made of these findings? First, it is apparent that men are increasingly being concerned about their body shape in this visual age. Women have suffered a disparity between the thin-female beauty ideal and biological reality for decades, and now men’s body ideal also seems to be drifting further away from biological health. Second, muscle dysmorphia is worthy of recognition as a disease entity. Third, this secret and shameful impediment has not yet received the attention that its female equivalents have. However, the disorder may not be as novel as its proponents imply. In 1969 Sir Martin Roth construed male body-image disorders as a form of hypochondriasis “with a history of marked . . . health consciousness and athleticism” in which “ardent devotion to athletic pursuits continued well beyond youth may be an over-compensation for real or imagined physical inferiorities”.10 The questions of nosology and treatment remain outstanding. Where does muscle dysmorphia fit in a psychiatric classification? Does it lie within the spectrum of mood disorders, obsessive-compulsive disorders, or eating disorders? The core features of body-image disturbance and body-shape manipulation intuitively wed muscle dysmorphia to the eating disorders, but further epidemiological research based on operationally defined diagnostic criteria is needed. What treatment is appropriate to its management? Trials of cognitivebehaviour therapy and selective serotoninergic reuptake inhibitors would seem to be the most appropriate first line of approach. But research into novel male bodyimage disorders must be matched by a recognition of the woefully inadequate provision of treatment services for men with established eating disorders.11 Men with eating disorders are more concerned with muscle shape than weight, but weight loss is more easily recognised and researched, which creates a natural gender-bias in both treatment and investigation. As long as fat is nothing but a feminist issue, doctors will continue to under-diagnose men with eating disorders, restrict access to specialist treatment facilities, and struggle with the management of gender-specific issues.12 John F Morgan Department of Psychiatry, St George’s Hospital Medical School, University of London, London, SW17 ORE, UK 1

2

3 4 5

Brownell KD, Napolitano MA. Distorting reality for children: body size proportions of Barbie and Ken Dolls. Int J Eat Dis 1995; 18: 295–98. Pope HG Jr, Olivardia R, Gruber A, Borowiecki J. Evolving ideals of male body image as seen through action toys. Int J Eat Dis 1999; 26: 65–72. Morant H. BMA demands more responsible media attitude on body image. BMJ 2000; 320: 1495. Raphael FJ, Lacey JH. Sociocultural aspects of eating disorders. Ann Med 1992; 24: 293–96. Pope HG Jr, Phillips KA, Olivardia R. The Adonis Complex. New York: The Free Press, 2000.

THE LANCET • Vol 356 • October 21, 2000

6

Olivardia R, Pope HG Jr, Hudson JI. Muscle dysmorphia in male weightlifters: a case-control study. Am J Psychiatry 2000; 157: 1291–96. 7 Pope HG Jr, Gruber AJ, Mangweth B, et al. Body image perception among men in three countries. Am J Psychiatry 2000; 157: 1297–301. 8 Pope HG, Gruber AJ, Choi P, Olivardia R, Phillips KA. Muscle dysmorphia. an underrecognized form of body dysmorphic disorder. Psychosomatics 1997; 38: 548–57. 9 Fallon AE, Rozin P. Sex differences in perceptions of desirable body shape. J Abnormal Psychol 1985; 94: 102–05. 10 Slater E, Roth M. Personality deviations and neurotic disorders. In: Slater E, Roth M, eds. Clinical psychiatry, 3rd ed. London: Bailliere, Tindall & Cassell, 1969: 143. 11 The Eating Disorder Association (UK). Eating disorders in the United Kingdom: review of the provision of health care services for men with eating disorders. Norwich: Eating Disorder Association, 2000. 12 Morgan JF, Key A, Lacey JH. Gender issues in the management of multi-impulsive bulimia. Int J Eat Dis 1998; 24: 107–09.

Nomenclature for COX-2 Inhibitors 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. Publications of large-scale clinical trials against comparator drugs have been available for meloxicam for some time1,2, and only recently for celecoxib;3 they will be available soon for rofecoxib.4 These major trials have set in stone the general concept that the anti-inflammatory effects of NSAIDs are due to inhibition of COX-2, whereas the gastrointestinal toxicity is due to inhibition of COX-1. There is clearly a strong correlation between reduced gastrointestinal damage with these three drugs and their COX-1-sparing effects. Over the past few years, many degrees of COX-2 selectivity have been reported, ranging from more than 1000-fold (usually on isolated enzymes) for prototype compounds to five-fold, with many classic NSAIDs showing selectivity towards COX-1. As a consequence, scientific reports and the advertisements are littered with adjectival descriptions of COX-2 inhibitors. Some tidying-up is called for. What should survive from descriptions such as “non-selective”, “preferential”, “selective”, “highly selective”, and “specific”, not to mention “coxibs”? “Specific” is a term that pharmacologists use with great exactitude. It should not be redefined by marketeers to cover only therapeutic concentrations at which a particular drug inhibits COX-2 but not COX-1. What if higher concentrations are used in some of the new indications, such as prevention of colon polyps? Some ␤-blockers are properly classified as cardioselective, but none as cardiospecific. ACE inhibitors are not described as specific. As far as COX-2 inhibitors are concerned, the term “specific” should be abandoned. Patrignani and colleagues’ human in-vitro wholeblood assay5 has become an accepted and reproducible standard for measuring the effects of anti-inflammatory 1373

For personal use only. Not to be reproduced without permission of The Lancet.

COMMENTARY

drugs on COX-1 (in platelets) and COX-2 (in white cells). Warner et al6 used a modified version and found that celecoxib, etodolac, meloxicam, and nimesulide fell within the range of 5–20 times more active on COX-2, whereas rofecoxib was more than 50-fold more selective. Thus, in human blood cells, the range of selectivity is less than two orders of magnitude. Furthermore, the largescale clinical trials of celecoxib, meloxicam (including post-marketing surveillance), and rofecoxib all show similar striking reductions (of about 50%) in serious adverse events on the gastrointestinal tract over comparator non-selective compounds such as ibuprofen, diclofenac, naproxen, or piroxicam.1–4,7,8 Thus, even the 5–100 fold range of selectivity towards COX-2 in the human whole-blood assay has not been reflected by major differences in the reductions in serious gastrointestinal toxicity of these drugs in clinical trials. It is the results in patients that matter, so all of these drugs with well-proven lower toxicity on the gastrointestinal tract should be grouped together as “selective” COX-2 inhibitors. The other terms, such as “preferential” or “highly selective” should be discarded, for they simply give drug firms sticks with which they can try to beat their competitors. With respect to the use of the term “coxibs”, this WHO definition is of a chemical class (such as the “oxicams”) and says nothing about the pharmacology or selectivity towards COX-2. It should not be used in promotional material to imply otherwise. There is nothing new about COX-2 inhibitors —salicylate and aspirin, for example, have been used clinically for hundreds if not thousands of years. All of the NSAIDs are COX-2 inhibitors, for that is how they work in inflammation. What is new is that there are now drugs that do not concomitantly inhibit COX-1, so they have less gastrointestinal toxicity than do the older drugs. Perhaps a more accurate and descriptive term would be “COX-1 sparing drugs”. But alas, it is probably too late. J R Vane, T D Warner William Harvey Research Institute, London EC1M 6BQ, UK 1

2

3

4 5

6

7

8

Dequeker J, Hawkey C, Kahan A, et al. Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis. Br J Rheumatol 1998; 37: 946–51. Hawkey C, Kahan A, Steinbruck K, et al. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety Assessment. Br J Rheumatol 1998; 37: 937–45. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with Celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial. JAMA 2000; 284: 1247–55. Bombadier C. Summary of Vigor trial. EULAR meeting in Nice, June 22, 2000. Patrignani, P, Panara MR, Greco A, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 1994; 271: 1705–12. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclooxygenase-1 rather than cyclooxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA 1999; 96: 7563–68. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999; 282: 1929–33. Schoenfeld P. Gastrointestinal safety profile of meloxicam: a metaAnalysis and systematic review of randomized controlled trials. Am J Med 1999; 107 : 48S–54S.

1374

Shuffles Microsoft’s chief Bill Gates has been taking part in a US national bridge tournament this summer,1 finishing “below average”, a performance that will give great comfort to lesser mortals. Bridge has the potential, happily unrealised, of becoming a computationally demanding game, but in practice it is just a haphazard, error-prone, and occasionally amusing human activity that prompts more divorces than adultery does. Which is why all the fuss about how thoroughly a pack of cards should be shuffled is so bewildering.2 On a widely accepted scoring system with aces high and three, two, and one for the coat cards (no, not a misprint, “court cards” is wrong3), a standard pack carries 40 points, shared at random among four people playing in pairs if not in harmony. So although a player will seldom be dealt exactly 10 points, that will be the mean. However, far more often than is statistically plausible, the average player complains: “I haven’t had a decent hand all evening”, decent being defined as 12 points plus, while 20 or more induces ecstasy. I am afraid that mathematicians LN and LM Trefethen2 are wasting their time in calculating that a mere five, as opposed to the previously believed seven—or roughly log2n rather than 3/2log2n, where n is 52 for a full pack—shuffles will render the sequence of cards random for all practical purposes. To a bridge-player it is some avenging demon, not the immutable laws of probability, that decides what 13 cards are dealt, and I am on an especially bad run at present. In high-level competitive bridge hands may be shuffled and dealt by computer but round the kitchen table cruder methods survive. My own shuffle technique is the gentle, vertical, but mathematically less effective one. Divide in two, bend cards at the edges, and reassemble violently is the alternative, which is why the queen of diamonds in a curved pack at home has a revealing midabdominal scar. But shuffling and cutting is just part of the ritual. Most amateurs, even if they were capable of recalling the occasional small sequence of cards after an inefficient shuffle, would make a pig’s ear of using the information. David Sharp The Lancet, London WC1X 8RR, UK 1 2 3

Forrester T. Attack is barred by Gates. Daily Telegraph, Oct 11, 2000, p46. Trefethen LN, Trefethen LM. How many shuffles to randomize a deck of cards? Proc R Soc A 2000; 456: 2561–68. Alder P. Kings, queens and playing cards. In: Forrester T. The bridge player’s bedside book. Cambridge: Colt Books, 1997: 104.

What’s next at The Lancet website The course of The Lancet’s marriage with the internet has been hectic. In March, 1998, with the unveiling of The Lancet Interactive, we were one of the first general medical journals to deliver full-text editorial content online. Then, this month we went one step further and launched thelancet.com, the home page for The Lancet Publishing Group, in which we introduced the new titles The Lancet Oncology and Lancet Neurology Network. There is also a new look and feel to the website. These developments are only a taster of what is to come. The innovations can be sampled at http://www.thelancet.com. Pia Pini, Craig Canham The Lancet, London, WC1X 8RR, UK

THE LANCET • Vol 356 • October 21, 2000

For personal use only. Not to be reproduced without permission of The Lancet.