- Email: [email protected]
COX-2 inhibitors
COMMENTARY
CORRESPONDENCE COX-2 inhibitors Sir—C J Hawkey’s review of COX-2 inhibitors (Jan 23, p 307)1 contained omissions relating to etodolac. He does not refer to recent work by Riendeau et al2 which compared three NSAIDs marketed as COX-2 selective. Etodolac had 1000-fold selectivity for COX-2 over COX-1, which was three times the selectivity for meloxicam.2 G-MNA, the active metabolite of nabumetone was found not to be selective for COX-2 in this assay. Hawkey points out that many data for the new agents are available only as abstracts. However, a study published in full3 concluded that celecoxib is a more potent inhibitor of COX-1 than etodolac. Such data lead us to believe that the use of the term COX-2 specific is inappropriate for these agents since this implies that they have no activity other than on COX-2. He draws attention to the importance of data on the effect of NSAIDs on prostaglandin synthesis in human gastric mucosa at therapeutic doses. He cites only work on rofecoxib, but etodolac has been shown to cause no overall suppression of gastric and duodenal prostaglandins in patients with active rheumatoid arthritis and in healthy volunteers. As Hawkey mentions, rofecoxib has been studied with the Cr51-labelled red cell technique for measuring faecal blood loss. Etodolac has also been shown not to lead to an increase in faecal blood loss in contrast to the other NSAIDs with which it was compared, including ibuprofen.4 He refers to unpublished data from a clinical trial comparing rofecoxib with ibuprofen (2400 mg per day), but not to the published data from a 3-year clinical trial comparing etodolac with ibuprofen (2400 mg per day):5 a significantly higher incidence of gastrointestinal ulcers and bleeding was seen in the ibuprofen versus the etodolac group over the 3-year study period. Towards the end of the review he speculates about safety issues that, in theory, could arise with COX-2 inhibitors. The data sheet for etodolac includes a warning that the use of NSAIDs may result in deterioration of renal function and caution is advised in patients with renal, cardiac, or hepatic
THE LANCET • Vol 353 • April 24, 1999
impairment, especially those taking diuretics. However, there were no clinically relevant renal impairments among 1382 patients studied, with a total exposure to etodolac of 600 patient years. With over 13 years of clinical experience with the COX-2 inhibitor etodolac, there are many data available with which to address speculations about safety issues. Tim Tustin Monmouth Pharmaceuticals, Surrey Research Park, Guildford GU2 5RE, UK 1
Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. 2 Riendeau D, Percival MD, Boyce S, et al. Biochemical and pharmacological profile of tetrasubstituted furanone as a highly selective COX-2 inhibitor. Br J Pharmacol 1997; 121: 105–17. 3 Riendeau D, Charleston S, Cromlish N, Mancini JA, Wong E, Guay J. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol 1997; 75: 1088–95. 4 Arnold JD, Salom IL, Berger AE, et al. Comparison of gastrointesinal microbleeding associated with use of etodolac, ibuprofen, indomethacin, and naproxen in normal subjects. Curr Therapeut Res 1985; 37: 730–38. 5 Neustadt DH. Double blind evaluation of the longterm effects of etodolac versus ibuprofen in patients with rheumatoid arthritis. J Rheumatol 1997; 24 (suppl 47): 17–22.
Sir—C J Hawkey1 points out the difficulties in assessing the relative merits of the different assay systems used to produce COX-2 to COX-1 selectivity ratios and suggests that the non-inhibition of gastric prostaglandins should become the gold standard. It is surprising, therefore, that he makes almost no mention of the COX-2 selective drug that has been most extensively studied in this way; etodolac. The COX-2 selectivity of etodolac has been demonstrated,2 but it also meets the gold standard of noninhibition of human gastric prostaglandins recommended by Hawkey. Our work in comparing the effect on gastric and mucosal prostaglandins of repeated intake of therapeutic doses of etodolac (300 mg/twice daily) and naproxen (500 mg/twice daily) in
patients with active rheumatoid arthritis has been widely reported.3,4 This work established that both drugs had comparable antiarthritic effects but, whereas naproxen reduced the levels of gastric prostaglandins, etodolac did not. Endoscopically assessed mucosal damage was also reduced with etodolac compared with naproxen. Since then, others have published comparisons between etodolac, naproxen, and placebo in healthy volunteers showing similar effects on the levels of gastric prostaglandins, with naproxen suppressing these levels in contrast to etodolac and placebo.5 We have also compared etodolac with diclofenac, preliminary results showing similar favourable results for etodolac with respect to gastric mucosal prostaglandins and endoscopic findings. Thus we find etodolac meeting Hawkey’s gold standard again. The results of these studies offer an effective NSAID that maintains gastric prostaglandins without the use of synthetic prostaglandin analogues with conventional NSAIDs, at the risk of more side-effects and financial expense. Although these data are important indicators of the gastrointestinal safety of NSAIDs, they are no substitute for long-term observation in routine clinical use. There have been many false dawns in the treatment of arthritis and an agent that has stood the test of time, as etodolac has, holds a major advantage over new entrants. R I Russell University of Glasgow, Royal Infirmary, Glasgow G4 0SF, UK (e-mail: [email protected]) 1
Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. 2 Glaser K. Cyclooxygenase selectivity and NSAIDs: cyclooxygenase-2 selectivity of etodolac (Lodine). Inflammopharmacol 1995; 3: 335–45. 3 Russell RI. Endoscopic evaluation of etodolac and naproxen, and their effects on gastric and duodenal prostaglandins. Rheumatol Int 1990; 10 (suppl): 17–21. 4 Taha AS, McLaughlin S, Holland PJ, et al. Effect on gastric duodenal mucosal prostaglandins of repeated intake of therapeutic doses of naproxen and etodolac in rheumatoid arthritis. Ann Rheum Dis 1990; 49: 354–58. 5 Laine L, Sloane R, Ferretti M, Cominelli F. A randomised, double-blind comparison of
1439
placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production. Gastrointestinal Endoscopy 1995; 42: 428–33.
Sir—C J Hawkey reviews COX-2 inhibitors.1 Researchers generally agree that COX-2 inhibition does not fully account for the therapeutic effects of NSAIDs and COX-2 agents, but there is a noticeable absence of discussion on the difficulty in attributing all gastrointestinal side-effects to COX-1 inhibition. In fact much work in animals shows that over 90% reduction of mucosal prostaglandin is achievable with various NSAIDs without apparent damage, provided that direct contact of the drug with the gastric mucosa is avoided. This topical aspect of damage is also evident in man in whom as little as 75 mg of orally administered aspirin will suppress mucosal prostaglandin formation completely without major damage. 3 Yet there is progressively severe damage with increasing aspirin doses, so that with 3800 mg aspirin in the short-term most patients have an ulcer.4 Ulcers develop without a substantial increase in the degree of COX-1 inhibition. Last, COX-1 knockout mice that have gastric mucosal prostaglandin levels less than 1% of wild types, do not spontaneously develop gastrointestinal damage, as theory would predict. Hawkey cites a reference (no 70 in his paper) purporting to explain this lack of damage on the basis of up-regulation of intestinal nitric oxide synthesis. In fact, the reference does not mention upregulation or nitric oxide, and my group has indeed found intestinal nitric oxide products decreased, if anything, in COX-1 knockout animals. Consideration of these points, and many other observations, has suggested that the topical action of NSAIDs (defined as a non-prostaglandin mediated effect that requires direct contact with the mucosa after ingestion of biliary excretion of the drugs) is equally if not more important than COX-1 inhibition in the initiation of the damage. Hawkey then discusses two preferential COX-2 inhibitors (meloxicam and nimesulide) and two COX-2 agents (celecoxib and rofecoxib); the distinction between the two classes being in-vitro inhibitory (50%) concentration ratios. The validity of extrapolating the in-vitro data to invivo has been questioned, not least because the different in-vitro assays do not yield comparable data and that pharmacokinetic indices are important in possible differential inhibition of the enzymes in vivo. Nevertheless, Hawkey states that “nimesulide may not be selective for COX-2 because the doses
1440
used, &c.” A recent study of nimesulide, given at full therapeutic doses for a week, showed that the drug had no significant effect on platelet function, serum thromboxane-2 concentration, or gastric mucosal prostaglandins (all COX-1 dependent actions) whereas lipopolysaccharide stimulated wholeblood assay indicated COX-2 inhibition in excess of 95%.5 Hawkey ommitted that nitric oxide attachments to NSAIDs are achieved by esterification of the acidic carboxylic group of the NSAIDs and hence rendering them non-acidic, which reduces the short term gastric toxicity of NSAIDs in animals. Ingvar Bjarnason Department if Medicine, Guy’s King’s, St Thomas’ Medical School, London SE5 9JP, UK 1
Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. 2 Whittle BJR. Unwanted effects of aspirin and related agents on the gastrointestinal tract. In: Vane JR, Bolling RM, eds. Aspirin and other sallcylates. London: Chapman & Hall Medical. 1992: 465–509. 3 Donelly MT, Stacks WA, Richardson P, et al. Microencapsulated aspirin, Ascard, reduces endoscopic damage in healthy volunteers compared to conventional encapsulated aspirin. Gastroenterology 1998; 114: A107. 4 Lanza FL. A review of gastric ulcer and gastroduodenal injury in normal volunteers receiving aspirin and other non-steroidal anti-inflammatory drugs. Scand J Gastroenterol 1988; 24 (suppl 163): 24–31. 5 Murray FE, Shah AA, Thjodleifsson B, et al. Comparison on the effect of naproxen and the COX-2 selective NSAID, nimesulide, on prostanoid formation in man. Gastroenterology 1998; 114: A237.
Author’s reply Sir—In my review I emphasised the difficulties that arise because of the large number of ways in which COX-2 selectivity is assessed. The editors and I had to decide which drugs to include. The data from Riendeau1 certainly add to the evidence that etodolac may be COX-2 selective. However, they also illustrate the difficulties in making that judgment. In that paper, etodolac had 1000-fold selectivity in a transfected cell system, whereas Glaser2 had reported a level of selectivity similar to piroxicam in a human whole assay. These discrepancies emphasise the need for a consensus definition on COX-2 selectivity. Although I suggested that the focus should shift to the (non) effects of drugs on gastric mucosal prostaglandin synthesis (and consequent injury), there is currently even less consensus here. For that reason I omitted—in addition to the etodolac and nimesulide papers—ones on other drugs such as meloxicam, 3 which contained methodological uncertainties.
I would like to take issue on factual grounds with some of Ingvar Bjarnason’s assertions. Aspirin 75 mg does not completely suppress mucosal prostaglandin formation and moreover is associated with important toxicity. Most people taking 3800 mg of aspirin in the short-term do not have an ulcer. Reference 70 in my paper was to the observation that COX-1 knockout mice are resistant to ulceration, not to the possible explanation I suggested. The important point is that prostaglandins are not the only protective mediators in the stomach, and enhanced protection from other systems as a result of developmental changes mean that the data from COX-1 knockout mice cannot be regarded as pivotal evidence one way or the other. I am aware of his data on nimesulide but hesitant to assess their importance because of the incomplete methodological description and the apparently extremely high prostaglandin levels reported in his abstract publication. As for nitric-oxide NSAIDs, only one has been tested in humans. The level of protection seen with that nitric-oxide NSAID and the need to test others which have been much more protective in animals still lead me to the cautious conclusion in the final sentence of the paragraph on those drugs. I would like to take the opportunity to correct two errors that arose in the final version of my article. The recommended daily dose for celecoxib is 200 mg once daily or 100 mg twice daily for osteoarthritis and 100–200 mg twice daily for rheumatoid arthritis. Celecoxib 50 mg was compared with placebo in reference 37 and it was this dose (not 100 mg twice daily as suggested by the legend to table 3) that was better than placebo for some measures only and less effective than higher doses. C J Hawkey School of Medical and Surgical Sciences, Division of Gastroenterology, University Hospital, Nottingham NG7 2UH, UK (e-mail: [email protected]) 1
Riendeau D, Charleson S, Cromlish W, Mancini JA, Wong E, Guay J. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors using sensitive microsomal and platelet essays. Can J Physiol Pharmacol 1997; 75: 1088–95. 2 Glaser K, Sung ML, O’Niell K, et al. Ethodolac selectivity inhibitors prostaglandin G/H synthase 2 (PRHS-2) versus human PGHS-01. Eur J Pharmacol 1995; 281: 107–11. 3 Lipscomb GR, Wallis N, Armstrong G, Rees WD. Gastrointestinal tolerability of meloxicam and piroxicam: a double-blind placebo-controlled study. Brit J Clin Pharmacol 1998; 46: 133–37.
THE LANCET • Vol 353 • April 24, 1999
CORRESPONDENCE COX-2 inhibitors Sir—C J Hawkey’s review of COX-2 inhibitors (Jan 23, p 307)1 contained omissions relating to etodolac. He does not refer to recent work by Riendeau et al2 which compared three NSAIDs marketed as COX-2 selective. Etodolac had 1000-fold selectivity for COX-2 over COX-1, which was three times the selectivity for meloxicam.2 G-MNA, the active metabolite of nabumetone was found not to be selective for COX-2 in this assay. Hawkey points out that many data for the new agents are available only as abstracts. However, a study published in full3 concluded that celecoxib is a more potent inhibitor of COX-1 than etodolac. Such data lead us to believe that the use of the term COX-2 specific is inappropriate for these agents since this implies that they have no activity other than on COX-2. He draws attention to the importance of data on the effect of NSAIDs on prostaglandin synthesis in human gastric mucosa at therapeutic doses. He cites only work on rofecoxib, but etodolac has been shown to cause no overall suppression of gastric and duodenal prostaglandins in patients with active rheumatoid arthritis and in healthy volunteers. As Hawkey mentions, rofecoxib has been studied with the Cr51-labelled red cell technique for measuring faecal blood loss. Etodolac has also been shown not to lead to an increase in faecal blood loss in contrast to the other NSAIDs with which it was compared, including ibuprofen.4 He refers to unpublished data from a clinical trial comparing rofecoxib with ibuprofen (2400 mg per day), but not to the published data from a 3-year clinical trial comparing etodolac with ibuprofen (2400 mg per day):5 a significantly higher incidence of gastrointestinal ulcers and bleeding was seen in the ibuprofen versus the etodolac group over the 3-year study period. Towards the end of the review he speculates about safety issues that, in theory, could arise with COX-2 inhibitors. The data sheet for etodolac includes a warning that the use of NSAIDs may result in deterioration of renal function and caution is advised in patients with renal, cardiac, or hepatic
THE LANCET • Vol 353 • April 24, 1999
impairment, especially those taking diuretics. However, there were no clinically relevant renal impairments among 1382 patients studied, with a total exposure to etodolac of 600 patient years. With over 13 years of clinical experience with the COX-2 inhibitor etodolac, there are many data available with which to address speculations about safety issues. Tim Tustin Monmouth Pharmaceuticals, Surrey Research Park, Guildford GU2 5RE, UK 1
Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. 2 Riendeau D, Percival MD, Boyce S, et al. Biochemical and pharmacological profile of tetrasubstituted furanone as a highly selective COX-2 inhibitor. Br J Pharmacol 1997; 121: 105–17. 3 Riendeau D, Charleston S, Cromlish N, Mancini JA, Wong E, Guay J. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol 1997; 75: 1088–95. 4 Arnold JD, Salom IL, Berger AE, et al. Comparison of gastrointesinal microbleeding associated with use of etodolac, ibuprofen, indomethacin, and naproxen in normal subjects. Curr Therapeut Res 1985; 37: 730–38. 5 Neustadt DH. Double blind evaluation of the longterm effects of etodolac versus ibuprofen in patients with rheumatoid arthritis. J Rheumatol 1997; 24 (suppl 47): 17–22.
Sir—C J Hawkey1 points out the difficulties in assessing the relative merits of the different assay systems used to produce COX-2 to COX-1 selectivity ratios and suggests that the non-inhibition of gastric prostaglandins should become the gold standard. It is surprising, therefore, that he makes almost no mention of the COX-2 selective drug that has been most extensively studied in this way; etodolac. The COX-2 selectivity of etodolac has been demonstrated,2 but it also meets the gold standard of noninhibition of human gastric prostaglandins recommended by Hawkey. Our work in comparing the effect on gastric and mucosal prostaglandins of repeated intake of therapeutic doses of etodolac (300 mg/twice daily) and naproxen (500 mg/twice daily) in
patients with active rheumatoid arthritis has been widely reported.3,4 This work established that both drugs had comparable antiarthritic effects but, whereas naproxen reduced the levels of gastric prostaglandins, etodolac did not. Endoscopically assessed mucosal damage was also reduced with etodolac compared with naproxen. Since then, others have published comparisons between etodolac, naproxen, and placebo in healthy volunteers showing similar effects on the levels of gastric prostaglandins, with naproxen suppressing these levels in contrast to etodolac and placebo.5 We have also compared etodolac with diclofenac, preliminary results showing similar favourable results for etodolac with respect to gastric mucosal prostaglandins and endoscopic findings. Thus we find etodolac meeting Hawkey’s gold standard again. The results of these studies offer an effective NSAID that maintains gastric prostaglandins without the use of synthetic prostaglandin analogues with conventional NSAIDs, at the risk of more side-effects and financial expense. Although these data are important indicators of the gastrointestinal safety of NSAIDs, they are no substitute for long-term observation in routine clinical use. There have been many false dawns in the treatment of arthritis and an agent that has stood the test of time, as etodolac has, holds a major advantage over new entrants. R I Russell University of Glasgow, Royal Infirmary, Glasgow G4 0SF, UK (e-mail: [email protected]) 1
Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. 2 Glaser K. Cyclooxygenase selectivity and NSAIDs: cyclooxygenase-2 selectivity of etodolac (Lodine). Inflammopharmacol 1995; 3: 335–45. 3 Russell RI. Endoscopic evaluation of etodolac and naproxen, and their effects on gastric and duodenal prostaglandins. Rheumatol Int 1990; 10 (suppl): 17–21. 4 Taha AS, McLaughlin S, Holland PJ, et al. Effect on gastric duodenal mucosal prostaglandins of repeated intake of therapeutic doses of naproxen and etodolac in rheumatoid arthritis. Ann Rheum Dis 1990; 49: 354–58. 5 Laine L, Sloane R, Ferretti M, Cominelli F. A randomised, double-blind comparison of
1439
placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production. Gastrointestinal Endoscopy 1995; 42: 428–33.
Sir—C J Hawkey reviews COX-2 inhibitors.1 Researchers generally agree that COX-2 inhibition does not fully account for the therapeutic effects of NSAIDs and COX-2 agents, but there is a noticeable absence of discussion on the difficulty in attributing all gastrointestinal side-effects to COX-1 inhibition. In fact much work in animals shows that over 90% reduction of mucosal prostaglandin is achievable with various NSAIDs without apparent damage, provided that direct contact of the drug with the gastric mucosa is avoided. This topical aspect of damage is also evident in man in whom as little as 75 mg of orally administered aspirin will suppress mucosal prostaglandin formation completely without major damage. 3 Yet there is progressively severe damage with increasing aspirin doses, so that with 3800 mg aspirin in the short-term most patients have an ulcer.4 Ulcers develop without a substantial increase in the degree of COX-1 inhibition. Last, COX-1 knockout mice that have gastric mucosal prostaglandin levels less than 1% of wild types, do not spontaneously develop gastrointestinal damage, as theory would predict. Hawkey cites a reference (no 70 in his paper) purporting to explain this lack of damage on the basis of up-regulation of intestinal nitric oxide synthesis. In fact, the reference does not mention upregulation or nitric oxide, and my group has indeed found intestinal nitric oxide products decreased, if anything, in COX-1 knockout animals. Consideration of these points, and many other observations, has suggested that the topical action of NSAIDs (defined as a non-prostaglandin mediated effect that requires direct contact with the mucosa after ingestion of biliary excretion of the drugs) is equally if not more important than COX-1 inhibition in the initiation of the damage. Hawkey then discusses two preferential COX-2 inhibitors (meloxicam and nimesulide) and two COX-2 agents (celecoxib and rofecoxib); the distinction between the two classes being in-vitro inhibitory (50%) concentration ratios. The validity of extrapolating the in-vitro data to invivo has been questioned, not least because the different in-vitro assays do not yield comparable data and that pharmacokinetic indices are important in possible differential inhibition of the enzymes in vivo. Nevertheless, Hawkey states that “nimesulide may not be selective for COX-2 because the doses
1440
used, &c.” A recent study of nimesulide, given at full therapeutic doses for a week, showed that the drug had no significant effect on platelet function, serum thromboxane-2 concentration, or gastric mucosal prostaglandins (all COX-1 dependent actions) whereas lipopolysaccharide stimulated wholeblood assay indicated COX-2 inhibition in excess of 95%.5 Hawkey ommitted that nitric oxide attachments to NSAIDs are achieved by esterification of the acidic carboxylic group of the NSAIDs and hence rendering them non-acidic, which reduces the short term gastric toxicity of NSAIDs in animals. Ingvar Bjarnason Department if Medicine, Guy’s King’s, St Thomas’ Medical School, London SE5 9JP, UK 1
Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. 2 Whittle BJR. Unwanted effects of aspirin and related agents on the gastrointestinal tract. In: Vane JR, Bolling RM, eds. Aspirin and other sallcylates. London: Chapman & Hall Medical. 1992: 465–509. 3 Donelly MT, Stacks WA, Richardson P, et al. Microencapsulated aspirin, Ascard, reduces endoscopic damage in healthy volunteers compared to conventional encapsulated aspirin. Gastroenterology 1998; 114: A107. 4 Lanza FL. A review of gastric ulcer and gastroduodenal injury in normal volunteers receiving aspirin and other non-steroidal anti-inflammatory drugs. Scand J Gastroenterol 1988; 24 (suppl 163): 24–31. 5 Murray FE, Shah AA, Thjodleifsson B, et al. Comparison on the effect of naproxen and the COX-2 selective NSAID, nimesulide, on prostanoid formation in man. Gastroenterology 1998; 114: A237.
Author’s reply Sir—In my review I emphasised the difficulties that arise because of the large number of ways in which COX-2 selectivity is assessed. The editors and I had to decide which drugs to include. The data from Riendeau1 certainly add to the evidence that etodolac may be COX-2 selective. However, they also illustrate the difficulties in making that judgment. In that paper, etodolac had 1000-fold selectivity in a transfected cell system, whereas Glaser2 had reported a level of selectivity similar to piroxicam in a human whole assay. These discrepancies emphasise the need for a consensus definition on COX-2 selectivity. Although I suggested that the focus should shift to the (non) effects of drugs on gastric mucosal prostaglandin synthesis (and consequent injury), there is currently even less consensus here. For that reason I omitted—in addition to the etodolac and nimesulide papers—ones on other drugs such as meloxicam, 3 which contained methodological uncertainties.
I would like to take issue on factual grounds with some of Ingvar Bjarnason’s assertions. Aspirin 75 mg does not completely suppress mucosal prostaglandin formation and moreover is associated with important toxicity. Most people taking 3800 mg of aspirin in the short-term do not have an ulcer. Reference 70 in my paper was to the observation that COX-1 knockout mice are resistant to ulceration, not to the possible explanation I suggested. The important point is that prostaglandins are not the only protective mediators in the stomach, and enhanced protection from other systems as a result of developmental changes mean that the data from COX-1 knockout mice cannot be regarded as pivotal evidence one way or the other. I am aware of his data on nimesulide but hesitant to assess their importance because of the incomplete methodological description and the apparently extremely high prostaglandin levels reported in his abstract publication. As for nitric-oxide NSAIDs, only one has been tested in humans. The level of protection seen with that nitric-oxide NSAID and the need to test others which have been much more protective in animals still lead me to the cautious conclusion in the final sentence of the paragraph on those drugs. I would like to take the opportunity to correct two errors that arose in the final version of my article. The recommended daily dose for celecoxib is 200 mg once daily or 100 mg twice daily for osteoarthritis and 100–200 mg twice daily for rheumatoid arthritis. Celecoxib 50 mg was compared with placebo in reference 37 and it was this dose (not 100 mg twice daily as suggested by the legend to table 3) that was better than placebo for some measures only and less effective than higher doses. C J Hawkey School of Medical and Surgical Sciences, Division of Gastroenterology, University Hospital, Nottingham NG7 2UH, UK (e-mail: [email protected]) 1
Riendeau D, Charleson S, Cromlish W, Mancini JA, Wong E, Guay J. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors using sensitive microsomal and platelet essays. Can J Physiol Pharmacol 1997; 75: 1088–95. 2 Glaser K, Sung ML, O’Niell K, et al. Ethodolac selectivity inhibitors prostaglandin G/H synthase 2 (PRHS-2) versus human PGHS-01. Eur J Pharmacol 1995; 281: 107–11. 3 Lipscomb GR, Wallis N, Armstrong G, Rees WD. Gastrointestinal tolerability of meloxicam and piroxicam: a double-blind placebo-controlled study. Brit J Clin Pharmacol 1998; 46: 133–37.
THE LANCET • Vol 353 • April 24, 1999