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NSAIDs, Cox-2 inhibitors, and the gut
ubidecarenone protects against warfarin-induced alopecia. Ubidecarenone was originally developed to improve cardiac metabolism in heart failure. Ubidecarenone may improve mitochondrial respiration in hair roots; alternatively, it may stop hair loss by reducing INR. However, the latter is not likely since neither thromboplastin time or INR changed much. *Tetsuhiko Nagao, Setsuro Ibayashi, Kenichiro Fujii, Hiroshi Sugimori, Seizo Sadoshima, Masatoshi Fujishima Second Department of Internal Medicine, Kyushu University, Maidashi 3-1-1. Higashi-ku, Fukuoka 812-82, Japan
1 Flesch P. Inhibition of keratinizing structures by systemic drugs. Pharmacol Rev 1963; 58: 653-71. 2 Umlas J, Harken DE. Warfarin-induced alopecia. Cutis 1988; 42: 63-64. 3 Spigset O. Reduced effect of warfarin caused by ubidecarenone. Lancet
1994; 344: 1372-73.
NSAIDs, Cox-2 inhibitors, and the gut SIR-The
development of non-steroidal anti-inflammatory drugs (NSAIDs) without gastrointestinal side-effects is being intensely investigated. Selective inhibitors of cyclooxygenase-2 (Cox-2) may well be an important advance in this respect, but more information is needed. In their Aug 26 commentary, Hayllar and Bjarnason discuss the topic and point out that NSAIDs could cause mucosal damage in various ways. However, even only concerning prostaglandin synthesis other aspects should be considered. The ratio of the ICso values for inhibition of Cox-1 and Cox-2 is important, but the effect on Cox-1 should also be examined at concentrations that inhibit Cox-2 more strongly. A good anti-inflammatory/analgesic effect probably needs substantially greater than 50% inhibition of prostaglandin formation, and concentration-response curves for the two enzymes are called for. We have previously discussed several other aspects of NSAID-induced gastric mucosal damage.’ Acidic NSAIDs given by mouth are partly absorbed in the stomach and so produce high local concentrations. Furthermore, bloodborne acidic NSAIDs accumulate in mucosal cells because of the low extracellular pH. An important consideration is the extent of Cox-1 inhibition at the high concentrations produced in the gastric of NSAIDs that give therapeutic mucosa by doses concentrations at target sites. Drugs excreted in the bile have increased exposure to the upper small intestine (and to the stomach if reflux occurs), so producing higher local concentrations for longer. We postulated’ that because prostaglandins might have a longlasting protective effect, tissue damage might be greatest when their synthesis has been inhibited continuously for several hours. In addition to local drug accumulation and tissue re-exposure, the drug halflife in blood determines the time for recovery of prostaglandin synthesis and the resultant renewal of mucosal protection. This action might help to explain why ibuprofen (halflife about 2 h) can cause less gastric mucosal damage than piroxicam (halflife about 2 days), which is a weaker inhibitor of prostaglandin synthesis in human isolated gastric mucosa.’ Studies of nimesulide, which should be added to Hayllar and Bjarnason’s list as a Cox-2 inhibitor, raise other questions. Nimesulide was the first commercially available drug with Cox-2 selectivity," and there is substantial clinical experience with it. Nimesulide had no inhibitory effect on purified Cox-1 from ram seminal vesicles, but it decreased prostaglandin formation by Cox-2 from sheep placentaIn man nimesulide reduced prostaglandin formation by leucocytes (Cox-2), and also to some extent by isolated
gastric mucosa/submucosa2,3 (presumed to be Cox-1). Some important aspects are the amounts of Cox-1 and Cox-2 in human gastrointestinal mucosa, the degree of similarity of the human and animal enzymes and the effects of drugs on them, and the extent of Cox inhibition needed to damage the mucosa or hinder its repair. Some Cox-2 activity might in human gastrointestinal mucosa because of occur leucocytes either present normally or attracted by inflammatory processes. The Cox-2 possibly present in the human mucosal specimens used to study nimesulide2,3 might have been active in vivo or perhaps at least in part only after the surgical and laboratory procedures. Although nimesulide is a well-tolerated and effective NSAID, with some valuable features such as apparent safety in asthmatics who bronchoconstrict with aspirin, it does produce some gastric mucosal damage. The extent to which these features involve selectivity for Cox-2 is not known. It is still too early to decide on the importance of Cox-2 selectivity in avoiding damage to the gastrointestinal mucosa. Furthermore, it remains to be seen whether new Cox-2 inhibitors will be adequately effective NSAIDs and safe for the kidneys, but it is encouraging that nimesulide passes both these tests well. *Alan Bennett,
Ignatius A
Tavares
Department of Surgery, The Rayne Institute, King’s College School of Medicine and Dentistry, London SE5 9NU, UK 1
2
3
Tavares IA, Collins PO, Bennett A. Inhibition of prostanoid synthesis by human gastric mucosa. Aliment Pharmacol Ther 1987; 1: 617-26. Tavares IA, Bishai P, Bennett A. Activity of nimesulide on constitutive and inducible cyclo-oxygenases. Arzneim Forsch Drug Res 1995; 45: 1093-95. Tavares IA, Bennett A. Activity of nimesulide on constitutive and inducible prostaglandin cyclo-oxygenases. Presented at 6th interscience world conference on inflammation, antirheumatics, analgesics, and immunomodulators, Geneva, Switzerland, 1995; abstract 108.
Bjarnason discuss selective inhibition of (COX-2) relative to COX-1 a target in the development of new non-steroidal anti-inflammatory drugs with improved gastrointestinal safety. Low COX-2/COX-1 ratios (ratio of the concentration required to inhibit COX-2 compared with COX-1) do indeed indicate selectivity for COX-2. However, in their table, they have combined results from several test systems for measuring such ratios. In these tests, quite
SiR-Hayllar
and
inducible cyclo-oxygenase-2 (the constitutive isoform) as
different values for the same NSAIDs have been obtained. Sources of variation are between animal and human preparations, between recombinant enzymes and cells, and times of incubation. Even on similar preparations, such as microsomal human enzymes, ratio values depend on time of incubation. For instance, the activity of indomethacin increases several hundred-fold over the first 20 min of incubation (and more so for COX-2) whereas that for ibuprofen does not.’ Thus, compounds with COX-2/COX-1 ratios obtained from different systems should not be directly compared, as Hayllar and Bjarnason have done in their overview. Additionally, they quote a ratio of 0-014 for the pro-drug nabumetone, which is inactive against COX. Its active metabolite (6-methoxy-2-naphthylacetic acid) has consistently demonstrated no selectivity using human recombinant enzymes’ or in human cells in vitro or ex vivo2 or in our own test systems. Hayllar and Bjarnason have concluded that there is no clear relationship between lower COX-2/COX-1 ratios and improved gastrointestinal tolerability among NSAIDs for which epidemiological data are available. However, for the reasons explained above, this conclusion is flawed. A better approach is to establish an overall picture of differential inhibition of COX-1 and COX-2 by NSAIDs. When individual ratios from several systems are examined, it is 1105
Odds ratio for bleeding and perforation (Garcia Rodnguez) or acute gastrointestinal bleedng (Langman), and Committee for Safety of Medicines rank order of serious reports of gut toxicity expressed per million prescriptions in the first 5 years of marketing. Table: Ranking of gastric toxicity in man and COX-2jCOX-1 ratios
clear that the rank order of COX-2 selectivity is broadly similar between systems (table). In fact, when this overall picture is considered, a good relationship is indeed shown between COX-2 selectivity and an improved gastrointestinal side-effect profile as seen from epidemiological studies
(table).
Hayllar and Bjarnason suggest that only very highly selective COX-2 inhibitors now in clinical development are likely to show any advantage in terms of gastrointestinal safety. However, we already know that ibuprofen and diclofenac show the lowest gastrotoxicity in epidemiological studies (see table) even though they have a modest selectivity towards COX-1. Drugs with selectivity towards COX-2, such as meloxicam, have an even lower gastrotoxicity in man, as extensively reported at the XIII European Congress of Rheumatology (EULAR ’95) meeting on June 18-23, 1995, in Amsterdam. Much evidence supports the hypothesis that the unwanted side-effects of NSAIDs are due to their inhibition of COX-1 and that their anti-inflammatory effects are due to inhibition of COX-2. The development of selective COX-2 inhibitors will surely lead to advances in the safe and effective treatment of arthritic patients. John R Vane William Harvey Research Institute, St Bartholomew’s Hospital Medical London EC1M 6BQ, UK
1
2
College,
coating of acrylic resin based on polymethacrylic acid and polyacrylic acid esters (Eudragit L30D). The polymer may contain up to 0-1% monomers (methyl acrylate [MA] and ethyl acrylate [EA]) as impurity because of incomplete polymerisation. van Velzen supports his hypothesis by claiming that no association has been found between fibrosing colonopathy and products which are not prepared with Eudragit (Pancrease, Pancrex V, Creon, and Creon 25000). We report a child receiving Creon, a standardstrength pancreatin, which is not formulated with this coating. A 6-year-old boy presented to his local hospital in April this year with symptoms suggestive of distal ileal obstruction. His mother reported that he had been having increasingly frequent bouts of abdominal pain since returning to lowstrength pancreatin 14 months ago. Previously his progress on high-strength pancreatin (Creon 25000, Solvay Healthcare, 14-18000 units lipase/kg per day) was satisfactory, with height and his weight on the 75th centile and a normal bowel habit. In February, 1994, following concern over high-strength pancreatin preparations, he was dose of 13-15 000 units of later routine abdominal lipase/kg ultrasonography was reported as normal, apart from the suggestion of early fibrotic change in the liver. He was readmitted to this unit in May, 1995, with a right-sided caecal mass. Contrast examination of the colon showed a
returned
to
standard Creon at daily. 6 months
a
Laneuville O, Breuer DK, De Witt DL, et al. Differential inhibition of human prostaglandin endoperoxide H synthase-1 and -2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther 1994; 271: 927-34. 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.
4
Bateman DN. NSAIDs: time to re-evaluate gut toxicity. Lancet 1994; 343: 1051-52. Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxgenase. Proc Natl Acad Sci USA
5
Engelhardt G.
3
1993; 90: 11693-97. Meloxicam inhibits Pharmacol 1994; 47: A98.
preferentially COX-2. Eur J Clin
Fibrosing colonopathy in pancreatin
a
child
on
low-dose
SIR-van Velzen and Jones and colleagues (Aug 19, p 499) of fibrosing colonopathy. van Velzen’s case was remarkable in that stricturing occurred in a child receiving standard-strength pancreatin (Nutrizym GR [Merck], 10 000 units of lipase and 650 units of protease per capsule) rather than one of the high-strength preparations (22-25 000 units of lipase and 1100-1250 units of protease per capsule) implicated in previous reports. van Velzen suggests that the link between the high-strength preparations Pancrease HL, Nutrizym 22, and Panzytrat 25000, which have been previously implicated with colonic strictures, and Nutrizym GR was that all these products have an enteric comment on cases
1106
Figure: Barium follow-through examination showing persistent narrowing of the ascending colon and ulceration of the terminal ileum
1 Flesch P. Inhibition of keratinizing structures by systemic drugs. Pharmacol Rev 1963; 58: 653-71. 2 Umlas J, Harken DE. Warfarin-induced alopecia. Cutis 1988; 42: 63-64. 3 Spigset O. Reduced effect of warfarin caused by ubidecarenone. Lancet
1994; 344: 1372-73.
NSAIDs, Cox-2 inhibitors, and the gut SIR-The
development of non-steroidal anti-inflammatory drugs (NSAIDs) without gastrointestinal side-effects is being intensely investigated. Selective inhibitors of cyclooxygenase-2 (Cox-2) may well be an important advance in this respect, but more information is needed. In their Aug 26 commentary, Hayllar and Bjarnason discuss the topic and point out that NSAIDs could cause mucosal damage in various ways. However, even only concerning prostaglandin synthesis other aspects should be considered. The ratio of the ICso values for inhibition of Cox-1 and Cox-2 is important, but the effect on Cox-1 should also be examined at concentrations that inhibit Cox-2 more strongly. A good anti-inflammatory/analgesic effect probably needs substantially greater than 50% inhibition of prostaglandin formation, and concentration-response curves for the two enzymes are called for. We have previously discussed several other aspects of NSAID-induced gastric mucosal damage.’ Acidic NSAIDs given by mouth are partly absorbed in the stomach and so produce high local concentrations. Furthermore, bloodborne acidic NSAIDs accumulate in mucosal cells because of the low extracellular pH. An important consideration is the extent of Cox-1 inhibition at the high concentrations produced in the gastric of NSAIDs that give therapeutic mucosa by doses concentrations at target sites. Drugs excreted in the bile have increased exposure to the upper small intestine (and to the stomach if reflux occurs), so producing higher local concentrations for longer. We postulated’ that because prostaglandins might have a longlasting protective effect, tissue damage might be greatest when their synthesis has been inhibited continuously for several hours. In addition to local drug accumulation and tissue re-exposure, the drug halflife in blood determines the time for recovery of prostaglandin synthesis and the resultant renewal of mucosal protection. This action might help to explain why ibuprofen (halflife about 2 h) can cause less gastric mucosal damage than piroxicam (halflife about 2 days), which is a weaker inhibitor of prostaglandin synthesis in human isolated gastric mucosa.’ Studies of nimesulide, which should be added to Hayllar and Bjarnason’s list as a Cox-2 inhibitor, raise other questions. Nimesulide was the first commercially available drug with Cox-2 selectivity," and there is substantial clinical experience with it. Nimesulide had no inhibitory effect on purified Cox-1 from ram seminal vesicles, but it decreased prostaglandin formation by Cox-2 from sheep placentaIn man nimesulide reduced prostaglandin formation by leucocytes (Cox-2), and also to some extent by isolated
gastric mucosa/submucosa2,3 (presumed to be Cox-1). Some important aspects are the amounts of Cox-1 and Cox-2 in human gastrointestinal mucosa, the degree of similarity of the human and animal enzymes and the effects of drugs on them, and the extent of Cox inhibition needed to damage the mucosa or hinder its repair. Some Cox-2 activity might in human gastrointestinal mucosa because of occur leucocytes either present normally or attracted by inflammatory processes. The Cox-2 possibly present in the human mucosal specimens used to study nimesulide2,3 might have been active in vivo or perhaps at least in part only after the surgical and laboratory procedures. Although nimesulide is a well-tolerated and effective NSAID, with some valuable features such as apparent safety in asthmatics who bronchoconstrict with aspirin, it does produce some gastric mucosal damage. The extent to which these features involve selectivity for Cox-2 is not known. It is still too early to decide on the importance of Cox-2 selectivity in avoiding damage to the gastrointestinal mucosa. Furthermore, it remains to be seen whether new Cox-2 inhibitors will be adequately effective NSAIDs and safe for the kidneys, but it is encouraging that nimesulide passes both these tests well. *Alan Bennett,
Ignatius A
Tavares
Department of Surgery, The Rayne Institute, King’s College School of Medicine and Dentistry, London SE5 9NU, UK 1
2
3
Tavares IA, Collins PO, Bennett A. Inhibition of prostanoid synthesis by human gastric mucosa. Aliment Pharmacol Ther 1987; 1: 617-26. Tavares IA, Bishai P, Bennett A. Activity of nimesulide on constitutive and inducible cyclo-oxygenases. Arzneim Forsch Drug Res 1995; 45: 1093-95. Tavares IA, Bennett A. Activity of nimesulide on constitutive and inducible prostaglandin cyclo-oxygenases. Presented at 6th interscience world conference on inflammation, antirheumatics, analgesics, and immunomodulators, Geneva, Switzerland, 1995; abstract 108.
Bjarnason discuss selective inhibition of (COX-2) relative to COX-1 a target in the development of new non-steroidal anti-inflammatory drugs with improved gastrointestinal safety. Low COX-2/COX-1 ratios (ratio of the concentration required to inhibit COX-2 compared with COX-1) do indeed indicate selectivity for COX-2. However, in their table, they have combined results from several test systems for measuring such ratios. In these tests, quite
SiR-Hayllar
and
inducible cyclo-oxygenase-2 (the constitutive isoform) as
different values for the same NSAIDs have been obtained. Sources of variation are between animal and human preparations, between recombinant enzymes and cells, and times of incubation. Even on similar preparations, such as microsomal human enzymes, ratio values depend on time of incubation. For instance, the activity of indomethacin increases several hundred-fold over the first 20 min of incubation (and more so for COX-2) whereas that for ibuprofen does not.’ Thus, compounds with COX-2/COX-1 ratios obtained from different systems should not be directly compared, as Hayllar and Bjarnason have done in their overview. Additionally, they quote a ratio of 0-014 for the pro-drug nabumetone, which is inactive against COX. Its active metabolite (6-methoxy-2-naphthylacetic acid) has consistently demonstrated no selectivity using human recombinant enzymes’ or in human cells in vitro or ex vivo2 or in our own test systems. Hayllar and Bjarnason have concluded that there is no clear relationship between lower COX-2/COX-1 ratios and improved gastrointestinal tolerability among NSAIDs for which epidemiological data are available. However, for the reasons explained above, this conclusion is flawed. A better approach is to establish an overall picture of differential inhibition of COX-1 and COX-2 by NSAIDs. When individual ratios from several systems are examined, it is 1105
Odds ratio for bleeding and perforation (Garcia Rodnguez) or acute gastrointestinal bleedng (Langman), and Committee for Safety of Medicines rank order of serious reports of gut toxicity expressed per million prescriptions in the first 5 years of marketing. Table: Ranking of gastric toxicity in man and COX-2jCOX-1 ratios
clear that the rank order of COX-2 selectivity is broadly similar between systems (table). In fact, when this overall picture is considered, a good relationship is indeed shown between COX-2 selectivity and an improved gastrointestinal side-effect profile as seen from epidemiological studies
(table).
Hayllar and Bjarnason suggest that only very highly selective COX-2 inhibitors now in clinical development are likely to show any advantage in terms of gastrointestinal safety. However, we already know that ibuprofen and diclofenac show the lowest gastrotoxicity in epidemiological studies (see table) even though they have a modest selectivity towards COX-1. Drugs with selectivity towards COX-2, such as meloxicam, have an even lower gastrotoxicity in man, as extensively reported at the XIII European Congress of Rheumatology (EULAR ’95) meeting on June 18-23, 1995, in Amsterdam. Much evidence supports the hypothesis that the unwanted side-effects of NSAIDs are due to their inhibition of COX-1 and that their anti-inflammatory effects are due to inhibition of COX-2. The development of selective COX-2 inhibitors will surely lead to advances in the safe and effective treatment of arthritic patients. John R Vane William Harvey Research Institute, St Bartholomew’s Hospital Medical London EC1M 6BQ, UK
1
2
College,
coating of acrylic resin based on polymethacrylic acid and polyacrylic acid esters (Eudragit L30D). The polymer may contain up to 0-1% monomers (methyl acrylate [MA] and ethyl acrylate [EA]) as impurity because of incomplete polymerisation. van Velzen supports his hypothesis by claiming that no association has been found between fibrosing colonopathy and products which are not prepared with Eudragit (Pancrease, Pancrex V, Creon, and Creon 25000). We report a child receiving Creon, a standardstrength pancreatin, which is not formulated with this coating. A 6-year-old boy presented to his local hospital in April this year with symptoms suggestive of distal ileal obstruction. His mother reported that he had been having increasingly frequent bouts of abdominal pain since returning to lowstrength pancreatin 14 months ago. Previously his progress on high-strength pancreatin (Creon 25000, Solvay Healthcare, 14-18000 units lipase/kg per day) was satisfactory, with height and his weight on the 75th centile and a normal bowel habit. In February, 1994, following concern over high-strength pancreatin preparations, he was dose of 13-15 000 units of later routine abdominal lipase/kg ultrasonography was reported as normal, apart from the suggestion of early fibrotic change in the liver. He was readmitted to this unit in May, 1995, with a right-sided caecal mass. Contrast examination of the colon showed a
returned
to
standard Creon at daily. 6 months
a
Laneuville O, Breuer DK, De Witt DL, et al. Differential inhibition of human prostaglandin endoperoxide H synthase-1 and -2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther 1994; 271: 927-34. 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.
4
Bateman DN. NSAIDs: time to re-evaluate gut toxicity. Lancet 1994; 343: 1051-52. Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxgenase. Proc Natl Acad Sci USA
5
Engelhardt G.
3
1993; 90: 11693-97. Meloxicam inhibits Pharmacol 1994; 47: A98.
preferentially COX-2. Eur J Clin
Fibrosing colonopathy in pancreatin
a
child
on
low-dose
SIR-van Velzen and Jones and colleagues (Aug 19, p 499) of fibrosing colonopathy. van Velzen’s case was remarkable in that stricturing occurred in a child receiving standard-strength pancreatin (Nutrizym GR [Merck], 10 000 units of lipase and 650 units of protease per capsule) rather than one of the high-strength preparations (22-25 000 units of lipase and 1100-1250 units of protease per capsule) implicated in previous reports. van Velzen suggests that the link between the high-strength preparations Pancrease HL, Nutrizym 22, and Panzytrat 25000, which have been previously implicated with colonic strictures, and Nutrizym GR was that all these products have an enteric comment on cases
1106
Figure: Barium follow-through examination showing persistent narrowing of the ascending colon and ulceration of the terminal ileum