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`
`journal of the British Society of Gastroenterology
`
`Editorial
`
`461 (cid:9) Short rapid communications
`
`Leading article
`
`462 (cid:9) Sulphasalazine in ulcerative colitis: in memoriam?" Hayllar, I Bjarnason
`
`Alimentary tract
`
`Liver, biliary,
`and pancreas
`
`464 (cid:9) Histamine concentration of gastric mucosa in Helicobacter pylori positive and negative children
`D M M Queiroz, E N Mendes, G A Rocha, A J A Barbosa, A S T Carvalho, J R Cunha-Melo
`467 (cid:9) Diagnostic efficiency of an ultrarapid endoscopy room test for Helicobacter pylori A V Thillainayagam,
`A S Arvind, R S Cook, I G Harrison, S Tabaychali, M y G Farthing
`470 (cid:9) Effect of cisapride on delayed gastric emptying in gastro-oesophageal reflux disease G,J Maddern,
`G G Jamieson, I C Myers, P_J Collins
`475 (cid:9) Hyperglycaemia stimulates pyloric motility in normal subjects R Fraser, M Horowitz, J Dent
`479 (cid:9) Preoperative evaluation of gastric cancer by endoscopic ultrasound K Akahoshi, T Misawa, H Fujishima,
`Y Chijiiwa, A Maruoka, A Ohkubo, 11 Nawata
`483 (cid:9) Gastrointestinal adaptation to diets of differing fat composition in human volunteers K M Cunningham,
`J Daly, M Horozvitz, N W Read
`487 (cid:9) HLA association with dermatitis herpetiformis is accounted for by a cis or transassociated DQ heterodimer
`M A Hall, J S S Lanchbuiy, W j Bolsover, K I Welsh, P j Ciclitira
`Factors influencing postoperative recurrence of Crohn's disease in childhood A M Griffiths, D E Wesson,
`B Shandling, M Corey, P ill Sherman
`496 (cid:9) Structural heterogeneity of faecal ot i antitrypsin shown by immunoblot analysis in patients with Crohn's
`disease F Boege, W Fischbach
`500 (cid:9) Primary bile acid diarrhoea without an ileal carrier defect: quantification of active bile acid transport across
`the ileal brush border membrane A y13 van Tilburg, F W M de Rootj, J W 0 van den Berg,
`M van Blankenstein
`504 (cid:9) The presence in experimental animals of a colon specific Mr 40 000 protein(s) with relevance to ulcerative
`colitis L Biancone, L S Wise, K M Das
`509 (cid:9) How prevalent is cancer family syndrome? F Kee, B j Collins
`513 (cid:9) Prognosis in familial non-polyposis colorectal cancer F Kee, B j Collins, C C Patterson
`517 (cid:9) Local eradication of rat colon cancer with photodynamic therapy: correlation of distribution of
`photosensitiser with biological effects in normal and tumour tissue H Barr, P Chatlani, C J Tralau,
`MacRobert, P B Boulos, S G Bown
`
`491 (cid:9)
`
`524 (cid:9) Focal nodular hyperplasia of the liver: results of treatment and options in management/ A Pain,
`A F S Gimson, Roger Williams, E R Howard
`528 (cid:9) Effect of a new synthetic ascorbic acid derivative as a free radical scavenger on the development of acute
`pancreatitis in mice A Nonaka, T Manabe, 7' Tohe
`533 (cid:9) Molecular differences between human and experimental pancreaticobiliary diversion-induced rat
`pancreatic neoplasia 1' A Hall, N R Lemoine, G Murphy, R II Dowling
`536 (cid:9) Persistence of symptoms after gall bladder clearance with cholecystolithotripsy S H Lee, I I J Burhenne
`539 (cid:9) Gall stone disease in African patients with sickle cell anaemia: a preliminary report from Yaounde,
`Cameroon R F Billa, S Bizvole, A G juimo, B I Bejanga, K Blacken
`
`S42 (cid:9) Case reports Letters to the editor Book review Notes Correction
`
`A5S3 British Society of Gastroenterology
`
`BRITISH MEDICAL ASSOCIATION TAVISTOCK SQUARE LONDON WC1H 9JR
`This material was copied
`atth
`
`Ex. 1061 - Page 1
`
`

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`•
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`,,,, 777. (cid:9)
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`, , . 777,7777,-!•77.77,...! . .... ,nr• (cid:9)
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`. ...
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`This material was copied
`MI RAr,'Lb r1 maybe
`
`Pi
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`refl
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`Published by British
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`or •• (cid:9)
`
`. (cid:9)
`. •
`
`""""""rt".
`
`Leading article
`
`Gut, 1991, 32, 462-463
`
`Sulphasalazine in ulcerative colitis: in memoriam?
`
`While the aetiology of ulcerative colitis remains unknown,
`treatment is empirical. Sulphasalazine is effective in control-
`ling moderately active disease' and in prolonging remission.'
`Speculation about the drug's mode of action has continued
`since its introduction in the 1940s for use in patients with
`rheumatoid arthritis. Received wisdom holds that in ulcera-
`tive colitis the reduction of the azo bond by colonic bacteria
`releases the active moiety of sulphasalazine, 5 aminosalicylic
`acid (5ASA) which acts topically, and sulphapyridine which
`is rapidly absorbed causing side effects. Various pharma-
`cological means have been developed for delivering pure
`5ASA to the colon since uncoated 5ASA is rapidly absorbed
`and is thus ineffective. Three formulations are currently
`licenced in the United Kingdom for use in ulcerative colitis,
`mesalazine (Asacol, a pH sensitive polyacrylic resin coating of
`5ASA, and Pentasa, which contains ethylcellulose coated
`1 mm granules of 5ASA) and olsalazine (Dipentum, two
`5ASA molecules joined by an azo bond); mesalazine may have
`captured as much as 30% of the market from sulphasalazinc.
`Several assumptions underly these new agents. Firstly,
`that the side effects of sulphasalazine are due to the sulpha-
`pyridine molecule alone. Secondly, that unmetabolised
`sulphasalazine and sulphapyridine have no activity in ulcera-
`tive colitis. Thirdly, that sulphasalazine is simply a pro-drug,
`a means of delivering 5ASA which overcomes the rapid
`absorption of 5ASA from the small intestine. Fourthly, that
`where sulphasalazine is ineffective this is due to insufficient
`concentrations of 5ASA reaching the site of disease activity.
`The side effects of sulphasalazine (incidence 15-30%) are
`dose dependent (dyspepsia, nausea and vomiting, headache,
`and reversible oligospermia) or idiosyncratic (fever and
`neutropenia, inflammatory reactions affecting lung, liver,
`myocardium, and pancreas): Pure 5ASA preparations by
`eliminating sulphapyridine should prevent these unwanted
`effects. Adverse responses to sulphasalazine, however, have
`also been seen with 5ASA products, although at least 70% of
`sulphasalazine intdlerant patients will find 5ASA products
`acceptable.'
`Changing the delivery system from an azo bond to mech-
`anical or pH dependent release has two important implica-
`tions. Firstly, it reduces the effectiveness of colonic 5ASA
`delivery from 80-98% to 40-95% and, secondly, it alters
`5ASA pharmacokinetics. The ethylcellulose coating of
`Pentasa granules dissolves gradually during passage through
`the small bowels while the resin coating of Asacol may allow
`for rapid release of free 5ASA (at an appropriate pH). Free
`5ASA is acetylated both in the small bower and colonic
`epithelium.' In the small bowel this process can be overloaded
`by rapid release of 5ASA. This allows appreciable amounts of
`non-acetylated 5ASA to be absorbed, which is clearly nephro-
`toxic in experimental animals, while acetylated 5ASA is not.'
`4 Aminosalicylic acid (para aminosalicylic acid previously
`used in the treatment of tuberculosis) and phenacetin were
`important causes of crystalluria, haematuria, and nephritis;
`the structure and metabolism of these drugs are closely
`similar to non-acetylated 5ASA. Recent reports of interstitial
`nephritis,' including three biopsy proved cases (Committee
`on Safety of Medicines, R R Shah, personal communication),
`(cid:9) and
`nephrotic syndrome,'" pyuria," and rises in urea.
`creatinine after mesalazine treatment are therefore par-
`
`ticularly worrying. A recent bulletin from the Committee on
`Safety of Medicines highlights nine reports of serious nephro-
`toxic reactions associated with the use of mesalazine" and
`concludes that the drug is best avoided in patients with
`established renal impairment. Greater recognition of these
`side effects (avoided with sulphasalazine or olsalazine because
`of the completeness of 5ASA acetylation in the colon)
`prompted one group to suggest monitoring renal function
`during mesalazine treatment.''
`Early studies showed a dose-response relation between
`sulphasalazine and its efficacy in moderately active disease"
`and in maintaining remission' with daily doses of between 1
`and 18 g." Because of dose dependent side effects a compro-
`mise of giving 4 g daily for active disease and 2 g for
`maintenance treatment is common, providing 1600 mg and
`800 mg 5ASA respectively. If sulphasalazine is merely
`delivering 5ASA to its site of action it should follow that the
`higher the local concentration of 5ASA the more effective the
`treatment. While, however, studies have shown 5ASA com-
`pounds to be as effective as therapeutic doses (3-4 g) of
`sulphasalazine none has been superior even with doses of
`5ASA equivalent to 12 g sulphasalazinc, suggesting there is
`more to the action of sulphasalazine than 5ASA.
`In rheumatoid arthritis the sulphapyridine component of
`sulphasalazinc has been shown to have disease modifying
`(immunomodulatory) activity,' requiring at least six weeks
`to take effect; nevertheless, it is precisely the systemic and
`delayed onset of action of sulphapyridine that has not been
`studied in patients with ulcerative colitis in contrast to its
`documented inefficacy when given topically in the short
`term.'"
`It is interesting to compare the actions in vitro of sulpha-
`salazine and 5ASA on the inflammatory cascade. After tissue
`damage there is disruption of cell membranes with release of
`arachidonic acid, the late of which is determined by the
`relative activity of cyclo- and lipoxygenase. The former
`generates prostaglandins, which may promote healing, the
`latter produces leucotrienes, which are potent neutrophil
`chemoattractants and vasoconstrictors and may cause further
`damage. There is appreciable overproduction of leucotrienes
`in active disease and some increase in concentrations of
`prostaglandins." Work in vitro suggests that therapeutic
`concentrations of sulphasalazine inhibit lipoxygenase more
`potently than 5ASA.'' In contrast, both agents block cyclo-
`oxygenase (a potentially serious effect seen in exacerbations
`of inflammatory bowel disease after ingestion of non-steroidal
`anti-inflammatory drugs)." Sulphasalazine mediated inhibi-
`tion of prostaglandin degradation, however, causes a net
`increase in tissue prostaglandin level concentrations'' and
`thus promotes healing.
`Neutrophils are the chief effector cell in tissue destruction
`in ulcerative colitis, causing damage by lysosome release and
`the generation of damaging oxygen free radical species."
`Sulphasalazine, 5ASA, and sulphapyridine are all effective
`free radical scavengers." Sulphasalazine, however, alters
`neutrophil function in ways distinct from ASA and sulpha-
`pyridine." Sulphasalazine, but neither of its metabolites, has
`appreciable inhibitory effects on B lymphocytes in vitro
`reducing immunoglohulin synthesis at pharmacological
`doses.' Again in contrast to 5ASA, sulphapyridine and
`
`This material was copi ed
`
`Ex. 1061 - Page 3
`
`

`

`4.'"":!?••"V".'
`
`Sulphasalazine in ulcerative colitis: in memoriam?
`
`463
`
`sulphasalazine inhibit natural killer cell activity," while at
`high doses sulphasalazine has profound suppressive effects
`on T and B cell mitogen induced lymphocyte transformation
`of murine spleen cells." Thus many observations show that
`sulphasalazine, sulphapyridine and 5ASA have different and
`potentially beneficial actions in ulcerative colitis in con-
`trolling inflammation.
`The use of steroids delayed the widespread adoption of
`sulphasalazine in rheumatoid arthritis for over 30 years."
`Before sulphasalazine is discarded as an outmoded treatment
`for ulcerative colitis in favour of more modern 5ASA
`compounds, a greater understanding is needed of the ways in
`which these drugs work, lest in throwing out the bathwater
`we lose rather more of the baby than expected.
`
`J HAYLLAR
`I BJARNASON
`
`Clinical Research Centre,
`Watford Road, Harrow,
`Middlesex HA! 3U1
`
`Correspondence to: Dr J Hayllar.
`
`1 Baron JH, Connell AM, Lennard-Jones JE, Avery-Jones F. Sulphasalazine and
`salicylazosulphadimidine in ulcerative colitis. Lancet 1962; i: 1094-6.
`2 Khan AKA, Howes DT, Piris J, Truelove SC. Optimum dose of sulphasalazine
`for maintenance of remission in ulcerative colitis. Gut 1980; 21: 232-40.
`3 Das KM, Eastwood MA, McManus JPA, Sirens W. Adverse reactions during
`sulphasalazine treatment and the relation with drug metabolism and acetyla-
`tor phenotype. N Engl j Med 1973: 289: 491-5.
`4 Austin CA, Cann PA, Jones TH, Holdsworth CD. Exacerbation of diarrhoea
`and pain in patients treated with 5-aminosalicylic acid for ulcerative colitis.
`Lancet 1984; i: 917-8.
`5 Rasmussen SN, Bondeson S, Hivdberg EF, a al. 5-Aminosalicylic acid in a
`slow release preparation: bioavailability, plasma level and excretion in
`humans. Gastroenterology 1982; 83: 1062-70.
`6 Pieniaszek HJ, Bates TR. Capacity limited gut wall metabolism of 5ASA,
`therapeutically active metabolite of SZP in rats. .7 Pharm Sci 1979; 68:
`1323-5.
`7 Ireland A, Priddle JD, Jewell DP, Acetylation of 5ASA by isolated human
`colonic epithelial cells. Clin Sci 1990; 78: 105-11.
`
`8 Calder IC, Funder CC, Green CR, Ham KN, Tange TD. Comparative toxicity
`of aspirin and phenacetin derivatives. BM1 1971; ii: 518-21.
`9 Ruf-Ballauf W, Hofstadter F, Krentz K. Akute interstitielle nephritis durch
`5-aminosalicylaure? Internist 1989; 30: 262-4.
`10 Novis BH, Korzets Z, Chen P, Bernheim J. Nephrotic syndrome after
`treatment with 5-aminosalicylic acid. BMj 1988; 296: 1442.
`11 Tremaine WJ, Schroeder KW. Urinary sedimentary abnormalities in patients
`on long term oral 5rASA for chronic ulcerative colitis. Gastroenterology 1988;
`94: 465.
`12 Riley SA, Mani V, Goodman MJ, Herd ME, Dutt 5, Turnberg LA.
`Comparison of delayed-release 5-amino salicylic acid (mesalazine) and
`sulphasalazine as maintenance treatment for patients with ulcerative colitis.
`Gastroenterology 1988; 94: 1383-9.
`13 Committee on Safety of Medicines. Current Problems 30 December 1990.
`14 Bachrach WH. Sulphasalazine: I An historical perspective. Am. Gastroenterol
`1988; 83: 487-96.
`15 Neumann V, Taggart A, LeGallez P, Astbury C, Hill J, Bird H. A study to
`determine the active moiety of sulphasalazine in rheumatoid arthritis.
`j Rheumatol 1986; 13: 285-7.
`16 Klotz U, Maier K, Fischer C, Heinkel K. Therapeutic efficacy of sulpha-
`salazine and its metabolites in patients with ulcerative colitis and Crohn's
`colitis. N Engl.? Med 1980; 303: 1499-502.
`17 Svartz N. Sulphasalazine: II Some notes on the discovery and development of
`salazopyrine. Am j Gastroenterol 1988; 83: 497-503.
`18 Lauritson K, Laurson LS, Bukhave K, Rask-Madsen J. In vivo profiles of
`eicosanoids in ulcerative colitis, Crohn's colitis and Clostridium diffictle colitis.
`Gastroenterology 1988; 95: 11-7.
`19 Nielsen ST, Beninati L, Buonatao CB. Sulfasalazine and 5ASA inhibit
`contractile leukotriene formation. Scand j Gastroenterol 1988; 23: 272-6.
`20 Kaufman HJ, Taubin HL. Non steroidal anti-inflammatory drugs activate
`quiescent inflammatory bowel disease. Ann Intern Med 1987; 107: 513-6.
`21 Hoult JRS, Moore PK. The effects of sulphasalazine and its metabolites on
`prostaglandin synthesis inactivation and actions on smooth muscle. Br.
`Pharmacol 1980; 66: 719-30.
`22 Weiss S J. Tissue destruction by neutrophils. N Engl j Med 1989; 320: 365-76.
`23 Aruoma 01, Wasil M, Halliwell B, Hoey BM, Butler J. The scavenging of
`oxidants by sulphasalazine and its metabolites. Biochem Pharm 1987; 36:
`3739-42.
`24 Molin L, Stendahl 0. The effect of sulphasalazine and its active components on
`human polymorph nuclear leukocyte function in relation to ulcerative colitis.
`Acta Medica Scandinavica 1979; 206: 451-7.
`25 Comer SS, Jasin HE. In vitro immunomodulatory effects of sulphasalazine and
`its metabolites./ Rheumato/ 1988; 15: 580-6.
`26 Gibson PR, Jewell DP. Sulphasalazine and derivatives, natural killer activity
`and ulcerative colitis. Clin Sci 1985; 69: 177-84.
`27 Sheldon P, Webb C, Grindulis KA. Effect of sulphasalazine and its metabolites
`on mitogen ihduced transformation of lymphocytes - clues to its clinical
`action. Br j Rheumatol 1988; 27: 344-9.
`28 McConkey B. History of the development of sulphasalazine in rheumatology.
`Drugs 1986; 32 (suppl 1): 12-7.
`
`This material was copi ed
`at the NLM and may be
`Subject US Copyright Laws
`
`Ex. 1061 - Page 4
`
`

`

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`
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`F0005 GUT
`1991 VOLUME 32 ISSUE 5
`SISAC
`
`111111111111111
`0017-5749(1991)32 5-L
`Ref:3042366/01
`
`The future for your
`ulcerative colitis patients
`
`
`Effective acute and maintenance therapy"' • Available as tablets and suppositories
`n Free from sulphapyridine -associated side effects
`
`•
`
`IIIIIIII
`11111111 ~ 1111111 (cid:9)
`Mesalazine* (s-aminosalicylic acid)
`Helps free your ulcerative colitispatients
`
`Prescribing Information:
` Presentation: Asaid. Tablets, PL
`containing 400 nig mesalazine (5-
`0002/0173, each
`arninosalicylic acid) coated with a pH-dependent
`acrylic based resin (Eudragit S) formulated to release the active ingredient in the
`terminal ileum and colon. Blister packs of 12o (6 x 2o), £28.58. Asacol' Suppositories
`25o mg, P1.0002/01 c8, each containing 25o mg n)esalazine. 2o, f,;6.5o. 'Asacol'
`Suppositories Soo mg, PL 0
`Uses: Treatment of .
`002/o195, each containing coo mg mesalazine. lo, L6.50.
` mild to moderate acute exacerbations of ulcerative colitis.
`Maintenance of remission of ulcerative colitis. Suppocitories particularly appropriate
`for distal disease. Dosage and administration:
` Adult;: Tubleis: Acute di scare: 6 tablets a
`day, in divided doses, with concomitant corti
`, v;teroirl then py wh,,r, c
`indicated. Maintenance therapy: ,„t,, 6 tablets a day, in d (cid:9)
`liically
`i vidi•ili,.;,. (cid:9)
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`d
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`recommendation. Contra-indications: A history of ',,111,111711y 1, , ',.,Ii, yl.ilf-; ',,•,/,'),•
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`t in eldelyaft;
`renal impairment
`
`or siolill'
`mmended inpatients with renal impairment. Cauuon in patien
`
`Not recommended
`(cid:9) or proteinuria. Avoid during pregnancy and lactation. Cautioll
`blood urea
`
`Nausea' ' obi
`tion is normal. Do not give tablets with lactulose Aiorhoe
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`preparations which headlaocwhee.r EsxtaocoselrbpatHio. IlAodfvse,rs
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`

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