Influence of Olsalazine on Gastrointestinal Transit in Ulcerative Colitis

Gut: first published as 10.1136/gut.28.11.1474 on 1 November 1987. Downloaded from

Glit, 1987, 28, 1474- 1477

Influence of olsalazine on gastrointestinal transit in ulcerative colitis

S S C RAO, N W READ, AND C D IIOLDSWORTII

Froom t1e Gastrointestisnal Uniit, Royal Hall(tishlire Hospital, .Slljfie ll

SUMMARY The effect of olsalazine on stool output and the transit of a solid radiolabelled meal through the stomach, small intestine and colon was studied in six patients with ulcerative colitis intolerant of sulphasalazine. Olsalazine 250 mg four times daily significantly accelerated gastric emptying (mean±SD; 45-3±24-2 min v 67-3±33-1 min, p<)-05), mouth to caecum transit time (242±41 min i, 325+33 min, p<()-()2) and whole gut transit time (6(05±26 h v 37-8±17-8 h, p<()-()5). No significant changes were seen in mean daily stool weight (215±41 g v 162±62 g) and mean daily stool frequency (2-2±()-6 v 2-4±1-8). None of these patients developed diarrhoea, but acceleration of gastric and intestinal transit m'ay be responsible for the diarrhoea reported in some patients taking this drug.

Sulphalsala.zine (SASP) conisists of 5-arminosalicylic ulcerative colitis all of whom were intolerant of acid (5-ASA) and sulphapyridine linked together by SASP. The clinical detaills of the patients and the http://gut.bmj.com/ ain a(zo bond. 5-ASA has ilOW beenl conlfirimled as the adverse effects previously experienced with SASP beneticial moiety of SASP for the treatment of are shown in Table 1. None of the patients had ulceraitive colitis.' Olsalazine is a forniuliation of previously experienced an exacerbation of diarrhoea 5-ASA alnd has a similar structure to SASP except with SASP. The studies were not placebo controlled that ainother 5-ASA molecule is substitutcd for as the satfety and tolerance of olsalazine wias allso sulphapyridine. This formulation has now been being investigated aind were not randomlised acs the shown to be effective in the treatment of colitis and drug hals a long serumii half life" and it was thought to is tolerated by 85%, of pattients intolerant of SASP.i' be unethical not to prescribe any medication while on October 3, 2021 by guest. Protected copyright. Up to lt0% of patients are reported to haive experi- waliting for the drug to clear from the body. One of enced an exacerbation of diarrhoea while tlkintg the six paitients was taking 1 5 g/day of SASP and one olsalazine,4 however, ain adverse effect only rarely other patient wias tiaking 1 -2 g/day of mesalazine, seen with SASP. In order to study the patho- both of which were discontinued one week before the physiology of the diarrhoea induced by olsalazine, stLidy. The remaining four patients were on no the effect of the drut on stool output and triansit of a longtermii therapy. The first study served as the solid meal through the stomrach, small intestine and colon wats measured in patients with ulceriative Table Clinical (IleUils of inilients withi lcerativei' colitis colitis. I)Oteat' I)Diaacta Ad versrea(uonttlo I)uultion of/ Methods a1 Age eXex(' unt (Sc/t,titt'i uIpIlaa-/IZtul C dit(ose ' (Yr) 1 75 11 Total (?lcsccnt Rash 6 PA I IF.N l S 2 44 F Distal Quiecscenit lDspepCpsia 15 Paired studies were carried out in six paticints with 3 66 1 D)istal Activtc )sspepsia. headacle IX 4 42 M llioctitis Qulliescent i)cprcssion.lhieadialic C1 s)Cepsia A\ddre..ss tot caori-cspaondcntcc I) (' 1) Iaolds%athtl (iastaroillaaitaltaI ta 5 7(0 F Distal OLiecSeClt Iash1 3 6 a3 M D)istal ()utlescnlt i)xspSpia 3 RcitI c rt pubtI licatI ion ') A prt.il19)87. 1474 Gut: first published as 10.1136/gut.28.11.1474 on 1 November 1987. Downloaded from

Infltence( ofolsalaZinle oOil (gst(roinltestinlaI trtitisit ini ulcerativ cColiti1s 1475 control and no nmedicatioIn Wa1s taken except in the concentration defined als a rise of 3 ppFm over three case of patient 3 (Table 1) who w.ls on oral predniso- consecutive 1) miniute recordings. To record whole lone sulphate which was continued. After completion gut transit time, subjects were requested to collect of the first study, the patients were prescribed the results of etcih bowel movemiienit in separate olsalazine (250) mg capsules), the dose of which was polythylene bags for a period of at least 72 hours and gradually increased over the first week to one capsule label them with the date aind time. These were four times daily. After four weeks the meail trainsit weighed and radiographed to determiinle the numiiber study was repeated, giving one capsule with the meal. of markers present. The time taken for the subhject to Sigmoidoscopy and rectal biopsy were done a few void 50)' of markers provided an index of the wthole days before each study to assess the activity of the gut transit. disease. A full blood count, ESR, and liver bio- chemiiistry were also checked before each study. ETIiHICA ( ONSIDERA T ION The methods used for measuring transit were The protocol for the study was approved on 6 identical to those described previously.""' In brief. November, 1984, by the Ethical Committee for the the meal consisted of 150 g mashed potato. 120 g Sheffield Hlealth Authority. All patients gavc written baked beains, and 50 ml water. ....Tc-tin colloid 0(93 informetd coinsent for the studics to be cairr-ied oUt. MBq and 50 segments (2 mm x 3 mm) of radioopaque tubing were incorporated in the mashed potato. All STATISTI(AI. ANALYSIS subjects ingested the meail after an overnight fast and The significance of the differenices in meatsurem11enits gastric emptying was determined from radioactive of gastrointestinal triansit and stool output, between counts recorded every 10( minutes by means of a the first and secontd studies was determiinied usilng single crystail scintillation detector (Type DMI-2, Student's paired t tcst. Nucleair Enterprises Ltd) positioned in front of the stomach over the area of maximum radioactivity. Results The time taken for the radioactive counts to flll to half the initial value (ti ) was taken as aIn index of (iASI RI(' EIMJ YIN(Y(ING ) glstric emptying. Mouth to caecum transit was deter- The half time for gastric emptyiing wits signiticaniitly mined by measuring the time interval between eating accelerated during olsalazine administration (Fig. 1 the meal and a sustained rise in breath hydrogen Tatble 2). 1401 4201 http://gut.bmj.com/

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1476 Rao, Read, (tii(I Holdswortlh

Table 2 Efec(i *Jolsalallzitie(oo ol gasiroitilesilial Ir(als.i. (ltl(I stool outpin pal etiels with ulcerative colitis 300-

Baseline' Ol.()tsatil(' p 5 \250 Gaistric eimptying til (miIn) 67-3±33+ 1 45A3_+4-2 <0-05 Mouth to eIecuni transit (iiilt) 325 ±33 242±41 <0(02 4- ~~~~200- Wholc gut transit (h)()6t5±h6 37X8± 17 8 <00 .05 Mcein dalily stool trcutiucicy 1.4± 1.±2024+06 NS Mcan Clalil stool weigit (g) 162±62 251+±76 NS 3- ~~~~150

RZesults are cxprcssed as meian ±SI). c ~~~~~~~~50 MOUTII TO CAECUM TRANSIT J~~~~~ The mouth to caecum transit time was also significantly faster during ingestion of olsalazine (Fig. 1, 0 ~~~~~~0 Table 2).

WHOLE GUT TRANSIT TIME The time taken to void 50% of markers wa1s signifi- Fig. 2 El feet ofolsalazine ot Sftool outp)t. Bars indicate cantly accelerated during administration of olsalazine tnean±.SEM. (Fig. 1, Table 2). the six patients noine of them reported ain exacerbation of diarrhoea. This could be because the ffact thit STOOI OUTPUT The daily stool weight was higher during olsalazine five patients had distal colitis alnd only one had total treatment in five of the six patients hut the increase colitis. In a large study, exacerbation of diarrhoea during olsalazine treatment was predominiintly seenl was not statistically significant (Fig. 2. Table 2). in patients with total colitis atnd was unusual in those There were no differences in the daily stool fre- ml two Table with distal colitis. Moreover, ingestion of 100 quency between the periods (Fig. 2, 2). dilute duphalac (Duphar) contiaining 20 g lactulose causes diarrhoea in patients with total colitis, but not TOLERANCE OF OLSALAZINE " All six patients tolerated olsalazine without any in patients with distal colitis. These data suggest that while patients with distal can absorb the http://gut.bmj.com/ adverse experience. No haemratological or bio- colitis chemical abnormalities were detected during the increased fluid load from the ileum, induced by be at olsalazine, patients with total colitis fail to do so and study. Five patients continued to in remission may therefore experience diarrhoea. four weeks and the diseatse activity of p-atient 3 (Table A further reasoni for the low incidence of clinically 1) was unchanged. evident ditarrhoea produced by olsaldazine is that I)iscussion intestinal transit is usually slow in patients with ulcerative colitis'' and olsalazine may reduce trainsit on October 3, 2021 by guest. Protected copyright. The results of this study show that olsalazline tacceler- times to values that are very similar to those seen ated transit in normal subjects (mean±SD. mouth to caecum gastric emptying, mouth to caecum anid triansit Iminil whole gut transit 48X8± whole gut transit time of a solid meal. The acceler- 230±65, [hJ a 22 3)." Indeed in those patients who develop hard ated gastric emptying is presumably the result of stools that are difficult to evacutate"'' olsalaznlel direct effect of the drug on gastric motility. The rapid could soften the stool. small bowel transit could be either because of a direct action of the drug on small intestinal contractile The authors to Mrs C Brown and Mrs C activity or drug induced hypersecretion or dimin- aire grateful ished absorption,'' which could enhance propulsion Brtuce for their technical assistance, to Pharmacil by distending the lumen and inducing peristalsis. The Limited for supply of Olsalazine capsules and to Mrs net effect in either case will be atn increased volume of J Wilson for her secretfarial help. Dr Rao is supported fluid entering the colon from the small intestine. This by a grant from the Special Trustees for the Former is consistent with the observation that olsalazinie United Sheffield Hospitals. increases ileostomy effluent.' The normal colon will References accommodate an additional load of 2-3 litres of fluid/day without diatrrhoea" but this capacity may be I Azat Khain ALl. Pins.l. Truclovc SC'. An cxpcrilicnit to reduced in patients with ulcerative colitis.'' In our dctcrniiniic thc activc nioicty of sulphasalazinc. Lancet study, although the stool weight did increase in five of 1977; ii: 892-95. Gut: first published as 10.1136/gut.28.11.1474 on 1 November 1987. Downloaded from

Influence ofolsalazine oni gastroinitestinial tratnsit in iulcer(atilve colitis 1477

2 van Hees PAM, Bakker JH, van Tongeren JHM. Effect 11 Goerg KJ, Wanitschke R. Breilitig K, Franke M. The of sulphapyridine, 5-aminosalicylic acid and placebo in cffect of disodium azodisalicylate (DSA) on water aind patients with idiopathic proctitis: a study to determine electrolyte trainsfer of the rat ileum and colon in vivo the active therapeutic moiety of sulphasalazine. Clit compared with sulfasalazine (SASP), 5-a1mino salicylic 1980; 21: 632-5. acid (SA) and Sulfapyridine. Gastroenterology 1984; 86: 3 Willoughby CP, Aronson JK, Agback H, Bodin NO, 1091. Truelove SC. Distribution and metabolism in healthy 12 Scandberg-Gertzen H1 Jarnerot G, BLukhaive K, volunteers of disodium Azodisalicylate. a potential Lauritsen K, Rask-Madsen J. Effect ot alzodisail sodiulil therapeutic agent for ulcerative colitis. Giit 1982; 23: and sulphasalazine on ileostomV OLItpLut of fluid, PGE, 1081-7. and PGF2, in suLbjects with a permainent ileostonixy. (Glt 4 Selby WS, Barr GD, Ireland A, Mason CH, Jewell DP. 1986; 27: 1306-1 1. Olsalazine in active ulcerative colitis. Br Med J 1985; 13 Debongnie JC, Phillips SF. Capacity ot humnan colon to 291: 1373-5. absorb fluid. Gastroenlerologv 1978; 74: 698-703. 5 Sandberg-Gertzen H, Jarnerot G, Kraaz W. Azodisal 14 Rask-Madsen .1. Functional alterations in ulcerative sodium in the treatment of ulcerative colitis. A study of colitis. In: Robinson JWl, ed. Intiesiinitil ioll tralnspor1t. tolerance and relapse-prevention properties. Gastro- Lancaster: MFIP Press 1976: 381-97. 1986; 90: 1024-30. enterology 15 Rao SSC, Read NW, tloldsworth CD. Is a failurc of 6 Rao SS, Cann PA, Holdsworth CD. Clinical experience colonic salvage of carbohydrate responsible for diarr- of the tolerance of Mesalazine and Olsalazine in patients hoea in ulceraitive colitis'? [Abstracti. (hut 1986; 27: intolerant of Sulphasalazine. Scand J Gastroenterol A 1257. 1987; 22: 332-6. 7 Schwartz AG, Targen SR, Saxon A, Weinstein WM. 16 Rao SSC, Rcad NW, Holdsworth CD. Gastrointestinal Sulfasalazine induced exacerbation of ulcerative colitis. transit aind stool output in the pathophysiology of N Engl J Med 1983; 306: 409-12. diarrhoea in ulcerative colitis (UC) [Abstract]. Clin Sci 8 Ring FA, Herschfield MB, Machin GA, Scott RB. 1986; 72: suppl 15: 41. Sulphasalazine induced colitis complicating idiopathic 17 Lennard-Jones JE, Langman MJS, Jones FA. Faecal ulcerative colitis. Can Med AssocJ 1984; 131: 43-5. stasis in procto colitis. (lit 1962; 3: 301-5. 9 Read NW, Miles CA, Fisher D, et al. Transit of a meal 18 Hendcrson NP. Whtat is ulceriative colitis'? Lancet 1954; through the stomach, small intestine and colon in i: 159-60. normal subjects and its role in the pathogenesis of 19 Lennard-Jones JE, Cooper GW, Newell AC, Wilson diarrhoea. Gastroenterology 1980; 79: 1276-82. CWE, Avcry Jones F. Observations on idiopaithic 10 Cann PA, Read NW, Brown C, Hobson N, Holdsworth procitis. Gult 1962; 3: 201-6. CD. Irritable bowel syndrome: relationship of disorders 20 Jalan KN, Walker RJ, Prescott RJ, Buttcrworth S1TG,

in the transit of a single solid meal to symptom patterns. Smith AN, Sircus W. Faccal stasis aind diverticular http://gut.bmj.com/ CGlt 1983; 24: 405-1 1. discase in ulcerative colitis. Glut 1970(; 11: 688-96. on October 3, 2021 by guest. Protected copyright.