CANADIAN FOUNDATION FOR ILEITIS AND COLITIS

Can you tell me about medication?

Tl IE PATIENT WITI I INFLA MMATORY

bowel disease (IBD) app:oaches decisions ahout medical treatment with a healthy skeptic ism. The diagnosis of IBD has been de layed weeks to months whi le abundant (and somet imes disa­bling) symptomatology is ascribed, first to an infectious e tiology, and then (with negati ve cultures) to a functiona l disorder of the bowel, with strong im ­plication that the patient is coping badl y with lifo's stresses. After a series of invasive, and sometimes uncomfort­able, investigat ions lead to a d iagnosis of IBD, the pa tient h.:is Lo rationalize afflictio n wi th a chronic disease, the cause of which is unknown. When the understandably pess imisLi c patients with newly diagn osed IBD nre adv ised that the ir treatment wi ll be symp­tomatic, ie , that when they arc quite sick they will ge t a lot of trcanncnt and when they arc quite wel l they wil l get none, discouragement is likely to in ­crease , at times approaching despa ir.

l t is extremely impo rtant in setting up a long term treatment plan for this chronic disease that the phys ic ian shows the good confidence that comes

T ERENCE L MCX.lRE, MD, FRC PC

from a full unde rstanding o ( the medi­cal theraries availahle and transfers this confidence to the pat ients by care­ful discussion of the trea tment options. It is equa lly important that the patients unde rsrnnd the e ffects and the side ef­fects of the treatment used so that in partnership with the ir ph ysician, they can come to the right conclusions about the effectiveness of the ir treat­ment.

Med ical trea tment never cures lBD, but it is dramatically effec tive. Thirty years ago the 10-year cumulative sur­vival ra te with both ulcerat ive colitis and Crohn's disease was under 80%; now it is over 9 5% and differs minim::il ­ly from survival in the general popula­tion ( l ). Equally important, but much harde r to mensure, is t he dramatic im­pact on patient symptoms. The phys ic ian will believe that a me<lical therapy which lo wers disease activity index is reduc ing the inAammarory process in the bo wel. The patient with IBO will come to know that the the rapies which reduce disease act iv ity reduce pa in and suffering. Those the rapies which have proven impact on

Division ofGasirnencerolvgy, Sc Michael's Hospital, Toronto, Ontario Correspondence and reprints: Dr T L Moore, Division of Gasiroenterology, St Michael's

Hospical, Toronto, Oncariv M5B IWB

CAN ] GASTROENTEROL Vm6 No 4 JUI Y/AUGUST 1992

disease activity and which , a lo ne or in concert , arc the present treatment for patients with IBD, arc reviewed he re. Newer drugs, which have a lready had a proven impact on disease activity in cl inical trials and arc now heing in tro­duced into everyday therapy, will also be briefly acknowledged.

STEPS IN THE SYMPTOMATIC TREATMENT OF IBD

The investigations of a patient with newly d iagnosed IBD are designed co dete rmine the d isease severity (both rhe extent and the activity o( the dis­ease process) . T reatment decisions rcAecr that severi ty. Because disease seve rity changes dramatical ly (and usua lly unpred ictahl y) it is good therapeutic strategy from rhe first visit ro decide wi th the patient not on ly what the present treatment will be, but also what change~ in treatment will be ava ilable as the disease responds (or worsens). A ll patients with I BD should receive ad vice on nu tri t ion; most will requi re long periods of treatment with modestly active, but minimally toxic , 5-aminosal icylic acid (5-ASA) com­pounds; many will benefit from short courses of very active, bur also very toxic, corticosteroid preparation s; and a few will e ither not tole raLe or fa il to

235

MOOIU·

D DD Nutrition 5-ASA Steroids Steroid Surgery

• Alternatives·

Disease Severity

Figure I ) Seeps in tl1e sym/)wmaiic treatmenc uf i11fkn11111awry bowel disease

rcsponJ rti stcroiJ s anJ may benefit from steroid 'alternatives', if surgical treatment of the ir disease is s1 ill not indicated (Figure I). All patients will climb up and down these treatment steps many times as the severi ty of their IBO fluctuates from year to yc,ir.

NUTRITION By the time lBD is d iagnosed, most

patients already have some nutritiona l deficiencies. Those patients whose dis­ease is severe enough Lo rc4uirc hospi­talization usually have experienced weight loss (two-thi rds of C rohn's dis­ease patients; one-half of ulcerative coli tis patients), wi th growth fa ilure in one-third of the pedi,mic: age group (2).

Of the many possih le causes fnr this malnutrition, by far the most important is food avoidance hy the p,1tient who realizes that symptoms arc often worse after earing (sitophobia).

It has been standard practice to in­corporate elimination d iets into the medical managemcnr of IBO. For ex­ample, patients wi th col iris arc advised to avoid milk and ice cream; patients with Crohn's disease of the small bowel who have pain after eating benefit from a restricted fibre diet . T he concept of 'resting the bowel' gained greate r crcdibili1y when it was shown in cl ini­cal tria ls that an clemenwl cntcra l diet was as effect ive as mid-range steroid treatment in helping lo remi t Crohn's disease over rwo- or four-week periods. And 'total bowel rest', with total parenteral nutri tion (TPN), rem itted C rohn 's disease in 60% of cases (3 ). N utritional recovery was virnmlly as­sured with comprehensive entcral or

parenteral feeding because adequate calorics could be guaranteed. But the CLmccpt of 'bowel rest' was clearly flawed. Paricnts with colitis (Crohn's disease or ulcerative coli tis) were less I ikcly to remi t thei r disease and patients who went into remission usual ly relapsed when they returned to

a normal diet . Lt is now recognized that bowel rest

can be equated to bowel atrophy - that the bowel lining, especially in the large bowel, th ins and works less effectively when nutrients (food) no longer arc exposed to it . The mechanisms of this atrophy arc complex, involving local changes in nerves, hormones and the immune system. This is forcing drama­tic changes in the thinking about nutri­tion in IBO treanncnt. Food is be ing thought of much like drug the rapy, i.e , high amounts of specific nutrition can have a pharmacological effect on bowel inflammatio n. Studies by G reenberg ( 4) c learly showed that defined formula diets, taken by mouth, were as efficient as TPN in remitting acute C rohn's dis, case, emphasizing that complete bowel rest was not necessary. Furthermore , studies with short chain fatty acids (produced when colonic bacteria fer­ment fibre), fish oils, food nucleot ides, etc, arc not only expanding knowledge of bowel nutrition but also unravelling the mysteries nf bowel inflammation and the body's immune re ·ponscs.

For t he present, nutrition is used primarily to replete nutritional deficits. In the future 'food pharmacology' wi ll be shown Lo reduce disease activity and will be a cornerstone in the ambulatory management of patients with IBO.

5-AMINOSAUCYUC ACID S ulphasalazinc (Salazopyrine; Phar­

mac ia) was used co treat active colitis for 40 years before it~ effi cacy wr1s con­firmed for both ulcerative coli tis (5) and C rohn\ col iris (6). Sulphasa lazine is a lso being uscJ to treat Crohn \ db­case of the small bowel, even though efficacy cr1nnot be considered proven. C lassic Bri tish clinical Lrials proved the usefulness of sulphasr1lazinc in main­taining remissions of ulcerative colitb in the '60s (7,8). But sulphasalazine has not shown benefit in ma intaining remissions of Crohn's disease (6). T he use of sulphasalazinc has been limited by side cffecth (nausea, imcrfcrencc with food folatc absorption, suppres­sion of sperm counts, hemolysis, ere) in 15% of patients. The studies of Azad Khan demonstrated tha t when ~ul­pbasalaz inc was cleaved to its two me­taboli tes (5-ASA and sulphapyridinc, 5-ASA was the active moiety and sul­phapyrid ine was considered to he an inactive carrier (9). Forrunatcly, the sulphapyridinc mo iety was rcsponsihlc for most of the side effects (Figure 2).

Topical 5-ASA {given by sup­pository o r enema) was shown LO he effective in the treatment of active dis­tal colitis ( LO), even in patients in­tolerant to sulphasalazinc, and is now

the initia l treatment of choice for patients with active colitis confined to

the left side of the colon ( 11 ). But pat ien ts with inflammation higher up in the colon or in the d istal small bowel requi re an oral preparation. This in i­tia lly pre ented a problem Rs 5-ASA is readily absorbed in the proximal small bowel and unavr1 ilablc for more d1stRl, ropical effect. Fortunately the pharma­ceutical industry responded ro this challenge by devising delivery systems for oral 5-ASA that release maximal concentrations of 5-ASA along thr small bowel (Pcntasa; Nord ic), in the ileocccal a rea (Salofalk; lncerfalk, Mesasal; S mithKlin.c Beecham), or colon (Asacol; Norwich Eaton, Dipen­tum; Pharmac ia).

There is not yet agn:emcnt on how wpicr1 I 5-ASA works to hlock inflam­mation in the bowel wall. lt may block prostaglandin synthesis or scavenge oxygen free rad icals in the howcl wall ,

236 C AN J GASTROENTEROL VOL 6 No 4 Jut Y/AUGUST 1992

or inhibit lcuko tricnc forma t inn by hlockmg rhc mernhnlism of arnchido­nic ac id in white hlood cells ( 12). T o deliver maximal conccnt ra tiom of 5-ASA Ln the colon, the drug 1s coated with an ac rylic rnlymer (Asacol, Salofalk, Mesa al) or linked to a second molec ule of 5-ASA ( Dircntum ) rc lcas­mg the drug mto the distal ileum and colo n . About ha lf of the drug is ah­w rhed ,md can rarely g ive rise to those side effects attriburnhlc to sa l icylatcs (headache, rhinitis, urt1o m a, asthma, hair loss, e tc). The dimcric (double molecule ) 5-ASA drug (D1re ntum ) b

muc h more likely ( l 5% ) to produce d1arrhc;1 th,m the other oral 5-ASA prepa rations (4% ), hccausc of an effect on sma ll bowe l secre tion unique to that dimc ric formulation .

The re is almost universal agreement on the effec ti veness of the new oral 5-ASA drugs in trent ing first a ttacks of ulcerative colius ( I 3) and 111 mainta in­ing remissio ns of ulcerati ve colitis. O ral 5-ASA rrcparatiom have equiva lent effec ti veness l e) sulrhasalazinc with fewer side e ffects, hut arc more thnn twice as expensive. They have a lready become the drugs of choice in racic nts with diffuse, mildly acti ve or quiescent ulcerative colitis who arc in tolerant to ,ulphasalazme.

It is muc h harde r to prove drug ef­ficacy 111 Crohn\ disease tha n It is in ulcerative colitis. C lin ic.i i n:m1ss1on from C rohn \ disease is very diffic ult to define and even more difficult to achieve. It 1s becoming obvio us from uncontrolled clinical trials that highe r doses of oral 5-ASA (up to 5 g per day) will lx· needed to remit Crohn's disc,1sc. Hopefully, the development of new drug de livery systems to ncl11cvl' max i­mal concentrations higher in the sma ll bowel (Pcnt ,1sa ) will pro\'C more useful in pmicnts whose actiw C rohn 's J b ­easc is locatcJ morl' pnn..11na lly in the small howcl o r in the swnmch . A n in­ternational study group ( 15) has repo rt ­ed tha t pau c nts with Crohn's disease in remission arc less likely lo exacerba te their disease when treated wnh l. 5 g per day of C laversal (S mithKlinc Beecham ) for up 10 one year (22.4% relar se rate versus 36.21){, in placebo­trea ted cont rols) . Rut tht· evide nce 1s

(6\ \:sij)

CFIC: Medication

8 Therapeutic

Toxic:

GI upset W rash

U marrow U tolic acid U sperm count

Figure 2) S11lp/wsalazine and its component metabolites - the 1hcra/1cw.rc 5-mninosa/1c'1l1c acid (5-ASA) moiet"I, and the mactit•e, wxic rnlpha m11ict"1 m /J1hapyndmc

no t yet conv inc 111g en ough lo use oral 5-ASA routinely in the prophylax is of 'quiescent ' Crohn 's d i~casc.

With better delivery syste ms and dosing schemes, proven by controlled cl inical tria b and with improved un­derstanding of drug ac tion on gut in­fla mma tion , the fu ture of oral 5-ASA drugs in the trea tment of C rnhn\ dis­ease is assured. The future b a lreaJ y he re in the treatml'nt of ulcerative w l1ris with 5-ASA.

STEROlDS Steroids arc effec ti ve in the trea t­

me nt of lBD. Within days of starring mid -range prcdnisonc (30 to 40 mg per J ay) rmicnts experie nce a n improved sense of well-be ing with return of ,1p­pct itc and ;111 111creasc 111 ene rgy. By t wn weeks, d rug action to cont rol inflam­mation in the bowel is peaking, symptoms arc reced ing and the gradual withd rawal of thl' drug can usua ll y be commenced. The proof tha t ste roids (corti sone) work in acurc ulce rati ve colirb came withm two yea rs of the ir 111 troduct1o n 111 the early '50s ( 16). A nJ the development of syn t he tic steroids (cg, prcdn1solonc) reduced tox icity and permit tcd topica l use (as enemas, sup­positories and rectal foams) depending on the ex tent of the colitis (1 7). The usc of corticosteroids 111 acuve Crnhn's disease is similarly effecti ve with about th rel'-quarre rs of patients remn rmg their disease, cl inically (6) but not cndoscopically ( 18 ) . As with u lcernrive coli tis, steroids fo il to ma intain remis­sions of C rohn's disease; c hronic use of stcrrnds, even in low doses, is to be

avoided in patie nts whose [Bl) 1s 111

c li n ical remission . Everybody knows t ha t stc rrnds arc

tox ic drugs. Patien ts given mid-range prcdnisnne often experience ir­ritabi lity, depressive reaction and s leeping d ifficu lues. If the d isease docs no t remit as an tic ipated find the do5e of prcdnisonc is cnntinued , the patient sh ows v1s1hlc side effects (facia l swe ll ­ing, easy bruisi ng, elevated blooo pres­sure, etc). There arc also concerns ahout less v 1siblc comp I icatio ns, such ns adrenal suppress io n, cataracts, myo­path y, avascular necrosis of the hip jo ints, e tc. Even with topical steroid ene mas given c hron ica lly, there is suf­fic ie nt absorption into the body to g ive these systemic side effec ts.

A nd so, wh ile cvcryhody uses steroid med1catiom in the acute cxaccrbatinm of d i ff use I RD, the deve lopme nt of b s tox ic steroid drugs is eagerly awaited. Roth t ixocorto l p i va lai e and budcsnnidc, given hy enema, arc as ef­fec ti ve in treating d istal ulcerat ive col 1t 1s as betamcthasonc or hydrocor­tisonc enemas ( 19,20). A lthough I he drugs arc ahsorhcd, they arc rapidly cleared hy the li ver and k idneys, dramatically reduc ing systemic tox ic ity. T h eir use in treating dista l col itis 1s presently limi ted by avai lahil ity (and the success with 5-ASA cncmns) . Because ste roids have this topical act1v 1t y 111 the guc, it 1s hoped rhm new steroids will he developed char can be taken hy mouth, can h ave topical act ivity and, hy being either poorly absorbed or rapid ly cx­creu.:d , can be free from the side effec ts

CAN J GAslll()INTl-ll\) J VOi 6 N~) 4 JULY/AUGUST 1992 237

MOORE

TABLE 1 Changing medical treatment of inflammatory bowel disease

Nutrition 5-Aminosalicylic

a c id Steroids

'Old' treatments

Elimination diets Sulphasalazine

Prednisone

'New' treatments

Enteral formulas. short c hain fatty acids Asacol'"', Dipentum'". Mesasal,.,.

Pentaso'"'. Salofalk<'"

Tixocortil. budesonide lmmunosuppressives 6-Mercaptopurine. Cyclosporine. methotrexate

azathioprine

"Registerd trademark

which limit the use of th is Jramatically effective grour of drugs.

STEROID ALTERNATIVES Most patients whll arc acutely ill

with ex tensive IBO respond to steroids given in a decreasing do-e (beginning 40 mg of preclnisone) over a short period of time (two to three month~). The steroid toxicity is acceptable and less toxic drugs (usually 5-ASA) can then be used Lo maintain clinical im­provcmcnl. But some of these sic k patients (up to 20%) arc steroid resis­tant a nd face certain toxicity from long term use of steroids. For these patients, the steroid 'alternatives' have a lready begun to offer safer and more effect ive medica l treatment. 6-Mcrcaptopurine and azathioprine : T han ks largely to the persistence of a group of New York gastrocnterologists, 6-mercaptopurine ( 6-M P) is the best studied and most acceptable steroid a l­ternati ve. Azachioprine (lmuran; Bur­roughs W e llcomc ), an active metabo­lite of 6-MP, has comparable cl in ical efficacy. In both ulcerative colitis and Crohn's d isease (especia lly when it in­volves the colon ), re mission rates of 50 to 70% can be expected. By us ing a rel ative ly low drug dosage of I mg/kg bodyweight, most of the toxicity of these drugs is rrcd ictahle and rever­sible. Pancrcatiti~ occurs in 3% of cases hct ween rh rcc a nd four weeks of starr­ing treatment, a nd reverses without permanent damage when chc drug is stopped. Bone ma rrow suppression (2%) c,m be avoided by mo nitoring per ipheral blood counts and lowering drug dosage if count~ fa ll. The deve lo pment of opportunistic infccLions with immunn­supprcssion is less t han with prcdnisone. Although the drugs arc mutagenic, there has been no unusual occurrence of car-

c inoma or lymphoma with their use (2 l). Although the drugs arc tcrato­gen ic in highe r doses, there is good evidence of their safety in pregnancy at rhc doses used to treat IBO (22). A therapeutic bonus in Crohn's disease has been the healing of enccrocucancous and internal fistulae in some (50%) of the patients treated with 6-MP or aza­thioprine. The major lim itation of the drug (apart from s ide effects) is the long time required for the drug to become active (3. l months). Usually this means that the patient faces a nother three months of sLcroid tox icity, once che dec ision has been made co use 6-MP o r azathioprinc. The search for o the r, fast­er acting, steroid alternatives continues. Cyclosporine: The re are pre liminary repo rts thac cyclosporinc, an immuno­suppressive drug used in organ trans­plantation , acts rap idly to improve steroid-refractory patients with e ither C rohn 's disease o r ulcerative coli tis ( 2 5). Because the d rug has frequent side effects (numbness in the limbs, inner trembling, renal tox icity, etc) it has usually been used for short periods of time (less than three months). It is like­ly that the d rug will be maximally useful if used for longer periods of time (espe­cially as the disease rec urs rapidly when the drug is discontinued). Because of its toxicity, cyclosporinc shou ld be used in long term studies only in clinical re­search programs at centres experienced in the use of this drug. Methotrexatc: Methotrexatc is an anti­mctabo l i tc primarily used in cancer c hemotherapy. When found to have anti-inflammacory properties its use was cxLcmlcd to seve ral chronic d iseases, such as psorias is and rh e umato id arth ritis. ln small, open trials it impro­ved both refractory u lcerat ive colitis and C rohn's disease in about three-

quarters of case~. !ts advantage~ wou ld appear LO be rapid onset of action (two to e ight weeks) and case of delivery (25 mg by intramuscular injccLion once a week). S ide cffccl (marrow suprrcs­s io n , gastrointestinal upset , liver damage) arc ignificam. If the early en­thusiasm for chis new trea tment can be confirmed in cl inical tria ls, Lhc result~ wi II certainly uutwcigh the side effects, and mcthotrexate will become an im­portant a I rcrnati ve to steroids when quick clinical response is rc4uircd in very sick pmi.cnts. Antibiotics: There can be little doub1 that a ntibiotics arc useful in treating many of the complicmions of I BO. Met­ronidazo lc (Flagy l; Rhi'me- Poulenc) given in large doses (500 mg three t ime~ per day) for long periods of ti me ( over six mon ths) improves pcrianul Crohn\ disease (27). Vancomycin (Vanocin; Lilly) improves ulcerative colitis and Crohn 's disease of the colon when there is complicating Clo.midium difficile in­fection (28) . There is also exciting pre­liminary ev ide n ce rhat an! ibiot ics (such as mctronidazolc) which have ac­tivity against the bacLcria of the colon, may reduce the activity of the primary disease process. Tria ls arc underway to sec if less tox ic a ntibi otics, mo re suitable for long term u c (cg, norflox­acin [Noroxin; Merck Sharp Dohmel) may be useful in treating 180.

SUMMARY T he medical treatment of lBD is

changing (Table I). Elimina1 ion diet~ arc giving way to dietary supplcmem~ to nourish the bowel a nd reduce in­flammation. The frequently w xic com­ponent of sulphapyridinc has been removed to produce the new 5-ASA preparations (and the vehicle replacing the sulpha mo iety pe rmits targeting o(

maximal drug concentrations a ll along rhc bowel). New, Lopically active steroids arc clearly less toxic Lhan glu­cocorticoids in present use and seem to be as effective. New immunosuppres­sivc a nd an ti- inflammatory drugs arc producing usefu l alternaLivcs to steroid therapy. ln the past 30 years, the lethal impact Ll lBD has hccn removed; in the next IO years, pain and ~uffcring will be dramatica lly reduced.

238 CAN J UASTROENTFRUL VOL 6 No 4 JUI Y/ AU< ,UST 1992

CFIC: Medication

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1110ammatory hPwcl disease. In: enemas. Lancet 1981 ;i i:270- 1. hude:,unide vc r:,u:, predni:,,>lonc Kir,ner JB, S horter R. lnOanunatory 11. Suthcrh1nd LR, Martin F, Greer S, retention enemas in active di,tal Bowel Disease. Phil.Klclphia: Lea et al. 5-arni,wsa licy lic acid encm;i in colim,. ScandJ Ga:,troem eml Fch1ger. 1988. the treatment ufdistal ulcerative l 989:22;987-994

2. Se idman EG. Nutmional rn,111age mcnt colitis, pmctosigmnidit 1s and procutis. 2 1. Prescm DI I, Meltzer SJ. c t ,ii. ol inOamnw tory hnwl·I d1sea:,e. Ga:,troemcmlngy 1987;92: 1894-8. 6 -Mercaptopurinc 111 thc 111,111agcmcnt Gastrucntcrol C lin North Alll I 2. Robinson MO. New oral ~a licy latcs in of inOmnmatory howcl di,c,1,c: Shon 1989; 18.1: 129-S'i. the therapy of d1wnic idiopathic ,rnd long term toxicity. A nn Intern

1. Christ i<: PM, Hill C L. Effects nf inOammar,,ry bowel disease. Gastrn- Med 1989; 1 I 1:641-9. intrnvcn nu, nutrition nn nutrllion and entcml Clin North Am 1989; 18:43-50. 22. A lste,1J EM, Ritchie JK, l!l al. S.ifcty nf func t iun in acute attacb ,if 13. Rao SS, Dunda~ SA, 1 loldswmth CD, azath1oprinc 111 pregnancy and inOammmory howcl disease. l'l a l. O ba l.1:inc or :,ulpha,alazme in inflammatory bowel di:.ease. Gastmcnterok,gy 1990;99: 7 30-6. first attacks t>f ulccrnt ive cnl it is? A Ga,Lrocm erology I 990:99:44 3-7.

4. G reenbe rg GR, Fleming CR, d ouble hi ind sllld y. G ut 1989: 10:675-9. 23. Pcltckian KM, Willi am, CN, Jccjecbhny KN, Rll,enherg ll 1, Sales 14. Riley SA, Mani V, Goodman MJ, ct al. MacDonald AS, Roy PD, C:l,lp111sbt L\ Tremaine WJ . Cllntmllcd trial nf Cnmpari,nn nf ,lclc1yed-rclcase E. Open trial of cyclospori nc 111 hmvcl re,t and nutritional support in 5-aminosalicylic acicl (mcs.1h1zine) and patients wi th severe active Crohn's the managemem (ifCmhn's disease. sulfm,almmc lls mnintcan,mce d i>em,c refractory to convenu nnal G ut 1988:29: I 309-15. treatment for patients with ulcerative therapy. Can J Ga:,troentcrol

5. Dick AE, Craystm MJ. Carpenter RG. wlitis. Gastroentcrolngy 1988;2:5- I I. ct al. Controlled tn::il of su lphas,11:izi n l! 1988;94: I 383-9. 24. Brynskov J, Freund L, ct al. A ph1ccbo in the treatmen t of ulcerati ve cnliti,. I 5. Thomson ABR, ct al. Coated or:i l controlled, dnuhle-blinc.l, ranJonuzcd Gut 1964; I 5:4 3 7-42. 5-aminosali<.:ylic ;1c iJ versus placchti in tri a l of cyclmporine therapy in act ivc

6. Summers RW, Swit z DM, Sc,sions JT, maintaining rcmis:,ion of inacuve chronic Cmhn's disease. N Engl J MeJ ct nl. Nationa l Cnopern1 ivc Crnhn's Cnihn's disca,c. Ali ment Pharmncnl l 989; 121 :845-50. di,case study: Results ,11 c.lrug Tim I 990;4 :55-64. 25. Lichtiger S, Present DI-I . Preliminary tn:atmem. l,astrocntC'n, logy 16. True love SC, Wi I Ls J. Cort bone in report: Cyclospori ne in treatment of 1979:77:84 7-69. ulccrat ivc coli us: Fin,11 report on a severe active ulcerative col it ts. Lancet

7. M 1sicwicz JJ, Lennard-Jones J E, therapeutic trial. Br Med J I 990:3 36: 16-9. Connell AM, ct al. Contn,l trial of I 955;2: 104 L-5. 26. Kozarcc RA, Patterson SJ, ct al. sulphasalazine in maintenance therapy 17. Jewell DE. Cnrtico,tero,ds fo r the Methotrexarc induces clinicn l and fo r ulcerati ve cnliti,. Lancet management of ulcerat ive coli t i, a nd histologic remi,,inn in pat ients with 1965:i: 185-8. Cn,hn 's c.li,easc. Med C lin North A m refractory mOammmory howel d isease.

8. Dissanayake AS, Truclnvc SC. 1989: I 8:21-34. A nn Intern Med 1989: 11 0:353-6. A cont rolled t herapcuti c tri al of 18. Modigliani R, Mary J-Y, ct al. C linica l, 27. Brandt LJ, Bcrnstc111 LI I, ct al. long-term ma 1ntenance t reatml'nt of billlogical. ,rnd endoscopic picture tll Metronid;i:olc t hernpy for pcrianal ulcerat ive colitb with , ulphasalazine attacks of C rohn \ di,easc. Evolut ion o{ Crohn's disease. A fol low-up study. (Sah zopyrin) . Gut 1971; 14:92'1-(1. prcdniM,lnne. G,istrocmcrology Gm,tmentcrolngy 1982;83:383-7.

9. Arnd Khan AK, Piris J , T ruelove SC. 1990;98:8 I I -8. 28. Trynka YM, Lamont JT. Association A n experiment to determine the 19. l lanc1uerS8, K1r,ncr JB, Barrett WE. of ClostTidium difficile lllxin with active therapeutic mt>icty llf The treat mcnt of left -sided colit is with ,ympLOmatic rclap~c 111 chron ic sulpha,ala: inc. Lancet I 977;ii:892-5. tixncortol pivala rc. Gast roentcrology inflammatory howcl J i,easc.

JO. Cllmpicri M, Lafranchi GA, Bazwch 1 1986;90: I 449. Gastroentcrolngy 198 1 ;80:693-6.

CAN J GASTR,WNTl'R()I V()I 6 N,1 4 JULY/Au,;usT I 992 239

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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of

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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Research and TreatmentAIDS

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Gastroenterology Research and Practice

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Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com