Gut 1996; 38: 229-233

A randomised trial comparing mesalazine andprednisolone foam enemas in patients with acute

distal ulcerative colitis

F I Lee, D P Jewell, V Mani, M R B Keighley, R D Kingston, C 0 Record, R H Grace,S Daniels, J Patterson, K Smith

Department ofMedicine, VictoriaHospital, BlackpoolF I Lee

Gastroenterology Unit,John RadcliffeHospital, OxfordD P Jewell

Department ofGastroenterology,Leigh Infirmary,Leigh, ManchesterV Mani

Department ofSurgery, QueenElizabeth Hospital,BirminghamM R B Keighley

Department of ClinicalStudies, TraffordGeneral Hospital,ManchesterR D Kingston

Department ofMedicine, RoyalVictoria Infirmary,NewcastleC 0 Record

Department of Colo-Rectal Surgery, NewCross Hospital,WolverhamptonR Grace

SmithKline BeechamPharmaceuticals,Welwyn Garden City,HertfordshireS DanielsK SmithJ Patterson

Correspondence to:Mrs K Smith, MedicalDepartment, SmithKlineBeecham Pharmaceuticals,Mundells, Welwyn GardenCity, Herts.

Accepted for publication24 August 1995

AbstractDistal ulcerative colitis can be treatedwith oral or rectal mesalazine, or both. Afoam enema preparation has been devel-oped and its efficacy investigated. Theaim of this study was to evaluate the effi-cacy and safety of mesalazine foam ene-mas compared with prednisolone foamenemas in the treatment of patients withacute distal ulcerative colitis. Patientsaged over 18 years presenting with arelapse of distal ulcerative colitis wererandomly allocated treatment withmesalazine foam enema (n= 149 evaluablepatients) and prednisolone foam enema(n= 146 evaluable patients) for four weeks.A randomised multicentre investigatorblind parallel group trial was conducted.It was found that after four weeks oftreat-ment, clinical remission was achieved by52% of mesalazine treated patients and31% of patients treated with prednisolone(p<O.OO1). There was a trend in favour ofmore patients in the mesalazine groupachieving sigmoidoscopic remission (40Gbv 31%, p=O.10). Histological remissionwas achieved by 27% and 21% of patientsreceiving mesalazine and prednisolonerespectively. Symptoms improved in bothtreatment groups. Significantly moremesalazine patients had no blood in theirstools after four weeks of treatment (67%v 40/0, p<O.OO1). Prednisolone treatedpatients had significantly fewer days withliquid stools than mesalazine patients,with a median of 0 and 1 days respectivelyby week 4 (p=O.001). In this studymesalazine foam enema was superior toprednisolone foam enema with regards toclinical remission, this was supported byfavourable trends in sigmoidoscopic andhistological remission rates. Both treat-ments were well tolerated.(Gut 1996; 38: 229-233)

Keywords: mesalazine foam enema, distal ulcerativecolitis, randomised, controlled trial.

Ulcerative colitis is a chronic, recurrent diseaseofunknown aetiology in which part or all of themucosa of the colon and rectum becomesinflamed. Distal ulcerative colitis refers toinflammation confined to the rectum, sig-moid, and descending colon. The principalsymptoms are diarrhoea with urgency ofdefecation and rectal bleeding.

Mesalazine (5-aminosalicylic acid, 5-ASA)is the active moiety of a variety of aminosali-cylic based drugs for inflammatory boweldisease. The efficacy of mesalazine is due toits topical action, and various methods anddelivery systems have been used to get theactive constituents specifically to the inflamedmucosa (that is, combination with a sulpha-pyridine carrier, enteric coating, slow releaseformulations, enemas, and suppositories).The use of oral mesalazine in the treatment

of ulcerative colitis is now well established.'-3In cases of acute distal colitis, a corticosteroidenema is often added to the background of oralmesalazine. Liquid mesalazine enemas areavailable and have been shown to be superiorto placebo4 5 and as effective as corticosteroidenemas at inducing remission in acute mild tomoderate distal ulcerative colitis.6 7 Liquidenemas are difficult to retain, however, requir-ing patients to lie down for at least 30 minutes,and a recent study showed that patients preferfoam rather than liquid enemas.8We conducted a randomised investigator

blind parallel group trial in 295 evaluablepatients with acute distal ulcerative colitis andevaluated the efficacy and safety of mesalazinefoam enema (Asacol) compared with a com-mercially available prednisolone foam enema(Predfoam).

MethodsThe study was conducted in patients aged 18years and above attending outpatient clinics in39 centres in the United Kingdom betweenOctober 1990 and June 1993.To be eligible for the trial, patients had to

have a confirmed diagnosis of distal ulcerativecolitis that did not extend beyond the splenicflexure and be in a state of clinical andsigmoidoscopic relapse. Patients were excludedifthey had taken oral or rectal corticosteroids orrectal 5-ASA preparations in the month prior toentry or required such treatment during thecourse of the study, had severe allergy orbronchial asthma, had a known hypersensitivityto corticosteroids or salicylates, had a specificcause of their colitis, for example, Crohn'scolitis, had any clinically significant cardiac,hepatic or renal disease or were pregnant,lactating or not using reliable contraception.Maintenance treatment of oral mesalazine orsulphasalazine was permitted provided thistreatment had been stable for one month.The protocol conformed to the Declaration

of Helsinki and all amendments and was

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Lee, Jewell, Mani, Keighley, Kingston, Record, Grace, Daniels, Patterson, Smith

approved by the local ethics committees of allthe participating hospitals. All the patientswere informed of the nature and purpose of thestudy and gave their written consent.The enrolment of patients by centre ranged

from 1 to 32 with a median value of 6. Of the337 patients screened 334 were randomised(167 in each treatment group), using acomputer generated list prepared bySmithKline Beecham, to receive, at bedtime,over a four week period, either 2 g mesalazinefoam enema, given rectally in two meteredapplications (total volume 120 ml) or 20 mgprednisolone foam enema given rectally in onemetered application (total volume 30 ml). Bothtreatments were presented as blank cylindricalaerosol cans with disposable applicators, how-ever, the prednisolone can was approximatelyhalf the size of the mesalazine cans. To main-tain investigator blindness every effort wasmade to ensure they did not see the cans.

Patients were provided with loperamide cap-sules as escape antidiarrhoeal medication ifclinically indicated.At screening, patients were examined by flex-

ible or rigid sigmoidoscopy or colonoscopy anda biopsy specimen taken to confirm the diag-nosis. Stool culture was performed to excludeenteropathogens and a blood sample taken forbaseline haematology and biochemistry tests.Patients' demography, medical history, currentsymptoms, and concomitant medication wererecorded. Once randomised, patients wereasked to complete a symptom diary card duringthe study period, and the data were collected ateach visit. Patients returned to the clinic forrepeat clinical assessments after two weeks(14±3 days) and four weeks (28± 3 days) whensymptom assessment (rectal bleeding andmucus, stool frequency and consistency,abdominal pain, urgency, incontinence, andtenesmus), global symptom improvement, con-comitant medication, and adverse events wererecorded. A repeat sigmoidoscopy and biopsywas undertaken at week 4 along with repeathaematology and biochemistry tests. Wherepossible any patients withdrawn during thestudy period underwent a repeat sigmoido-scopy, biopsy, and provided a blood sample atthe time of withdrawal. Clinical remission wasdefined as 63 stools/day with no blood.

Sigmoidoscopy enabled the appearance ofthe mucosa to be graded as I (normal findingsincluding minor abnormalities in the vascularpattern), II (abnormal loss of vascular patternwith mucosal granulation but without bleed-ing), or III (abnormal with visible bleeding,including ulceration). Sigmoidoscopic remis-sion was defined as grade 1 at week 4 or atwithdrawal.

Biopsy specimens taken during thesigmoidoscopic examination were sent to asingle blinded consultant histopathologist forgrading. Each patient was assigned an 'activeinflammation' score9 (minimum 0, maximum9) along with a descriptive assessment of thehistopathology. Histological remission wasdefined as an active inflammation score of 0 atweek 4 or at withdrawal in patients where thescore was greater than 0 at entry.

Safety was assessed by haematological (fullblood count, platelets and erythrocyte sedi-mentation rate) and biochemical (urea, creati-nine, albumin, bilirubin, alkaline phosphatase,serum aspartate aminotransaminase, and ala-nine aminotransferase) assessments at week 0and week 4 and by recording of adverse eventseither observed by the investigator or reportedby the patient at each follow up visit.

Statistical methodsTwo hundred and eighty patients were requiredto complete the study assuming an 80%improvement with prednisolone comparedwith mesalazine. This sample size enabledsignificance testing at the 5% level to have an80% probability of detecting a true differencebetween treatments of 15%.Of the 334 patients randomised, 295

patients were included in the efficacy evaluablepopulation. These patients had no majorprotocol violations and had received at least 11days of randomised treatment. Thirty ninepatients (18 in the 5-ASA group and 21 receiv-ing prednisolone) were excluded from theanalysis; the main reason being that they hadreceived oral corticosteroid treatment or hadchanged the dose of their oral mesalazine/sulphasalazine medication in the previousmonth (nine in the 5-ASA group and 17receiving prednisolone). Other reasons forexcluding data were that patients had Crohn'sdisease, were non-compliant, or had a normalsigmoidoscopy at entry.

Statistical analysis, by an extemal con-sultant, was performed using the Mantel-Haenszel x2 test and Wilcoxon rank sum test.Previous use of prednisolone foam enema andconcurrent use of mesalazine or sulphasalazinewere introduced as strata. Treatments werecompared using two sided tests with a nominalsignificance level of p=0.05. The results wereexpressed as the difference between the twogroups along with the 95% confidenceintervals around the difference. No adjust-ments were made to the p values to account formultiple testing, but statistical tests were keptto a minimum.

ResultsOf the 295 eligible patients 149 receivedmesalazine 2 g and 146 received prednisolonefoam enema 20 mg. Both groups were wellmatched with respect to age (range 18-88years), sex, previous ulcerative colitis history,disease extent, and concurrent mesalazine/sulphasalazine use (Table I). Altogether 40patients withdrew from the study, the mainreason being lack of efficacy (five patientsin the mesalazine group, 13 patients in theprednisolone group). A further three patientswere excluded from the week 4 analysis forbeing outside of the specified visit window.At entry all eligible patients had an abnor-

mal sigmoidoscopy, the median grade was III.The median 'active inflammation score' was 7in both treatment groups. Thus most patientshad a moderately inflamed rectal mucosa

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Ulcerative colitis andfoam enemas

TABLE I Patients' ulcerative colitis history

5-ASA foam Prednisoloneenema foam enema

Characteristics (n= 149) (n= 146)

Sex(%)Male 76 (51) 80 (55)Female 73 (49) 66 (45)

Age (y)Mean 44 45SD 13-6 15.0

Previous history of ulcerative colitis (%)Yes 128 (86) 125 (86)No 21 (14) 21 (14)

Median duration presentsymptoms (weeks) 8 6

Disease extent (%)Proctitis 14 (9) 15 (10)Sigmoiditis 97 (66) 101 (71)Left sided colitis 37 (25) 27 (19)Not known 1 3

Concomitant oral 5-ASA/SSZ (%)Yes 63 (42) 69 (47)No 86 (58) 77 (53)

(Table II). Baseline symptoms were well bal-anced between treatment groups (Table III).

Efficacy assessmentsTable II shows that after four weeks patientsin both treatment groups had improved sig-moidoscopically with a median in both groupsof grade II. The median 'active inflammationscore' was 2 in the mesalazine group and 3 inthe prednisolone group.

Clinical remission was achieved by signifi-cantly more patients treated with mesalazinethan with prednisolone (52% v 31% p<0-001)(Figure). The 95% confidence intervals (CI)indicate that the treatment difference may bebetween 10% and 32% in favour ofmesalazine.There was no statistically significant dif-

ference between treatment groups in terms ofsigmoidoscopic remission or histologicalremission. However, for both assessmentsthere was a trend in favour of patients treatedwith mesalazine; for sigmoidoscopic remission40% v 31% (p=0l10) and for histologicalremission 27% v 21% (p>0 2) (see Figure).Summary data recorded at week 4 showed

that symptoms improved for patients in bothtreatment groups with no statistically signifi-cant differences except for blood in the stools(see Table III). Mesalazine patients were stat-istically significantly less likely to have blood inthe stools after four weeks of treatment, 67% V

TABLE II Sigmoidoscopy and histology results at entry and afterfour weeks of treatment

Week 0 Week 4

5-ASA Prednisolone 5-ASA Prednisolonefoam enema foam enema foam enema foam enema

SigmoidoscopyNormal (%) 0 0 59 (47) 44 (35)Abnormal without visible bleeding (/) 62 (49) 57 (45) 52 (42) 62 (50)Abnormal with visible bleeding (/) 64 (51) 69 (55) 14 (11) 19 (15)Not known 0 0 1 1Median category 3 3 2 2

No of patients 126 126 126 126Active inflammation score (range: 0-9)Median category 7 7 2 3Minimum category 1 2 0 0Maximum category 9 9 9 9No result 6 3 4 5

No of patients* 116 116 118 114

*Omitting those patients in either group who had a result of 0 at week 0 (for the activeinflammation score) or no result available.

40% had no blood (p<0-001), the 95% CIindicate that the treatment difference may bebetween 16% and 40% in favour of mesalazine.The diary card data confirmed the summary

data and found a reduced number of daysduring week 4 with blood in the stools ofpatients treated with mesalazine foam enema(p<0001). Diary data also showed signifi-cantly fewer days with tenesmus in mesalazinerecipients (p=0.038). Tenesmus occurred ontwo or more days in week 4 for 15% patientstreated with mesalazine and for 29% patientstreated with prednisolone.

Conversely, patients treated with pred-nisolone had significantly fewer days withabnormal stool consistency compared withmesalazine (p=0001). Abnormal stoolsoccurred on three or more days in week 4 for39% of patients treated with mesalazinecompared with 23% of patients treated withprednisolone.

After four weeks of treatment 87% ofmesalazine patients and 80% of prednisolonepatients reported a global improvement in theirsymptoms (p=0O19), while 3% and 6% ofpatients respectively reported a global deterio-ration in symptoms.

Safety assessmentsNo clinically significant changes in haemato-logical or biochemical parameters were noted.Both treatments were well tolerated.As might be expected the most common

adverse events affected the gastrointestinaltract, with abdominal pain and bloating beingthe most common (Table IV).

Five patients withdrew from the studybecause of adverse events. Of the three patientswithdrawn from the mesalazine group onesuffered a pulmonary embolus, one had anelective prostatectomy, and the other hadsevere abdominal pain with rectal discharge.Only the last of these was considered drugrelated. The two prednisolone patients with-drawn for adverse events were due to a pul-monary embolus in one and eczema aroundthe pubic area and back in the other, again onlythe second of these was considered related tostudy medication.

DiscussionCompared with topical prednisolone foam,mesalazine foam enema was associated with asignificantly higher clinical remission rate,significantly fewer days with blood in the stools,and significantly fewer days of tenesmus andthere were trends favouring better sigmoido-scopic and histological remission rates.Prednisolone foam enema on the other handwas found to produce significantly fewer dayswith abnormal stool consistency.

Over a longer treatment period we may haveseen the trends favouring better sigmoido-scopic and histological remission in themesalazine group become more significant as ithas been shown in previous studies that histo-logical improvement lags behind symptomaticimprovement. 10

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Lee, Jewell, Mani, Keighley, Kingston, Record, Grace, Daniels, Patterson, Smith

TABLE iII Symptoms at entry and afterfour weeks of treatment

Week 0 Week 4

5-ASA Prednisolone 5-ASA Prednisolone p Valuefoam enema foam enema foam enema foam enema (week 4(n= 149) (n= 146) (n= 126) (n= 126) difference)

Average no of stools per dayMedian 4 4 2 2Minimum <1 0 1 1 p>0.2Maximum 20 15 13 15

Stool consistencyNormal (/) 38 (26) 29 (20) 82 (66) 93 (74)Liquid (%) 109 (74) 114 (80) 43 (34) 33 (26) p=0-17Not known 2 3 1 0

Blood in stoolsNo (/) 11 (7) 7 (5) 85 (67) 50 (40)Yes (/) 138 (93) 139 (95) 41 (33) 76 (60) p<0 001

Mucus in stoolsNo (/) 24 (16) 15 (10) 73 (58) 64 (51)Yes (/) 125 (84) 131 (90) 53 (42) 62 (49) p>0 2

UrgencyNo (/) 19 (13) 13 (9) 80 (63) 82 (65)Yes (%) 130 (87) 132 (91) 46 (37) 44 (35) p>0 2Not known 0 1 0 0

IncontinenceNo (%) 108 (72) 115 (79) 111 (88) 118 (94)Yes (%) 41 (28) 31 (21) 15 (12) 8 (6) p=0-14

TenesmusNo (%) 72 (48) 68 (47) 102 (81) 97 (78)Yes (/) 77 (52) 78 (53) 24 (19) 28 (22) p>0.2Not known 0 0 0 1

Abdominal painNo (/) 55 (37) 59 (40) 89 (71) 86 (68)Yes (/) 94 (63) 87 (60) 37 (29) 40 (32) p>0.2

*

remission(3 stools, no blood)

In terms of the improvement in other diseaseparameters, including symptoms such as incon-tinence, abdominal pain, and frequency therewas no difference seen between the two treat-ments. Both treatments were well toleratedwith similar adverse event profiles and nosignificant changes in haematological or bio-chemical parameters.The higher clinical remission rate found in

the mesalazine group was caused in part by thehighly significant reduction in the number ofpatients with blood in stools that occurred inthis treatment group, an effect that may relateto several factors such as the intrinsic activityof mesalazine on the ulcerated mucosa relativeto corticosteroids, the adherence properties ofthe foam, and the larger volumelbetter spreadof the mesalazine. The difference in volumesbetween the two drugs may, however, explainthe fewer days with abnormal stool consistencyassociated with the use of prednisolone.

Oral formulations of mesalazine and sul-phasalazine have been used for many years inthe treatment of acute ulcerative colitis,l actingtopically in the colon probably by reducing theacute inflammatory response." Treatment of

M 5-ASAM Prednisolone

t * p < 0.001tp=010

IUJIUU;UUsJIremission(Grade 1)

remission(Biopsy score 0)

Clinical, sigmoidoscopic, and histological remission rates afterfour weeks of treatment.

TABLE IV Most common adverse events (number (%o) ofpatients)

Foam enema

5-ASA PrednisoloneEvents (n= 167) (n= 167)

Patients with > 1 event 57 (34) 43 (26)Bloating 10 (6) 2 (1)Abdominal pain 12 (7) 7 (4)Deterioration of ulcerative colitis 5 (3) 7 (4)Nausea and vomiting 5 (3) 7 (4)Headache 7 (4) 4 (2)

distal ulcerative colitis can easily be given viathe rectum thus permitting direct topicalcoverage of the inflamed mucosa and a lowlevel of systemic absorption. 12 Thereforerectal formulations of mesalazine have beendeveloped, namely suppositories and retentionenemas. A number of studies have shown thatmesalazine liquid enemas are highly effective inacute ulcerative colitis provided the diseasedoes not extend beyond the splenic flexure.4-7

Mesalazine foam enema preparations havebeen developed recently; work by Campieri onan early Italian mesalazine foam enemashowed that when given in equal doses of 2 g aprompter remission was obtained in patientsreceiving a foam rather than liquid enema.Furthermore 81% of the patients expressed apreference for the foam as it was easier toretain and more comfortable and practical touse.8 This may be due to the tendency of foampreparations to adhere to the colonic mucosa,even after bowel evacuations. 13The extent of spread of the mesalazine foam

enema used in this study has been investigatedand found to disperse well into the descendingcolon and in some instances up to and beyondthe splenic flexure (unpublished finding).Retrograde spread of enema preparations isdependent on enema volume and the largervolume of the mesalazine foam enema com-pared with the prednisolone enema (120 ml v30 ml) may explain in part the greater efficacyseen in this study (all the commercially avail-able corticosteroid foam enemas are of com-parable volume).

Systemic absorption of mesalazine from thefoam enema has been investigated and wasfound to be similar to that of other marketedmesalazine preparations (unpublished find-ing), suggesting the foam enema will be a safeand effective treatment for patients withulcerative colitis.The prolonged use of corticosteroid enemas

including prednisolone foam enemas isundesirable as they are readily absorbed fromthe rectum and distal colon and are a potentialcause of systemic side effects. A newmesalazine foam enema will therefore providean effective alternative treatment without theside effects associated with the systemicabsorption of corticosteroids.14

In conclusion mesalazine foam enema is ahighly efficacious and well tolerated prepara-tion for the treatment of patients with acutedistal ulcerative colitis.

We would like to thank the following for their contribution to theabove study: Dr S P Wilkinson, Dr R Burnham, Dr I Cobden,Dr M J Goodman, Professor C Hawkey, Mr G Hutchinson,

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Ulcerative colitis andfoam enemas 233

Dr G Neale, Dr P Down, Dr P Evans, Dr P Cann, Dr J LShaffer, Dr A Axon, Dr C Pennington, Dr I Barrison, Dr GAllan, Dr I Chesner, Dr J Collins, Dr P B McIntyre, Dr R JDickinson, Mr R Leicester, Professor J E Lennard-Jones, Dr AManning, Dr J Wilson, Dr D G Colin-Jones, Dr TDaneshmund, Dr M E Denyer, Dr S B Desai, Professor MFarthing, Dr M Grayson, Dr R Lendrum, Dr P Trewby.Funding was provided by SmithKline BeechamPharmaceuticals.This study was presented as a poster at the 1994 Spring meet-

ing of the British Society of Gastroenterology at Manchesterand was published as an abstract (Gut 1994; 35 (suppl 2): S42).

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2 Dew MJ, Hughes P, Harries AD, Williams G, Evans BK,Rhodes J. Maintenance of remission in ulcerative colitiswith an oral preparation of 5-aminosalicylic acid. BMJ1982; 285: 1012.

3 Riley SA, Mani V, Goodman MJ, Herd ME, Dutt S,Tumberg LA. Comparison of delayed-release 5-amino-salicylic acid and sulfasalazine as maintenance treatmentfor patients with ulcerative colitis. Gastroenterology 1988;94: 1383-9.

4 Sutherland LR, Martin F, Greer S, Robinson M,Greenberger N, Saibil F, et al. 5-aminosalicylic acidenema in the treatment of distal ulcerative colitis, procto-sigmoiditis and prochitis. Gastroenterology 1987; 92:1894-8.

5 Willoughby CP, Campieri M, Lanfranchi G, Truelove SC,Jewell DP. 5-Aminosalicylic acid (Pentasa) in enema formfor the treatment of active ulcerative colitis. Ital JGastroenterol 1986; 18: 15-7.

6 Danish 5-ASA Study Group. Topical 5-aminosalicylic acidversus prednisolone in ulcerative proctosigmoiditis. DigDis Sci 1987; 32: 598-602.

7 Campieri M, Lanfranchi GA, Bazzocchi G, Brignola C,Sarti F, Franzin G, et al. Treatment of ulcerative colitiswith high dose 5-aminosalicylic acid enemas. Lancet 1981;ii: 270-1.

8 Campieri M, Paoluzi P, D'Albasio G, Brunette G, Pera A,Barbara L. Better quality of therapy with 5-ASA colonicfoam in active ulcerative colitis. A multicentre compara-tive trial with 5-ASA enema. Dig Dis Sci 1993; 38:1843-50.

9 Ruddel WSJ, Dickinson RJ, Dixon MF, Axon ATR.Treatment of distal ulcerative colitis (proctosigmoiditis)in relapse: comparison of hydrocortisone enemas andrectal hydrocortisone foam. Gut 1980; 21: 885-9.

10 O'Donnell LJDO, Arvind AS, Hoang P, Cameron D,Talbot IC, Jewell DP, et al. A double, controlled trial of 4-aminosalicylic acid and prednisolone enemas in distalulcerative colitis. Gut 1992; 33: 947-9.

11 Greenfield SM, Punchard NA, Teare JP, Thompson RPH.Review article: the mode of action of the aminosalicylatesin inflammatory bowel disease. Aliment Pharmacol Ther1993; 7: 369-83.

12 Campieri M, Lanfranchi GA, Boschi S, Brignola C,Bazzocchi G, Gionchetti P, et al. Topical administrationof 5 aminosalicylic acid enemas in patients with ulcerativecolitis. Studies on rectal absorption and excretion. Gut1985; 26: 400-5.

13 Campieri M, Corbelli C, Gionchetti P, Brignola C, BelluzziA, DiFebo G, et al. Spread and distribution of 5ASAcolonicfoam (Asacol) and 5ASA enema in patients withulcerative colitis. Dig Dis Sci 1992; 37: 1890-7.

14 McIntyre PB, Macrea FA, Berghouse L, English J, LennardJones JE. Therapeutic benefits from a poorly absorbedprednisolone enema in distal colitis. Gut 1985; 26: 822-4.

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