Clinical efficacy of oral ITlesalazine in Crohn ' s disease

A randomized controlled trial was performed to evaluate in Crohn's disease the clinical efficacy and safety of a higher dose of a new slow-release preparation of mesalazine (500 mg tablets). Twenty-four patients created with 3 g mesalazine/day were compared with 26 patients treated with sulfasalazine (3 g/day) and methylprednisolone ( initially 40 mg). All patients had active Crohn's disease diagnosed by endoscopy, sonography and radiology. Patients were ch aracterized before en try into the study and at two, four, e ight and 12 weeks of treatment by activity indices according to Best and van Hees, as well as by erythrocyte sedimentation rate, thrombocyte count, Broca index and serum a lbumin. All clinical and laboratory parameters were well matched for the two groups of patients. During treatment with mesalazine and sulfasalazine/methylprednisolone, clinical remission could be observed in 20 of 24 patients (83%) and 23 of26 patients (88%), respectively. There was no difference between the two groups except for a s lightly highe r increase of the Broca index in the combined treatment group. S ide effects were reported in three (12.5% ) and six (23%) patients treated with mesalazine and sulfasalazine/methylprednisolone, respectively. In conclusion, oral mesalazine at a dose of 3 g/day was effective in active C rohn's disease and was well tolerated by the patients. Can J Gastroenterol 1990;4(1):13,18

D RUG TREA Th1ENT OF CROI IN'S Jisease 1s baseJ mainly on the results of the American Cooperative Crohn \ Disease S tudy ( I ).While corticosteroic.barc indicateJ if inflammation is loc.1rcd in the small howel, su lfasalazinc ;md corticosteroids a re helpfu l ifboch small and la rge bowel are involved; if the disease 1s restricted to the colon, monmherapy with sulfasa lazine might he sufficient.Treatment failure of sulfasa lazinc in inflammacory processes of the small bowel is due to I h e fact that the active moiety of sulfasalazinc-5-aminosalicylate (mcsalazinc) -is not ava ilable there, because it is generated from its prodrug by reJuctive bacteria l cleavage of the azobnnd in the colo n (2)(3)(4).
The direct application of mesalazinc appea rs to be advantageous especially, therefore, if its low incidence of side effects (compared with sulfasa lazi ne) is considered (5).Likewise, higher doses of mesalazine might be used, since the d ose-depe ndent toxic potential of sulfapyridine has been eliminateJ (6,7).These perspectives initiated th e development of a 500 mg mesalazme tablet with a controlled release mechan ism.
Crohn's d isease was performed to assess the clinical efficacy and safety of mesalazine at a h igher dose of 3 g/day.For this reason the new dosage regimen was compared with t he established standard regimen of sulfasalazine (3 g/day) a nd methylprednisolone (initially 40 mg).

PATIENTS AND METHODS
After written informed consent was obta ined, 54 patients with active C rohn 's disease participatec.l in the controlled trial.Initially patients were hospitalized and, accord ing to t he severi ty of disease, treatment was con-TABLE 1 tinued ambulacorily (Table 1 ).Patients were randomly assigned to three months oral treatment either with mesalaz ine l g rid ( t hree X two tablets of Salofalk; lnterfalk ) or sulfasalazine l g tid ( three X two tablets of Azu lfidine; Pharmacia) and methylprednisolone (initially 40 mg/day; weekly reduction by 4 mg).
Diagnoses of Crohn's disease were based on endoscopy, sonography, radiology and extensive clinical examinations.Infectious coli tis was excluded by microbiological screening and testing for complement-bind ing reactions.Patiencs were excluded from the study if they met one of rhe following c riteria: known hypersensitivity to salicy lates or sulfonamides; extensive stenoses; indications for surgery; very active disease despite corticosteroid treat• ment; impaired liver or kidney function; or infectious colitis.None of the patients was pretreated with corticosteroids.

Demographic and clinical data (mean ± SD) of patients with
Clinical efficacy was assessed by the following criteria: decline in the activity indices accord ing co Best (8) and van Hees (9); reduction in erythrocyte sed imentation rate and platelet counts; and increase in scrum albumin and body weight (Broca index).Rem ission was defined as a Best index score of b ~ than 150.
A ll these parameters were monitored before and after two, four , eight and 12 weeks of the randomized treatment.In addition, at those t ime points the following laboratory parameter, were controlled: erythrocyte and leukocyte counts; hemoglobin; hematocrit; serum creatinine; sod ium; potassium; prothrombin time; alanine ami notransferase; aspartate aminotransferase; gamma-glutamyl transferase; and urine status.Patients were also interviewed for side effects and co-medication {no anti-inflammatory drugs such as azath iopri ne or metronidazole were allowed).
Patients were educated to record on cards number of bowel movements, consistency of stool, abdom inal discomfort a nd general health status.
Boch treatment groups were compared by the unpaired two-tailed S tudent's t test.

RESULTS
According to protocol the study was completed by 50 patients.T he four drop outs were due to withdrawal of given informed consen t, moving away, protocol violation and indication for surgery.Before entry into the study all the demograph ic and clinical data of both groups were comparable (Table 1 ).
C linical rem ission was induced in 20 patients (83%) of the mesalazine group and in 23 patients (88.5%) of the sulfasa lazine/corticosteroid group.The   Mesalazine in Crohn's disease me.:in values (± SD) for the various clinical anJ laboratory criteria arc sum -marizeJ in Table 2.In both groups there was an rilmost parnllel Jeclinc in the rwo activity inJiccs (Figures 1,2 ), erythrocyte scJimcntacion rate (Figure 3) an.d platelet count (Figure 4 ), as well as an increase in scrum a lbumi n (Figu re 5) nn<l boJy weight (Figure 6) Juring the treatment period of 12 weeks.The obscrvcJ siJc effects arc listed in Trible 3. The abso lu te anJ relative numbers of aJvcrsc events were higher in the sulfasa lazine/corticosteroid group (n=6; 23"X,) than in the mesalazine-treaceJ patients (n=3; 12.5%).In two p.:itients sulfasalazine had LO be withdrawn and in o ne pritient Jose was reduced beca use of increases in hepatic marker enzymes.Mesalnzi ne had to be disconcinueJ in one patient because of reversible increases in tran.saminases;ha ir loss and acne improved Jespite continuation of mesalazinc.Otherwise, none of the monitorcJ laboratory va lues (cg, scrum creatinine, electrolytes, transaminascs, prothrombin time, urine status) was affected by the d rug treat mcnt .

DISCUSSION
This comparati ve stud y clearly indica tes that oral mcsalazine at a dose of 3 g/day is effective in the treatment of active Crohn 's Jiscasc.According to common ly appl icJ activity inJices and lahnratory p;:irameters assessing the severity of the intla mmntory processes, the mcsa lazine-induccd remission rate with the new dose regimen ( I g tiJ) was comparable to chc established trcatmenr with sulfasa lazinc and cortico-stcroiJs (Table 2).In aJdition , mcsalazine was superior to the com-bineJ standard t reatment in terms of siJe effects (Table 3).
During the ranJomizcd controllcJ trial one minor difference was observed between ho th gro ups (Table 2).At the cnJ of the 12 week treatment period patients o n combineJ treatment ga ined slightly more hoJy we igh t (P=0.024)according to the Broca inJcx.This effect could also have been caused by the writer retaining effect of the co-admin-btcreJ mcth ylprcdnisolonc .
The time profiles in the ch.:i nges of  Lhc variou~ clinical rarnmctcrs (Figures 1-6) in<l1c..i te<l thar pmients wirh Crohn 's <liseasc respon<lcd somewhat earlier LO sulfasalazine/corticostcroith than ro mo no thcrapy with mesalazine.This marginal Jiffcrencc appear~ be due to the initial do~ing wi I h 40 mg methylpreJnisolone.Ncverthdess oral mesalazine at the higher do~e of 3 g/Jay offers an effecti ve a lternative (or patients with active Crohn's Jiseasc since its remission rnte of 83% is comparable to sta ndard treatment.Whether an even higher and/or faster remission rate coulJ be achieveJ hy combining m esalazine with corticosteroids remaim to be evaluated.I lowever, fo r the four nonresponJers to mesalazinc, if I 00 mg methylprednisolone were subsequently added to their drug regimen, remissio n w;is 111-<luced within four weeks.No siJc effects were observed during th is com bined treatment.These apparently additive effects are most likely due IO the d ifferent moJes of action of the two drugs.Where mesalazine proba bly acts both as an inhibitor of lcukmri ene synthesis (10)(11)(12) and a potent scavenger of tox ic oxygen radicals ( 13, l 4 ), corticosteroids affect the initial libern tio n of arachidonic aciJ from phospholipids.
S ince mesalazine's dl)Se/concentration-Jependcnr pharmaco logica l actions and the inflammatory processes bo th occur within the inrest111al mucous cells, it is important that sufficient active Jrug is available at these sites of inflammation.Apparently the present mesalazine stanuard dose of 1.5 g/day might be too low for some patie nts with Crohn 's disease as inJ,.cateJ by a Danish study ( l 5) or the autho rs' first experience ( in a few cases corticosteroids haJ l o be aJdeJ to mesalazine) ( 16).It appea rs to be important that mesalazine cahlets release eno ugh active ingreJients in the small howel which in mo re than 75 % of cases is inflamed in Crohn's disease.According to earlier pharmacokinetic stuJies in patie nts with chro nic inflammatory bowel disease this goal has been accomplished by the special galenic formulation of th e mesalazine preparation useJ ( 5). S ince the absorbed amo unts   of mesalazine are immediately acetylated by the in testina l mucosa and the liver (1 7,1 8), o nly low concentrations of unchanged mesalazine are found in the circulating blood (5,18).This extensive presystemic elimination can explain the low inc idence of side effects seen with mesalaz ine.
Intestinal transit time will probably affect how much of a mesalazine dose will actually reach its target.Therefore, it could be antic ipated that substances inhibiting motility such as loperamide could be of additional value in cases of accelerated gastrointestinal passage.Likewise, co-administration of cho lesryramine which binds bile acid migh t reduce diarrhea.
So far mesalaz ine ( in the fo rm of suppositories, enemas and tablets) has proven its clinical efficacy for inducing and maintaining rem rss10n in numerous patients with ulcerat ive colitis ( 2,(19)(20)(21)(22)(23)(24)(25)(26)(27).From th e present study it is apparent that a special oral form of mesalaz ine at a dose of 3 g/day is also an effect ive a nd safe treatment fo r patients with Croh n's d isease.As its cl inica l efficacy is comparahle to standard treatmen t and since it is even better tole ra ted, mesalaz ine may be conside red the d rug of c ho ice in active Crohn's d isease of moderate severity.

"
According to Westergren offer I h In mm: n Number of patients

Figure 2 )
Figure 2) Averaged time-deJ>endem decrease m ihe relarive 1,m 1 Hees activity index in patients with Crohn's disease treated with either mesalazine 1 g rid ( closed circles) or sulfasalazine I g rid and merhylprednisolone ( diamonds)

TABLE 2 Clinical and laboratory parameters (mean ± SD) for assessing clinical ef- ficacy in both treatment groups
ESRErythrocyte sedimentation rote: Sulfa Sulfosolozine Averaged rime-de/>endenr increase in the relariw 13roca mt.lex in J>ariems wirh Crohn's disease tr eared either wirh mesa/azine I g rid ( closed circles) or wirh sulf asalazine I g rid and merhylprednisolone( diamonds)