Aliment Pharmacol Ther 2002; 16: 69±77.
A double-blind comparison of balsalazide, 6.75 g, and sulfasalazine, 3 g, as sole therapy in the management of ulcerative colitis J. C. MANSFIELD*, M. H. GIAFFER*, P. A. CANN , D. MCKENNA*, P. C. THORNTONà& C. D. HOLDSWORTH* *Gastroenterology Unit, Royal Hallamshire Hospital, Shef®eld, UK;  Gastroenterology Department, South Cleveland Hospital, Middlesbrough, UK; and àBiorex Laboratories Ltd, En®eld, Middlesex, UK patient diaries, symptom assessment, sigmoidoscopic Background: Sulfasalazine is accepted therapy for active Results: Fifty patients were recruited: 26 allocated to ulcerative colitis, but side-effects and intolerance are the balsalazide group and 24 to the sulfasalazine group.
common. Balsalazide is an azo-bonded pro-drug which More patients withdrew due to adverse events in the also releases 5-aminosalicylic acid into the colon, but sulfasalazine group (nine patients vs. one patient in the balsalazide group, P ˆ 0.004). Improvement occurred Aim: To compare the safety and ef®cacy of sul- in both groups, with a tendency to a faster response fasalazine, 3 g, with balsalazide, 6.75 g, in the initial with balsalazide. Of the patients taking balsalazide, 61% daily treatment of mild to moderate ulcerative colitis.
achieved clinical and sigmoidoscopic remission.
Methods: A randomized, multicentre, double-blind, par- Conclusions: Balsalazide, 6.75 g, is effective as the sole allel group study was performed, with a treatment treatment for patients with mild to moderately active duration of 8 weeks. Patients on previous maintenance ulcerative colitis, with signi®cantly fewer withdrawals treatment were excluded. The trial medication was the due to side-effects than in a similar group of patients sole treatment for the colitis. Ef®cacy was assessed by it is split by colonic bacterial azoreductase into sulfa- pyridine and 5-aminosalicylic acid (mesalazine). Most of Sulfasalazine is an effective treatment for ulcerative the sulfapyridine is absorbed from the colon and is colitis in the maintenance of remission and in acute responsible for many of the sulfasalazine side-effects.6 active disease.1±4 A recent review concluded that The 5-aminosalicylic acid component is the therapeutic sulfasalazine remains the drug of choice for most agent and is believed to work topically at the colonic patients to induce remission in active ulcerative colitis.5 Many patients, however, are unable to tolerate the drug Oral 5-aminosalicylic acid is unstable in gastric acid at high doses, as side-effects necessitating withdrawal or and is rapidly absorbed from the small intestine. A dose reduction are common (up to 45%).3 Orally number of delivery systems have been devised to deliver administered sulfasalazine is largely unabsorbed in the 5-aminosalicylic acid to the colonic mucosa, including small intestine and mostly passes into the colon, where pH-dependent coating, delayed-release microspheresand azo-bonding of two 5-aminosalicylic acid molecules to each other.9 None of these delivery mechanisms has Correspondence to: Dr J. C. Mans®eld, Gastroenterology Department, Royal proved to be entirely satisfactory, with small bowel Victoria In®rmary, Newcastle-upon-Tyne, NE1 4LP, UK.
absorption of 5-aminosalicylic acid, passage of intact capsules and diarrhoea being problems in some patients Balsalazide is a 5-aminosalicylic acid pro-drug, in This was a randomized, multicentre, double-blind, which 5-aminosalicylic acid is linked via an azo-bond to parallel group study comparing balsalazide, 6.75 4-aminobenzoyl-b-alanine, an inert and biologically g/day, with sulfasalazine, 3 g/day, administered in inactive carrier molecule.12 Balsalazide releases three divided doses, in the treatment of acute ulcera- 5-aminosalicylic acid into the colon by the action of tive colitis. Patients were screened for eligibility and bacterial azoreductase, in a manner similar to sulfasal- given placebo matching the trial treatments for the azine. The inert nature of the carrier molecule, in ®rst 2 days of the study to establish the baseline bowel contrast to sulfasalazine, may allow more patients to habit. Treatment for the next 2 days comprised tolerate the treatment and higher doses of 5-aminosal- balsalazide, 4.5 g daily, or sulfasalazine, 2 g daily, icylic acid to be delivered to the colon. Published trials equivalent to two-thirds of the full daily dose. On day with balsalazide have shown it to be superior to 5, treatment was increased to the full dose. Study mesalazine in the induction of remission,13±15 and as drugs were prepared, packed and labelled by Biorex effective as sulfasalazine and mesalazine in the main- Laboratories Ltd, En®eld, Middlesex, UK, in identical tenance of remission.16, 17 Trial data comparing balsa- gelatine capsules. The study was conducted prior to lazide to sulfasalazine in active disease are limited to the the introduction of the international code of Helsinki abstract reports of this and one other study.18, 19 Good Clinical Practice. Patients were treated over The aim of this study was to compare the safety and 8 weeks and visited the study sites at weeks 0, 2, 4 ef®cacy of balsalazide, 6.75 g daily (equivalent to and 8. At the ®rst visit, written informed consent was 2.36 g of 5-aminosalicylic acid), with sulfasalazine, taken and patient demographics and a history of 3 g daily (equivalent to 1.15 g 5-aminosalicylic acid), ulcerative colitis were collected. At each visit, weight, in the initial treatment of mild to moderately active pulse, general well-being, bowel frequency, the pres- ence/absence of stool blood, changes in smokinghabits, other drugs and side-effects were recorded.
Patients were also given diaries within which to record stool frequency, consistency and the presence of blood and/or mucus. These diaries were also used to collectany ill effects that the patients experienced whilst on Patients were recruited from three hospitals in northern study medication. On entry and at the end of the England. Patients gave written informed consent and study, laboratory biochemistry and haematology were local research ethical committee approval was obtained.
performed. Sigmoidoscopy was performed at weeks 0, The study was conducted under a clinical trials 4 and 8, with rectal biopsies for histology at weeks 0 certi®cate (approval number 0181/031). Adults with and 8. At the end of the study, an overall assessment newly diagnosed or recently relapsed ulcerative colitis was made to determine whether the patient had were included. Patients who had experienced a previous achieved remission. Remission was de®ned as a stool attack were eligible if they were not on maintenance frequency of two or less per day without blood and treatment. The diagnosis of active ulcerative colitis was with a sigmoidoscopic appearance of normal rectal con®rmed by the presence of friable or spontaneously bleeding mucosa at sigmoidoscopy, in conjunction with All histology specimens were examined and graded for a negative stool culture. Patients with systemic upset in¯ammation by one histopathologist blind to the indicating the need for treatment with corticosteroids were excluded. Patients who had been treated withcorticosteroids, including topical use, azathioprine or any 5-aminosalicylic acid preparations over the pre-ceding 2 months were excluded. Individuals with The sample size of 50 patients was calculated to have signi®cant renal or hepatic disease, known intolerance 80% power to detect a difference in intolerance, to sulfasalazine and women who were or might become measured by withdrawals due to adverse events, of pregnant during the study were also excluded.
35% (45% vs. 10%), at a signi®cance level of 5%.20 Ó 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 69±77 BALSALAZIDE VS. SULFASALAZINE IN ULCERATIVE COLITIS Demographic data and medical history were summar- day. Demographic data and disease history are shown ized by means and standard deviations or frequency in Table 1. The treatment groups were well matched for tables as appropriate. Remission rates for each treat- sex, age and weight. The sulfasalazine group contained ment were compared using a chi-squared test on the more smokers (6/24 vs. 1/26, P ˆ 0.045). This was the basis of an intention-to-treat analysis. Signs and ®rst attack for 40 of the 50 (80%) patients; the symptoms were summarized by means and standard remaining 10 patients had been diagnosed previously, deviations or frequency tables as appropriate, and but had not received medical treatment for at least treatments were compared either by the two-sample 2 months prior to the study. Of the six patients who had t-test or by the Wilcoxon rank sum test. Percentages in suffered from relapses in the last 2 years, three were the frequency tables of symptoms were based on the allocated to each group. The extent of disease was well total number of patients who had an assessment made balanced across the treatment groups.
and not on the total number of patients treated. P valueswere two-tailed.
Adverse events were summarized by tabulating the number of subjects who experienced each event.
The overall study outcome, including all patients, is Adverse events were categorized using a modi®ed World shown in Table 2. The most important statistically Health Organization Adverse Reaction table. Where the signi®cant difference between the two treatments was incidence of events was large enough to be compared that more patients were withdrawn for adverse events between treatments, the comparison was performed whilst taking sulfasalazine than whilst taking balsalaz- ide (P ˆ 0.004). There were trends in favour of balsalazide in respect of the rates of remission and thesmaller numbers of patients withdrawn because the treatment was ineffective, but these were not statisti- Two patients (one in each group) were withdrawn Fifty patients were recruited into the study: 26 allocated from the study because they failed to comply with the to balsalazide, 6.75 g/day, and 24 to sulfasalazine, 3 g/ protocol: one failed to attend the clinic visits and one Ó 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 69±77 took only one capsule (instead of three) three times 1.2 kg, and in the sulfasalazine group (n ˆ 11) was daily. A further patient in the balsalazide group was 0.4 kg, but the difference between the groups was not withdrawn at 2 weeks when it was realized that he had been taking sulfasalazine, 3 g daily, at the time of study Well-being was measured at each visit on a four-point scale ranging from normal to unable to work. The One patient in the balsalazide group and nine in the proportion of patients with normal well-being increased sulfasalazine group withdrew from the study because of at each visit for both treatment groups. In the adverse events. Summary information on these patients balsalazide group, 19 patients (86%) had normal well- is given in Table 3. None of the patients withdrawn for being at 8 weeks. In the sulfasalazine group, seven adverse events had received any previous exposure to patients (58%) reported this grade (P ˆ 0.18). The majority of the patients had their well-being at least Symptoms of general well-being, bowel frequency and impaired at entry, although there were slightly more stool blood were assessed at each visit and pulse rate patients with normal well-being at entry in the and weight were monitored. There was no clinically balsalazide group compared to the sulfasalazine group signi®cant change in pulse rate over the study. Weight gain from entry to 8 weeks was seen in both groups: the Bowel frequency was measured on a three-point scale mean increase in the balsalazide group (n ˆ 21) was (0, 0±2 bowel actions per day; 1, 3±5 bowel actions per Table 3. Patient withdrawals because of adverse effects (NK, not known) Recurred on rechallenge with sulfasalazine.
Events arising after full dosage achieved Ó 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 69±77 BALSALAZIDE VS. SULFASALAZINE IN ULCERATIVE COLITIS day; 2, more than 6 bowel actions per day). The study treatment, and who graded each biopsy on a four- proportion of patients with a bowel frequency of point scale from normal to severe in¯ammation. These between 0 and 2 per day increased during the study grades were assigned retrospectively after each patient for both treatments. The change in bowel frequency had ®nished the study. Two biopsies failed to yield from entry to 8 weeks is shown in Table 4. Improve- suitable tissue. Table 7 shows the frequency of patients ment in the balsalazide treatment group was signi®cant in each of the four categories of in¯ammation for each at 2 weeks (P ˆ 0.011), 4 weeks (P ˆ 0.011) and at treatment group. All but one of the patients had at least the end of treatment (P < 0.001), whilst, in the mild in¯ammation at entry, with 28 of 48 (58%) having sulfasalazine group, it was not signi®cant until week 4 severe in¯ammation. Some improvement in the histo- (P ˆ 0.03), indicating a faster improvement for balsa- logical grades can be seen on the ®nal assessment, but only 11 of 32 (34%) patients had no in¯ammation.
Rectal bleeding was assessed on a three-point scale at Both treatments showed similar histological improve- each clinic visit, ranging from absent to more than a ments among patients tolerating treatment.
trace. The number of patients with no blood in theirstools increased at each clinic visit for the balsalazide group, and increased at 2 weeks but then decreased slightly in the sulfasalazine group. The changes in rectal On a daily basis, patients recorded in their diaries the bleeding from entry to 8 weeks are summarized in consistency of their stools and whether blood and mucus were passed. Three patients (two in the sulfa- Rigid sigmoidoscopy was performed at entry, 4 weeks salazine group and one in the balsalazide group) did not and at the ®nal visit. The results were graded on a four- return their diaries. The diary data were analysed for point scale, ranging from normal to spontaneous 3-day periods at baseline, week 4 and at the end of bleeding, and are shown in Table 6. The proportion of treatment. The median number of loose stools was patients with normal sigmoidoscopic appearance reduced from eight at baseline in both groups to one for increased at each visit for both treatments. However, the balsalazide group and none for the sulfasalazine the difference between the treatment groups was not group at week 8. The median number of stools with blood and mucus at baseline was four for the balsalazide Rectal biopsies were performed at entry and at the ®nal group and ®ve for the sulfasalazine group. These visit. All the slides from these biopsies were reviewed by medians reduced to zero for the balsalazide group at one consultant histopathologist, who was blind to the 4 weeks and for both the balsalazide and the sulfasal- Ó 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 69±77 Table 6. Summary of sigmoidoscopic appearances (0, normal; 1, with sulfasalazine and aspirin. One patient on sulfasal- mild minimal/no bleeding; 2, contact bleeding; 3, spontaneous azine presented with chest pain on day 8 of the study and was found to have a venous thrombosis in the leg and carcinoma of the lung. Another patient on sulfasalazine was admitted to hospital on day 11 with acutepancreatitis which settled with conservative medical treatment. All patients had their study medication stopped at the time of the serious adverse events and As noted above, adverse events caused the withdrawal of 10 patients overall (nine on sulfasalazine and one on balsalazide) (P ˆ 0.004), of which three were de®ned as serious. A review of the incidence of adverse events showed that at least one non-serious adverse event wasexperienced by 17 of 26 (65%) patients in the balsalazide group and 21 of 24 (88%) patients in the sulfasalazine group (P ˆ 0.10). Many of these were mild aches and non-speci®c fatigue, and were balanced between the treatment groups. For three adverse events,there was an imbalance between the groups in favour of azine groups at 8 weeks. Overall, the diary data showed balsalazide. Headache was the most common side-effect similar improvements in both groups.
seen in this patient population, with an incidence of 5/26 (19%) in the balsalazide group and 13/24 (54%) in the sulfasalazine group (P ˆ 0.018). Gastrointestinal events, including abdominal pain and dyspepsia, were Details of any side-effects were recorded at each clinic evenly balanced between the groups; however, there visit. Adverse events were also collected in the well-being was an advantage for balsalazide with respect to nausea section, ®nal evaluation page and the patient's diary (2/26 (8%) vs. 8/24 (33%), P ˆ 0.035) and vomiting card. Three patients experienced adverse events categ- orized as serious by virtue of causing hospital admission.
One patient in the balsalazide group suffered from an erythematous rash on the neck on day 5 of treatment in response to the study medication and required a brief There were no signi®cant changes in any of the admission. This patient subsequently developed a rash haematological or biochemical tests performed at entry Ó 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 69±77 BALSALAZIDE VS. SULFASALAZINE IN ULCERATIVE COLITIS and at the end of the study period. In six of the 26 however, some interesting if minor differences between patients in the balsalazide group, the erythrocyte the groups. The degree of weight gain was slightly sedimentation rate fell from high to normal, as it did in higher for the balsalazide group. Changes in sigmoi- three of the 24 patients in the sulfasalazine group. Three doscopic grade and bowel frequency scores, while patients in each group showed a change from high to showing no statistically signi®cant differences between normal platelet counts. There was no signi®cant change the groups, showed trends supporting a better result in the urinalysis results from either patient group.
The inclusion of histology in the assessment of ef®cacy was intended to identify patients in whom clinical remission was also associated with histological remis- In this small study of the initial management of patients sion. The number of patients in categories 1 and 2 with active ulcerative colitis of mild to moderate (normal and minimal in¯ammation without active severity, balsalazide, 6.75 g, proved to be signi®cantly disease) increased in both treatment groups, from one better tolerated than sulfasalazine, 3 g.
patient in each group to 11 for balsalazide and seven for Sulfasalazine has been in use for many years for the sulfasalazine. In both groups, this represents over half treatment of ulcerative colitis and was included in this the patients completing the study. Histological improve- trial as an active control. The dose of 3 g daily for the ment is known to lag behind the clinical response, and sulfasalazine group was chosen because of previous the changes observed are compatible with the clinical clinical experience, which con®rmed published evi- dence,21 indicating that the use of a dose higher than In the planning of this trial, it had been hoped that 3 g was likely to be so poorly tolerated that no using double doses of available 5-aminosalicylic acid comparison of ef®cacy would be possible.
(mesalazine) in the balsalazide group would lead to In terms of patient tolerability, the results from this improved ef®cacy. The dose±response curve for mesal- study indicate a marked difference in favour of the azine, however, has been found to be ¯at with other newer compound, balsalazide. Of the 26 patients on delivery systems,23 although a recent report has balsalazide, one withdrew because of an adverse event, suggested that doses of oral mesalazine up to 4 g may whilst nine of 24 on sulfasalazine withdrew for the same be bene®cial.24 The doses of sulfasalazine and balsalaz- reason (P ˆ 0.004). All except one (on sulfasalazine) of ide given in this trial are equivalent to the doses of these adverse events were thought by the investigators mesalazine known to be clinically effective, but at the to be related to the trial drug. Of the more common lower end of the therapeutic range. The patient adverse events which did not lead to withdrawal, numbers for comparison of the two active treatments signi®cantly fewer patients in the balsalazide group are low. The marginal differences in symptomatic were recorded as suffering from headaches, nausea or ®ndings may re¯ect a possible dose±response relation- vomiting, whilst abdominal pain and dyspepsia were ship with mesalazine released by azoreductase into the evenly divided. The ®nding of the better tolerability of balsalazide compared to sulfasalazine has also been The treatment groups were generally well matched, observed in another study of balsalazide vs. sulfasal- but there were more smokers in the sulfasalazine group azine, in which oral and topical steroids were also (6/24 vs. 1/26, P ˆ 0.045). It is unlikely that this had used,19 and in a maintenance study of balsalazide and any impact on the result of the trial, particularly as smokers have a better outcome than non-smokers,25 The difference in the proportion of patients able to and nicotine patches have been reported as bene®cial in complete the trial may confound estimates of ef®cacy; however, the method of analysis is conservative to This study is unusual in two respects. Firstly, patients account for this. No difference emerged in the were selected who had previously received no treat- proportion of patients obtaining remission in the acute ment; because of this, most patients were in their initial attack (about 60% in each group) among patients able attack of ulcerative colitis. This allowed the inclusion of to tolerate treatment. The grading and measurement patients who had no previous experience of sulfasal- of symptoms and signs were consistent with the azine, thus eliminating an important bias seen in other clinical improvement in both groups. There were, studies of sulfasalazine vs. the newer 5-aminosalicylic Ó 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 69±77 acid-releasing agents, where patients intolerant of sul- In conclusion, in this double-blind study, balsalazide, fasalazine have been excluded.4, 27 Secondly, patients 6.75 g, was signi®cantly better tolerated than sulfasal- were treated with oral 5-aminosalicylic acid-releasing azine, 3 g, in the initial treatment of patients with active medication only; no rescue medication was allowed, ulcerative colitis of mild to moderate severity. The including the use of rectal preparations and corticos- results support the use of balsalazide as the sole teroids. The conclusion of the study, that sole treatment treatment of initial attacks of this condition.
with balsalazide, 6.75 g, is an effective and safe treatment for mild to moderate active ulcerative colitis,may not be applicable to other situations, for example, where patients are already on maintenance 5-amino- The help of Dr D. J. Dawson and Professor M. G.
salicylic acid treatment or where corticosteroids are Bramble is gratefully acknowledged. We are also co-administered. The study does not directly address the indebted to the patients and nursing staff involved.
question of whether patients with mild to moderate The study was initially sponsored by Biorex Laborat- ulcerative colitis should be prescribed corticosteroids at the onset of their initial attack. Only a direct comparison of corticosteroids with balsalazide can answer this, but this study would certainly support the withholding of corticosteroids in patients without systemic upset until 1 Lennard-Jones JE, Longmore AJ, Newell AC, Wilson CWE, the initial treatment with balsalazide has been explored.
Avery Jones F. An assessment of prednisone, salazopyrin, and The only studies in the literature to address the question topical hydrocortisone hemisuccinate used as out-patient treatment for ulcerative colitis. Gut 1960; 1: 217±22.
of whether 5-aminosalicylic acid-releasing treatment or 2 Baron JH, Connell AM, Lennard-Jones JE, Avery Jones F.
corticosteroids are required used sulfasalazine, and were Sulphasalazine and salicylazsulphadimidine in ulcerative subject to the same poor tolerability as seen in this 3 Dick AP, Grayson MJ, Carpenter RG, Petrie A. Controlled trial The delivery system, via the colonic bacterial azoreduc- of sulphasalazine in the treatment of ulcerative colitis. Gut tase, is not the subject of this study as both active 4 Sutherland LR, May GR, Shaffer EA. Sulfasalazine revisited: a treatments employed this mechanism; the differences meta-analysis of 5-aminosalicylic acid in the treatment of between the treatments involved the toxicity of the ulcerative colitis. Ann Intern Med 1993; 118: 540±9.
carrier molecule and the dose of 5-aminosalicylic acid 5 Sutherland L, Roth D, Beck P, May G, Makiyama K. Oral delivered. Other studies have compared the azo-bond 5-aminosalicylic acid for inducing remission in ulcerative reductase delivery system with pH-dependent release and colitis (Cochrane Review). In: The Cochrane Library, Issue 4.
time-dependent release in the setting of mild to moderate 6 Klotz U, Maier K, Fischer C, Heinkel K. Therapeutic ef®cacy of colitis.13±15 Although the designs of these studies were sulfasalazine and its metabolites in patients with ulcerative different, when considered with the results of this study, colitis and Crohn's disease. N Engl J Med 1980; 303: 1499±502.
it can be concluded that sulfasalazine is insuf®ciently 7 Azad Khan AK, Piris J, Truelove SC. An experiment to tolerated to be the drug of choice and pH-dependent determine the active therapeutic moiety of sulphasalazine.
release mesalazine (Asacol) may be less reliably delivered 8 van Hees PAM, Bakker JH, van Tongeren JHM. Effect of sul- to the diseased colon than balsalazide, which consistently phapyridine, 5-aminosalicylic acid, and placebo in patients appears to be effective and well tolerated.
with idiopathic proctitis: a study to determine the active Balsalazide is a relatively new drug compared to therapeutic moiety of sulphasalazine. Gut 1980; 21: 632±5.
sulfasalazine, and is therefore more expensive at current 9 Riley SA, Mani V, Goodman MJ, Herd ME, Dutt S, Turnberg prices. From the data presented here, the difference in LA. Comparison of delayed release 5-aminosalicylic acid (mesalazine) and sulphasalazine in the treatment of mild to cost of around £77 (UK prices £100 vs. £23) over moderate ulcerative colitis relapse. Gut 1988; 29: 669±74.
8 weeks is offset by the superior tolerability, with 10 Willoughby CP, Cowan RE, Gould SR, Machell RJ, Stewart JB.
intolerance reduced from 38% to 4%. The choice of a Double-blind comparison of olsalazine and sulphasalazine in well-tolerated therapy is especially important for initial active ulcerative colitis. Scand J Gastroenterol 1988; treatment, as successful ®rst-line therapy will prevent the loss of con®dence and escalation to more toxic 11 Giaffer MH, O'Brien CJ, Holdsworth CD. Clinical tolerance to three 5-aminosalicylic acid releasing preparations in patients Ó 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 69±77 BALSALAZIDE VS. SULFASALAZINE IN ULCERATIVE COLITIS with in¯ammatory bowel disease intolerant or allergic to colitis? Results of a randomized trial. Gastroenterology 1993; sulphasalazine. Aliment Pharmacol Ther 1992; 6: 51±9.
12 Green JRB. The treatment of ulcerative colitis with balsalazide 20 Altman DG. Practical Statistics for Medical Research. London: sodium. In¯ammopharmacology 1993; 2: 289±95.
13 Green JRB, Lobo AJ, Holdsworth CD, et al. Balsalazide is more 21 Azad Khan AK, Howes DT, Piris J, Truelove SC. Optimum dose effective and better tolerated than mesalamine in the treat- of sulphasalazine for the maintenance treatment in ulcerative ment of acute ulcerative colitis. Gastroenterology 1998; 114: 22 Rao SSC, Dundas SAC, Holdsworth CD, Cann PA, Palmer KR, 14 Levine DS, Pruitt R, Riff D, et al. A multi-center, double-blind Corbett CL. Olsalazine or sulphasalazine in ®rst attacks of dose±response trial of Colazide (balsalazide disodium) and ulcerative colitis? A double blind study. Gut 1989; 30: Asacol (mesalamine) for mild±moderately active ulcerative colitis. Gastroenterology 1997; 112: A1026(Abstract).
23 Hanauer S, Schwartz J, Robinson M, et al. Mesalamine cap- 15 Pruitt R, Hanson J, Safdi M, et al. Balsalazide is superior to sules for treatment of active ulcerative colitis: results of a mesalamine in the time to improvement of signs and symp- controlled trial. Am J Gastroenterol 1993; 88: 1188±97.
toms of acute ulcerative colitis. Gastroenterology 2000; 118: 24 Vecchi M, Meucci G, Gionchetti P, et al. Oral versus combi- nation mesalazine therapy in active ulcerative colitis: a dou- 16 McIntyre PB, Rodrigues CA, Lennard-Jones JE, et al. Balsa- ble-blind, double-dummy, randomized multicentre study.
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25 Rudra T, Motley R, Rhodes J. Does smoking improve colitis? Aliment Pharmacol Ther 1988; 2: 237±43.
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17 Green JRB, Gibson JA, Kerr GD, et al. Maintenance of remis- 26 Pullan RD, Rhodes J, Ganesh S, et al. Transdermal nicotine for sion of ulcerative colitis: a comparison between balsalazide 3 g active ulcerative colitis. N Engl J Med 1994; 330: 811±5.
daily and mesalazine 1.2 g daily over 12 months. Aliment 27 Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative 18 Mans®eld JC, Giaffer MH, Cann PA, Holdsworth CD, McKenna colitis: a randomised trial. Br Med J 1989; 298: 82±6.
DM, Thornton PC. Is high dose balsalazide better than sul- 28 Truelove SC, Watkinson G, Draper G. Comparison of cortico- phasalazine in the initial management of ulcerative colitis? steroid and sulphasalazine therapy in ulcerative colitis. Br Med 19 Green JRB, Swan CHJ, Rowlinson AE, et al. Sulphasalazine or high dose balsalazide to treat acute relapse in ulcerative Ó 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 69±77


¿qué es el dolor patelofemoral

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