ORIGINAL ARTICLE
A New Oral Delivery System for 5-ASA: Preliminary Clinical Findings for MMx Cosimo Prantera, MD,* Angelo Viscido, MD,† Livia Biancone, MD,‡ Antonio Francavilla, MD,§ Lucio Giglio, MD,* and Massimo Campieri, MDk
Background: Multi-matrix (MMx), a new delivery system for mesalazine, seems to release 5-aminosalicyclic acid (5-ASA) preferentially in the sigmoid colon. This study had 2 objectives: (1) to evaluate the therapeutic response to MMx in patients with active left-sided disease and (2) to gain additional insights as to how the therapy would compare with topical 5-ASA.
Methods: Patients received either 1.2 g of 5-ASA MMx three times per day plus placebo enema or 4 g of 5-ASA enema plus placebo tablets for 8 weeks. The primary endpoint was clinical remission (clinical activity index #4) at 8 weeks. Secondary endpoints were endoscopic and histologic remissions. Results: Seventy-nine patients were enrolled. Clinical remission rates at 4 and 8 weeks were 57.5% and 60.0% for patients treated with MMx and 68.4% and 50.0% for patients randomized to 5-ASA enemas, respectively (95% confidence interval for the difference at 8 weeks, 212 to +32). Endoscopic remission was achieved by 45.0% of patients on 5-ASA MMx and by 36.8% of those on enema, whereas 15.0% and 8% of patients, respectively, showed histologic remission. Compliance was 97.0% for oral and 87.5% for topical therapy. In the enema group, compliance was 88.0% for the patients in remission and 65.5% for those with active disease. Conclusions: Preliminary studies suggest that similar rates for induction of remission can be expected from 5-ASA enemas and MMx for patients with left-sided ulcerative colitis. Key Words: 5-aminosalicyclic acid, 5-aminosalicyclic acid multimatrix, left-sided ulcerative colitis, mesalamine (Inflamm Bowel Dis 2005;11:421–427)
Received for publication October 7, 2004; accepted January 24, 2005. From the *Department of Gastroenterology, Azienda Ospedaliera S. CamilloForlanini, Rome, Italy; †Department of Gastroenterology, Universita` La Sapienza, Rome, Italy; ‡Department of Gastroenterology, Universita` Tor Vergata, Rome, Italy; §Department of Gastroenterology, Universita` degli Studi", Bari, Italy; and kPoliclinico S. Orsola, Bologna, Italy. Reprints: Cosimo Prantera, MD, Division of Gastroenterology, Azienda Ospedaliera S. Camillo-orlanini, Rome, Italy (e-mail:
[email protected]) Copyright Ó 2005 by Lippincott Williams & Wilkins
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INTRODUCTION Ulcerative colitis (UC) is a chronic inflammatory disease that involves the rectum and a variable portion of the colon. In the majority of patients, the inflammation is limited to the left side of the colon.1,2 Aminosalicylates are the drugs of choice for either the induction or maintenance of remission. Two meta-analyses,3,4 consisting of 22 trials involving oral 5-aminosalicyclic acid (5-ASA) and sulfasalazine, failed to show a significant difference between the 2 treatments, but mesalazine given topically remains the treatment of choice for patients with localized disease.5,6 Long-term therapy with enemas is accepted only reluctantly by patients.6 5-ASA multi-matrix (MMx) 1.2-g tablets (SPD476) is a new formulation of mesalazine that is characterized by a patented polymeric matrix. In comparison with all other oral forms of mesalazine available it is distinguished by the presence of a double matrix: a lipophilic matrix dispersed within a hydrophilic matrix. In fact, the core of the tablet consists of mesalazine incorporated in microparticles of lipophilic matrix, dispersed in turn within a hydrophilic matrix. The core is coated with a gastroresistant polymer film with pH-dependent dissolution. Consequently, the tablet remains intact in the stomach. The coating begins to dissolve only in the final tract of the ileum; at this point, the hydrophilic matrix starts to erode, and the active ingredient diffuses out of the lipophilic matrix. In this way (i.e., through the combined mechanism of erosion and diffusion), mesalazine is delivered to the site of action through an almost linear kinetics profile. The release of 5-ASA is slow and gradual, which helps to provide a consistent and homogeneous distribution along the ascending, traverse, and descending colon and in the sigmoid flexure and rectum to treat localized pathologies in these areas, such as UC. The decision to proceed with preliminary studies of MMx, a new 5-ASA formulation, was based on 3 principles. First, in theory, the azo-bonded 5-ASA preparations (as Salazopyrine, olsalazine, and balsalazide) should, because of bacterial action, deliver more 5-ASA to the proctosigmoid colon than would other preparations that release 5-ASA mainly in the distal ileum and right colon.7 Second, the new formulation 1.2 g 5-ASA MMx tablets (SPD476) deliver more active
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drug to the colonic lumen than do other mesalazine formulations.8 Eighty percent of this absorption occurs in the colon. Third, a scintigraphic study with 153Sm showed that MMx was still detectable in the sigmoid colon 24 hours after ingestion.8 The effectiveness of topical 5-ASA therapy in patients with distal UC has already been established. Therefore, we conducted this study to compare the remission rates that could be achieved with 5-ASA MMx and 5-ASA enemas.
MATERIALS AND METHODS We undertook a randomized, double-blind, doubledummy trial to evaluate the therapeutic response to MMx in patients with active left-sided disease to provide the data for the sample size calculation required for a larger trial. Patient participation was limited to those with mildly to moderately active left-sided UC. The study was conducted in 5 Italian centers between November 2001 and March 2003.
Patient Selection Included patients were at least 18 years old with active left-sided UC (disease extending $15 cm but no further than the splenic flexure) of mild or moderate severity, as determined by a clinical activity index (CAI) $6.9 Exclusion criteria were extent of inflammation that was ,15 cm or beyond the splenic flexure; severe UC; infectious colitis; use of oral or topical steroids or immunosuppressive agents in the 4 weeks before the study; known intolerance to salicylates; pregnancy or ongoing lactation; severe diseases involving other organs or systems, including liver or renal failure; significant abnormalities on laboratory tests; local or systemic pathologic states requiring therapy with corticosteroids, immunosuppressive agents, or antibiotics; use of drugs that could affect the pH of the intestinal lumen, including laxatives or antibiotics; participation in experimental therapeutic studies in the 6 months before the study; and inability to follow the protocol for any reason. The study was performed in a double-dummy fashion. One group of patients received 5-ASA MMx 1.2-g tablets plus a placebo enema, whereas the other group received placebo tablets plus an Asacol 4 g/100 mL enema (Giuliani S.p.A., Milan, Italy). Both sets of tablets and enemas were identical in appearance and packaging. Tablets were taken as 1 tablet 3 times daily. Enemas were administered once per day, before bedtime. Patients were instructed to retain the enema as long as possible. In case of reduced ability to retain enema (,4 hours) patients could reduce the enema volume in the first day and increase the volume to 100 mL as soon as possible. No concurrent systemic or topical therapy for UC was allowed.
Evaluation The patients were clinically evaluated at baseline and after 4 and 8 weeks of treatment. A full colonoscopy was performed at the initiation of the study, and another endoscopy, at
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least up to the splenic flexure, was carried out at the time of the final visit.
Primary Efficacy Variable The aim of the study was to assess whether the treatment with 5-ASA MMx 1.2-g tablets, at the dosage of 3.6 g/d, was able to induce a similar percentage of remission in patients with mildly to moderately active left-sided UC to that induced by Asacol 4 g rectal suspension. The primary outcome variable was clinical remission defined as a Rachmilewitz CAI score #4 at 8 weeks.9 The index was calculated as the sum of the total score of 7 variables: number of stools in the past week, presence of blood in stools (based on weekly average), abdominal pain, investigator’s global assessment of disease activity, temperature (related to colitis), presence of extraintestinal manifestations, and alteration of laboratory findings (erythrocyte sedimentation rate, hemoglobin).
Secondary Efficacy Variables Secondary efficacy variables included (1) time to disappearance of symptoms (determined from patient diaries) and (2) changes in endoscopy and histology (comparison of endoscopic and histologic reports from procedures performed at study entry and study completion). Endoscopic activity was evaluated according to the endoscopic index (EI) developed by Rachmilewitz.9 This index takes into account the following variables: granularity (scattering of reflecting light), vascular pattern, vulnerability of mucosa (friability), and mucosal damage (mucus, fibrin, exudates, erosions, ulcer). Endoscopic remission was defined as El #2. The histologic index was evaluated using the score of Flore´n et al.10
Safety and Compliance The following laboratory tests were performed at the start of the study and at weeks 4 and 8: complete blood count, creatinine, aspartate aminotransferases, alanine aminotransferases, g glutamyltransferase, azotemia, alkaline phosphate, lipase, and urine analysis. Changes from baseline were assessed for their possible relationship to the treatment. Adverse events were recorded and assessed for severity and possible relationship to study drugs. In particular, renal and pancreatic laboratory tests were closely monitored, and any diarrhea or alopecia during the study was noted. Compliance was evaluated according to 2 criteria: (1) number of tablets and enemas dispensed to the patient and (2) a review of patient diary cards to ascertain the number of tablets or enemas taken.
Statistical Methods In this study aimed to estimate the therapeutic response to a new 5-ASA formulation, the sample size was one of convenience. However, the planned sample of 40 patients per group was able to give a 95% confidence interval (CI) 615% q 2005 Lippincott Williams & Wilkins
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wide for the estimate of the remission rate of each treatment and 622% for the difference of the remission rate between treatments. Patients were randomized into 2 treatment groups for each center using a computer-generated central list. The primary analysis was based on the intent-to-treat population that included all randomized patients who satisfied the inclusion and exclusion criteria. A per protocol analysis of the primary variable was also carried out that excluded patients who were considered lost to follow-up, withdrew consent, or became pregnant. For the statistical analysis of the CAI score, missing values were handled using the last value carried forward approach (based on the patient’s diary data). Patients were considered to have terminated the study if they withdrew because of the development of other pathologic states that could interfere with the disease or with the evaluation of study treatment, who withdrew consent, or were lost to follow-up and had no data available for the calculation of CAI at the time of discontinuation. These patients were considered treatment failures. Patients who discontinued the study because of the onset of severe or unexpected side effects or who required study treatment discontinuation, at the discretion of the patient or of the investigator, were also regarded as treatment failures, irrespective of the value of CAI at the time of discontinuation. The differences between the groups in baseline data were evaluated using analysis of variance for continuous data, x2 test for proportions, and the Mann-Whitney U test for categorical data. Differences between the 2 treatments were compared by determining the remission rates and 95% CIs during and at the end of the study. The CAI score and the endoscopic and histologic indices were analyzed using nonparametric tests. The time lapse before disappearance of symptoms (as recorded in patient diaries) was analyzed using survival analysis methods. Statistical analysis was carried out by the suitable procedures of the statistical package SPSS version 10.0 (SPSS, Chicago, Ill.).
Ethical Considerations This study was conducted according to the Helsinki Declaration (Edinburgh, October 2000), and we adhered to Good Clinical Practice Guidelines. The Ethical Committees at each center approved the study. All patients were given a detailed description of the study, and written informed consent was obtained before the randomization.
RESULTS
Oral 5-ASA MMx Compared to Enema in Left-sided Colitis
Fifty-nine patients had UC limited to the recto-sigmoid colon, whereas 20 had left-sided disease. One patient initially randomized to the enema group was excluded from the analysis for major protocol violation at entry, so that the intentionto treat analysis is based on 78 patients.
Clinical Effectiveness At the 4-week visit, clinical remission (CAI # 4), was achieved in 23 patients in the 5-ASA MMx group (57.5%) and in 26 patients in the enema group (68.4%). At 8 weeks (primary endpoint), 24 of 40 patients (60.0%; 95% CI, 44.8– 75.2) on 5-ASA MMx and 19 of 38 patients (50.0%; 95% CI, 34.1–65.9) on enema therapy were in remission (95% CI for the difference, 212.0 to +32.0). Between week 4 and week 8, no patients treated with enemas achieved remission, whereas 4 patients in the 5-ASA MMx group went into remission. Four patients in the enema group and 2 patients in the 5-ASA MMx group, in remission at 4 weeks, relapsed between 4 and 8 weeks. The trial profile is shown in Figure 1. The difference in CAI score from baseline to week 4 and week 8 was statistically significant in both groups (P , 0.05 by Wilcoxon rank sum test; Fig. 2). At the final visit, an additional 17.5% and 10.5% of patients treated with 5-ASA MMx and enema, respectively, showed a clinical improvement of at least 1 point on the CAI scale. Figure 3 shows the time of disappearance of symptoms, which was not statistically different between the groups. Abdominal pain disappeared approximately 5 to 6 days earlier in patients treated with 5-ASA MMx, whereas the other symptoms disappeared 1 to 2 days sooner in patients treated with enemas.
Per Protocol Analysis The per protocol analysis showed a trend similar to the intention-to-treat analysis.
Endoscopic and Histologic Effectiveness Endoscopic remission (EI # 2) was achieved by 18 patients (45.0%; 95% CI, 29.6–60.4) treated with 5-ASA MMx and by 14 patients (36.8%; 95% CI, 21.5–52.1) treated with enemas. There was a statistically significant improvement of EI value (P , 0.05 Wilcoxon rank sum test) in both groups in comparison with baseline value (from 6.7 to 2.9 and from 6.5 to 3.0 in 5-ASA MMx and enema groups, respectively). Histologic remission, according to the score of Flore´n et al10 was achieved in 9 patients: 6 (15.0%) in the 5-ASA MMx group and 3 (8.0%) in the enema group. The improvement of histologic score was statistically significant compared with baseline in both groups (P , 0.05 by Wilcoxon rank sum test).
Patients Characteristics
Withdrawals
Seventy-nine patients were randomized. Baseline characteristics of the patients are shown in Table 1. The patients in each group were similar with respect to clinical characteristics.
Twelve of 20 patients withdrew because of worsening of the disease, 5 of these withdrew before week 4 (3 in the 5-ASA MMx group and 2 in the enema group). At 8 weeks, in total,
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TABLE 1. Baseline Characteristics of Patients
Randomized patients M/F Mean age (yr) Extent of disease (n): Proctosigmoiditis Left-sided colitis Duration of disease (yr, mean, range) Smokers (%) CAI (mean, range) EI (mean, range) Flares in the last year (mean, range) Time since the last flare (mo, mean 6 SD) Duration of current attack (d, mean 6 SD) Oral 5-ASA in the last month
5-ASA MMx
Enema
Total
40 24/16 41.1 6 14.4
39 23/16 41.3 6 12.3
79 47/32 41.2 6 13.3
27 13 5.83 (0–34) 17.9% 7.75 (6–13) 6.73 (2–12) 1.0 (0–3) 13.8 6 15.2 38 6 54 29 (73%)
32 7 6.97 (0–33) 21.1% 7.67 (6–12) 6.49 (1–11) 0.8 (0–4) 14.1 6 15.1 32 6 58 26 (67%)
59 20 6.39 (0–34) 19.5% 7.61 (6–13) 6.61 (1–12) 0.9 (0–4) 14 6 15.1 35 6 55 55 (70%)
There are no statistically significant differences between treatment groups.
there were 5 withdrawals in the 5-ASA MMx group and 7 in the enema group. One patient in the 5-ASA MMx group withdrew before week 4 because of pregnancy. She gave birth to a healthy baby.
Two patients in the enema group had dropped out by the final visit; at the previous visit, one of them was in clinical remission, whereas the other had clinically active disease. Three patients withdrew consent (2 in the 5-ASA MMx group
FIGURE 1. Trial profile.
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FIGURE 3. Disappearance of symptoms (days, mean). FIGURE 2. Mean CAI value at entry and during the treatment.
and 1 in the enema group); at the time of withdrawal they were in clinical remission. The remaining 2 patients, both in the enema group, were considered to be protocol violators either because of the spontaneous use of topical steroids or withdrawal because of an adverse event after week 4. In the intention-to-treat analysis, all these patients, except the major protocol violation case, have been considered treatment failures.
Compliance Overall compliance was 97.0% for oral therapy (95.1% for active tablets, 99.0% for placebo tablets) and 87.5% for topical therapy (84.9% for active enema, 89.8% for placebo enema). In the group of patients who were treated with 5-ASA MMx, the compliance rate was 96.6% for patients in remission and 92.9% for patients with active disease. In the group of patients treated with active enemas, 88.0% of those in remission were compliant in comparison with 65.5% of patients with active disease.
Safety Analysis No severe or unexpected adverse events occurred during the study. Seventeen of 79 patients (21.5%) reported at least 1 adverse event: 11 of 39 patients (28.0%) in the enema group and 6 of 40 (15.0%) in the 5-ASA MMx group. Discontinuation of the study medication because of an adverse event occurred in 1 patient in the enema group (abdominal and anal pain, and headache). Three patients had abnormal laboratory test values during the trial period. One patient in the 5-ASA MMx group had an increase in serum lipase levels 5 times higher than normal but had a normal serum amylase at week 8. The value normalized 10 days after the study ended. Another patient with renal stones, treated with 5-ASA MMx, had an increase of serum creatinine of 1.4 mg/dL (normal value: 0.6– 1.2 mg/dL) at week 4. The baseline value of this patient was 1.26 mg/dL (normal range 0.4–1.3 mg/dL); 3 and 5 months after study end, the value was still slightly elevated (1.36 mg/dL at 5 months). q 2005 Lippincott Williams & Wilkins
At week 8, a third patient in the enema group showed a blood urea nitrogen increase up to 70 mg/dL (normal value, 16–46 mg/dL); the baseline and the 4-week values were normal. Two and 5 weeks after study completion, the value went back to normal.
DISCUSSION This preliminary multicenter trial in patients with leftsided active UC showed that 5-ASA MMx, a new mesalamine delivery system, was comparable with the 5-ASA enema in inducing remission after 8 weeks of treatment. From a therapeutic perspective, this is an important finding, because 80% to 90% of patients with UC have involvement distal to the splenic flexure.6,11 Sulfasalazine and 5-ASAs by oral or local administration are usually employed as treatment of these patients. The efficacy of 5-ASAs compounds is conditioned by the local concentration of the drug and by the amount of active substance that reaches the diseased site.12,13 Consequently, topical 5-ASA given by enema is considered the gold standard treatment of left-sided UC.5,6 In 3 randomized controlled studies that compared an oral 5-ASA compound with local 5-ASA, symptomatic improvement and remission spoke in favor of rectal administration.6 Unfortunately, enemas are not well accepted by patients, as confirmed by a UK enquiry in which more than 80% of patients with IBD preferred to be treated with a 5-ASA oral formulation.14 5-ASA MMx (SPD476) contains 1.2 g of 5-ASA per tablet. The tablets start to erode mainly in the ascending colon. The absorption rate of 1 tablet of 5-ASA MMx is only 9%, and 80% of the entire absorption occurs in the colon. Moreover, 5-ASA MMx is detected at high levels in the sigmoid colon 24 hours after the ingestion of 1 tablet.8 These characteristics rend this formulation theoretically competitive with the enema. This exploratory study provides data to suggest that 5-ASA MMx was effective at 4 and 8 weeks, with a slower response compared with enemas at 4 weeks, but with an increase of remission rate between 4 and 8 weeks. Compared with 5-ASA enemas, 4 more patients taking 5-ASA MMx went into remission after 4 weeks. Clinical remission at 4 and 8
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weeks was obtained in 68.4% and 50% of patients taking enemas, respectively. These figures are in the range of the response rates reported in other clinical studies with topical therapy.12,13,15–17 It is possible that, in our study in which oral and topical formulations are compared, the low compliance with rectal administration could have affected the response rate of the group treated with the enemas. This is suggested by the difference in compliance rates between patients in remission and patients with active disease. However, the effectiveness (i.e., how a drug works in clinical practice) depends not only on the activity of active substance in the inflamed part of the intestine,18 but also on compliance with the prescribed drug.19 The time to onset of action of 5-ASA MMx and of 5ASA enemas is calculated from the time of initiation of therapy to that of symptomatic relief. By the 15th day, nearly all the symptoms had remitted in both groups. A rapid response rate is important in clinical practice, inasmuch as it reduces the likelihood of early discontinuation because of presumed ineffectiveness. As expected, the endoscopic remission rates were lower than the clinical remission rates: 45.0% in the 5-ASA MMx group and 35.9% in the enema group. The endoscopic remission rate at 8 weeks with MMx, however, was higher than remission rates obtained with other mesalamine formulations,20–22 although it is difficult to compare trials with different study designs. The long retention time for mesalamine delivered by 5-ASA MMx in the rectum and sigmoid colon is a possible explanation for a response rate that was not different from that achieved with topical therapy. Various adverse events were reported during the trial. Nevertheless, few of them could be attributed to the tested drugs. Among them, 1 patient with renal stones in the MMx arm experienced a slight increase of creatinine at the 8-week visit (the values were also abnormal at the outset and 3 and 5 months after study completion). Other investigators have reported renal damage during mesalamine therapy,23 but this is probably related to disease activity.24–27 One patient in the 5-ASA MMx group withdrew from the study after 2 weeks because of pregnancy; a healthy baby was delivered 8 months later. In conclusion, this exploratory study has shown that a new delivery system that delivers a high concentration of 5-ASA to the colon can induce remission in active left-sided UC, with a comparable response rate with that achieved with rectal 5-ASA. Furthermore, the dose of 1.2 g in each MMx tablet, along with the long permanence of active drug in the colon, could improve patient’s compliance. We intend to use these results to prepare a large, multicenter trial.
ACKNOWLEDGMENTS We thank Dr. Giancarlo Naccari (Giuliani SpA, Milan, Italy) for supporting the study, Dr. Maurizia Brun (Giuliani)
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for help in preparing the bibliography, and Dr. Giuseppe Grandinetti for the statistical analysis. Dr. Prantera has served as consultant to Giuliani in preparing the study protocol, analyzing the data, and writing the manuscript. Participating investigators (number of patients enrolled in the study are in parentheses): C. Prantera, L. A. Giglio, and M. L. Scribano (Azienda Ospedaliera Camillo Forlanini) (27); R. Caprilli, A. Viscido, and A. Aratari (Universita` La Sapienza) (19); F. Pallone, L. Biancone, and F. De Nigris (Universita` Tor Vergata) (12); A. Francavilla and N. Ranaldo (Universita` degli Studi) (12); and M. Campieri, P. Gionchetti, and F. Rizzello (Policlinico S. Orsola) (9).
REFERENCES 1. Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural history and progression of ulcerative colitis. A long-term follow-up of 1116 patients. Dig Dis Sci. 1993;38:1137–1146. 2. Langholz E, Munkholm P, Davidsen M, et al. Changes in extent of ulcerative colitis. A study on the course and prognostic factors. Scand J Gastroenterol. 1996;31:260–266. 3. Sutherland LR, May GR, Shaffer EA. Sulfasalazine revisited: a metaanalysis of 5-aminosalicylic acid in the treatment of ulcerative colitis. Ann Intern Med. 1993;118:540–549. 4. Sutherland LR, Roth DE, Beck PL. Alternatives to sulfasalazine: a metaanalysis of 5-ASA in the treatment of ulcerative colitis. Inflamm Bowel Dis. 1997;3:65–78. 5. Cohen RD, Woseth DM, Thisted RA, et al. A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol. 2000;95:1263–1276. 6. Marshall JK, Irvine EJ. Putting rectal 5-aminosalicylic acid in its place: the role in distal ulcerative colitis. Am J Gastroenterol. 2000;95:1628– 1636. 7. Pruitt R, Hanson J, Safdi M, et al. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis. Am J Gastroenterol. 2002;97:3078–3086. 8. Brunner M, Assandri R, Kletter K, et al. Gastrointestinal transit and 5-ASA release from a new mesalazine extended-release formulation. Aliment Pharmacol Ther. 2003;17:395–402. 9. Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ. 1989;298:82–86. 10. Flore´n CH, Benoni C, Wille´n R. Histologic and colonoscopic assessment of disease extension in ulcerative colitis. Scand J Gastroenterol. 1987;22: 459–462. 11. Farrokhyar F, Swarbrick ET, Grace RH, et al. Excellent outcome of the first attack of ulcerative colitis in three regional cohorts. Gastroenterology. 1999;116:A711. 12. Ardizzone S, Doldo P, Ranzi T, et al. Mesalazine foam (Salofalk foam) in the treatment of active distal ulcerative colitis. A comparative trial vs Salofalk enema. Ital J Gastroenterol Hepatol. 1999;31: 677–684. 13. Pokrotnieks J, Marlicz K, Paradowski L, et al. Efficacy and tolerability of mesalazine foam enema (Salofalk foam) for distal ulcerative colitis: a double-blind, randomized, placebo-controlled study. Aliment Pharmacol Ther. 2000;14:1191–1198. 14. Moody GA, Eaden JA, Helyes Z, et al. Oral or rectal administration of drugs in IBD? Aliment Pharmacol Ther. 1997;11:999–1000. 15. Malchow H, Gertz B & the CLAFOAM Study Group. A new mesalazine foam enema (Claversal foam) compared with a standard liquid enema in patients with active distal ulcerative colitis. Aliment Pharmacol Ther. 2002;16:415–423. 16. Campieri M, Paoluzi P, d’Albasio G, et al. Better quality of therapy with 5-ASA colonic foam in active ulcerative colitis. A multicenter comparative trial with 5-ASA enema. Dig Dis Sci. 1993;10:1843–1850.
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17. Gionchetti P, Ardizzone S, Benvenuti ME, et al. A new mesalazine gel enema in the treatment of left-sided ulcerative colitis: a randomized controlled multicentre trial. Aliment Pharmacol Ther. 1999;13:381– 388. 18. Schroeder KW. Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications. Scand J Gastroenterol. 2002;37 (Suppl. 236):42–47. 19. Kane S, Huo D, Aikens J, et al. Medication nonadherence and outcomes of patients with quiescent ulcerative colitis. Am J Med. 2003;114:39–43. 20. Miglioli M, Bianchi Porro G, Brunetti G. Sturniolo GC and the Italian IBD Group. Oral delayed release mesalazine (Asacol) in the treatment of mild ulcerative colitis: a dose ranging study. Eur J Gastroenterol Hepatol. 1990;2:229–234. 21. Sninsky CA, Cort DH, Shanahan F, et al. Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis. A multicenter study. Ann Intern Med. 1991;115:350–355.
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22. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987;317:1625–1629. 23. Prakash A, Markham A. Oral delayed-release mesalazine: a review of its use in ulcerative colitis and Crohn’s disease. Drugs. 1999;57:383–408. 24. Fraser JS, Muller AF, Smith DJ, et al. Renal tubular injury is present in acute inflammatory bowel disease prior to the introduction of drug therapy. Aliment Pharmacol Ther. 2001;15:1131–1137. 25. Schreiber S, Ha¨mling J, Zehnter E, et al. Renal tubular dysfunction in patients with inflammatory bowel disease treated with aminosalicylate. Gut. 1997;40:761–766. 26. Riley SA, Lloyd DR, Mani V. Tests of renal function in patients with quiescent colitis: effects of drug treatment. Gut. 1992;33:1348–1352. 27. Mahmud N, O’Toole D, O’Hare N, et al. Evaluation of renal function following treatment with 5-aminosalicylic derivatives in patients with ulcerative colitis. Aliment Pharmacol Ther. 2002;16:207–215.
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