Alimentary Tract
Long-term oral plus topical mesalazine in frequently relapsing ulcerative colitis

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Abstract

Background.

In cross-sectional studies, it was demonstrated that the therapeutic effect of mesalazine is closely related to its mucosal concentration.

Aim.

This study was carried out to verify in a longitudinal study if it was possible to improve the clinical course of ulcerative colitis at high risk of recurrence by increasing mucosal mesalazine concentration.

Methods.

Eighteen consecutive ulcerative colitis patients on continuous oral 5-ASA treatment (2.4–3.2 g/day) in clinical remission who had had at least four moderate to severe relapses in the preceding 2 years (referred period) were assigned to assume oral (3.2–4.8 g/day) and topical (4 g/day) mesalazine in order to increase mucosal drug concentration and were followed up for 2 years (study period). The localisation of disease was 12 pancolitis, six left colitis. The number and severity of recurrences, number of visits and endoscopies, courses of steroids and days of hospitalisation were compared with those of the previous 2 years. Rank signed test for paired data was used for statistical analysis.

Results.

The total number of recurrences was significantly lower during the study period in comparison with that of referred period (8 versus 80, respectively, p < 0.0001). No courses of steroids or hospitalisation were necessary during study period in comparison with those of referred period (0 versus 33, p < 0.0001; 0 versus 93, p = 0.03, respectively). A total number of 249 visits were done during the referred period and 116 during the study period (p < 0.0001) with a total of 87 endoscopies during referred period and 44 during study period (p < 0.0001).

Conclusions.

The continuous use of topical mesalazine associated with a high oral dosage significantly improves the clinical course of ulcerative colitis patients at high risk of relapse.

Introduction

Mesalazine is the most commonly used drug in ulcerative colitis (UC), first as an active moiety of Salazopyrine, then as a single molecule contained in slow or controlled release capsules [1], [2]. In spite of the continuous use of the drug over the last 50 years, the therapeutic range of mesalazine remains to be clearly established and thus, its optimal dosage and route of administration are still debated [3], [4], [5].

A cross-sectional study has demonstrated that the anti-inflammatory effect of mesalazine is closely related to its mucosal concentration [6]. In other words, in a given colonic segment, the higher the mucosal concentration of mesalazine, the better the endoscopic and histological conditions of the mucosa. It is, therefore, reasonable to hypothesise that the optimal dose should be the one ensuring an adequate mucosal drug concentration in the affected sites [7]. However, mesalazine has a topical effect, which means that the drug may significantly concentrate into the intestinal mucosa only during its absorptive process. Thus, if it is absorbed by inflamed mucosa it may concentrate in the inflamed tissue, but if the drug is absorbed by normal mucosa it is almost completely lost for its therapeutic use. Thus, the goal of treatment is not only to achieve an optimal dosage, but especially to take the drug where it needs [8].

Pharmacokinetic studies have demonstrated that, when given per os, the active moiety of mesalazine is delivered mainly to the distal ileum and proximal large bowel thus ensuring a higher mucosal drug concentration in the right than in the left colon, with only negligible amounts of the drug reaching the rectal mucosa [9], [10]. The increase in the oral dosage further increases the mucosal concentration in the proximal colonic segments, but does not significantly modify distal drug distribution [11]. Conversely, topical mesalazine administration assures a considerable drug availability in the recto-sigmoid sites and, to a lower extent, also in the descending colon [12], [13]. Therefore, it appears that, if we would increase mucosal mesalazine concentration in UC patients along the entire length of their large bowel, beside an increase of oral dosage, a continuous topical treatment should be given.

On the basis of these pharmacokinetic considerations, the present longitudinal study was aimed to verify whether an increasing of oral dosage of mesalazine, associated with its continuous topical administration, could increase mucosal drug concentration and modify the clinical course of a particular group of UC patients at high risk of relapse, with a not mild disease, that actually need repeated hospitalisations, courses of steroids and/or immunosuppressive drugs [14], [15].

Section snippets

Patients and methods

This study was designed to compare the clinical course of UC patients recorded during the 2 years prior to the study (referred period RP) with that seen in the subsequent 2 years, when the same patients were assigned to the treatment under investigation (study period SP). This was a “before-after” comparison study in which each patient was compared with him/herself, thus representing his/her own control.

The clinical, endoscopic and histological characteristics of all consecutive UC patients

Results

During SP no severe or moderate recurrences were recorded and only six patients showed mild signs of relapse. A total number of 80 episodes of relapses were observed during RP and 8 during the SP (p < 0.0001). Mild relapses were 25 during RP and 8 during SP (p < 0.0001), moderate relapses were 36 during RP and none during SP (p < 0.0001) and severe relapses occurred in 19 instances during RP but in none during SP (p < 0.0001) (Table 2). All relapses occurred when the frequency of topical treatment was

Discussion

Previous cross-sectional studies have demonstrated that the efficacy of mesalazine is related to its mucosal concentration and that to increase large bowel drug availability, the oral dosage should be increased and a topical treatment should be continuously associated [6], [13], [20]. In the present investigation, we adopted this therapeutic strategy in a longitudinal study to establish whether or not it could change the clinical course of a particular group of UC patients with a moderate to

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