New oral salicylates in the therapy of chronic idiopathic inflammatory bowel disease

Sulfasalazine has been the mainstay of therapy for ulcerative colitis and Crohn's disease of the colon. More recently, it has become clear that 5-ASA is the active moiety of the compound and that the sulfapyridine component is responsible for most of the adverse responses to sulfasalazine. The modes of action of sulfasalazine and 5-ASA have not been determined despite active investigations. There has been great current emphasis on the development of delivery systems to allow maximum concentration of therapeutically active 5-ASA in the colon or other gastrointestinal mucosal locations. Olsalazine accomplishes this goal by creatively coupling two molecules of 5-ASA to each other by a diazo bond. Bacterial azoreductases uncouple the parent drug and deliver 5-ASA to the colonic mucosa. Several pharmaceutical manufacturers have devised variations in mesalamine (5-ASA) coatings designed to release in pH and time-related manners. Oral Rowasa, Claversal, and Asacol accomplish distal delivery with acrylic coating of tablets. Oral Pentasa seems unique in distributing 5-ASA throughout the small bowel as well as the colon by utilization of small ethylcellulose-coated microgranules. For this reason, Pentasa may be particularly useful in the treatment of small bowel Crohn's disease. There are no data to suggest that patients unresponsive to oral sulfasalazine will respond to 5-ASA in any form, although it is possible that better toleration of the 5-ASA formulations will allow more effective dosage levels to be delivered. There are also preliminary data supporting synergism between oral and topical rectal 5-ASA in certain patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral 5-aminosalicylic acid preparations in treatment of inflammatory bowel disease an update

Therapeutic efficacy of 5-aminosalicylic acid (5-ASA) preparations is reviewed. In the acute treatment of Crohn's disease, Pentasa and Salofalk seem to be more effective than placebo. When it is given in an equimolar 5-ASA regimen, Salofalk appears to be at least as effective as sulfasalazine (SAS) in the treatment of both Crohn's disease and ulcerative colitis. Asacol and SAS are equally effective in maintenance therapy of ulcerative colitis. Dipentum was more efficient than placebo. There was only a low incidence of side effects from oral 5-ASA preparations, but larger-scale trials may be needed for a more accurate profile of adverse reactions.     

Initial therapy for mild to moderate Crohn's disease: mesalamine or budesonide?

The initial choice of therapy for mild to moderately active Crohn's disease is controversial. Both the National Cooperative Crohn's Disease Study (NCCDS) and the European Cooperative Crohn's Disease Study (ECCDS) demonstrated that sulfasalazine is effective for the induction of remission. Subsequent studies of new mesalamine formulations showed inconsistent results; two trials, however, demonstrated a statistically significant improvement with Pentasa and Asacol treatment, and meta-analyses suggest a modest benefit of mesalamine maintenance therapy. The NCCDS and ECCDS trials found that corticosteroid therapy is much more effective than sulfasalazine for induction of remission, but corticosteroids did not show maintenance benefits. Corticosteroid use is frequently associated with adverse effects, and the majority of patients treated with prednisone become either steroid-refractory or steroid-dependent; many of these patients ultimately need treatment with immunosuppressives and/or surgery. Budesonide, a topical corticosteroid with high first-pass hepatic metabolism, is slightly less effective in inducing remission than conventional corticosteroids but is significantly less likely to cause side effects. Budesonide 9 mg/day was shown to be more effective than mesalamine (Pentasa 4 g/day) for induction therapy, but budesonide has been ineffective as a maintenance therapy. Mesalamine may be useful for patients with more extensive disease, those intolerant of sulfasalazine, or those with contraindications or intolerance to budesonide. Alternatively, sulfasalazine is effective in the presence of colonic disease. Clinicians must decide on the basis of the existing evidence whether budesonide or mesalamine is the preferred initial therapy for active Crohn's disease.     

Concentrations of 5-ASA and Ac-5-ASA in human ileocolonic biopsy homogenates after oral 5-ASA preparations.

Intramucosal 5-aminosalicylic acid (5-ASA) and acetylated 5-ASA (Ac-5-ASA) concentrations were determined in ileocolonic biopsy specimens from 61 patients with irritable bowel syndrome treated for one week with near equimolar doses of different slow release preparations of 5-ASA (Claversal, Asacol, or Pentasa) or azo-bound drugs (Salazopyrin, Dipentum). The transit time in these patients was accelerated by a laxative, metoclopramide, and colonic lavage. The presence of 5-ASA in the mucosa was confirmed by autofluorescence. The highest concentrations of 5-ASA were obtained after Asacol (mean (SEM), 298.5 (37.3) ng/mg wet wt), followed by Claversal 500 mg (108.8 (11.7) ng/mg wet wt) and Pentasa (25.7 (2.2) ng/mg wet wt). Very low concentrations only were observed after Claversal 250 mg (0.3 (0.03) ng/mg wet wt), Salazopyrine (1.2 (0.1) ng/mg wet wt), and Dipentum (11.0 (3.2) ng/mg wet wt). The results for Ac-5-ASA were similar but the concentrations were generally lower. Serum concentration-time curves over eight hours were obtained from 34 healthy volunteers after a single oral dose of 400 to 500 mg of the different drugs. For the slow release forms, an apparently inverse relationship was found between the area under the curve of the serum concentrations and the intramucosal concentrations, supporting the importance of the local availability of the drug. This inverse relationship was absent for the azo-bound drugs. Colonic washout induced mechanical removal of intraluminal 5-ASA with a secondary disturbance in absorption resulting in a rapid decline in the serum concentrations. However, only for Dipentum did this result in significantly lower 5-ASA mucosal concentrations. This is the first reported attempt to evaluate the mucosal availability of 5-ASA after different oral preparations. It shows that where transit time is accelerated higher mucosal concentrations occur after slow release preparations (except for Claversal 250 mg) than after azo-bound drugs. Additional studies are necessary to correlate these concentrations with clinical effects.     

Current medical therapy of inflammatory bowel disease

The current established drugs used to treat inflammatory bowel disease include glucocorticoids includingnewer agent budesonide, sulfasalazine and 5-ASA compounds such as Asacol, Pentasa, Dipentum andBalsalazide and immunomodulatory agents such as azathioprine, and 6-mercaptopurine. Additional drugswhich have been found to be useful, particularly in refractory cases of Crohn's disease including fistulizingtype of Crohn's disease, include cyclosporine A, methotrexate, humanized antibody against TNFa(cA2),FK506, IL-10, IL-11 and Probiotics. Various agents, whether used alone or in combination, have to betailored for each patient and none is ideal. Exciting new developments directed against proinflammatorypathways, cytokines, free oxygen radicals and cell surface related immune targets are areas of intense recentinvestigations and many novel therapeutic agents are expected to be available in the near future for medicaltreatment of inflammatory bowel disease.     

Sulfasalazine Desensitization in Children and Adolescents with Chronic Inflammatory Bowel Disease

Sulfasalazine is an important therapeutic agent in the management of chronic inflammatory bowel disease (CIBD). Unfortunately, adverse reactions to this drug have been reported in 5-55% of treated patients. These include dose-related side effects like nausea, malaise, and headache or hypersensitivity reactions such as rash, fever, hives, arthralgia, hepatitis, etc. Studies in adults with successful reintroduction of sulfasalazine after a desensitization program have been reported; however, with regard to children, no such data are available. Fourteen children and adolescents (5-16 yr old) diagnosed to have CIBD manifested hypersensitivity to sulfasalazine within 2 months of onset of treatment. All had pancolitis--secondary to Crohn's disease (CD) in four and to ulcerative colitis (UC) in 10. All of them were on steroids. Sulfasalazine was discontinued in all after symptoms of hypersensitivity developed. Three patients with severe reaction were diagnosed prior to desensitization experience. Desensitization, beginning with 5-50 mg of sulfasalazine/day, was attempted in the other 11 children. The dose was gradually increased by 5-50 mg increments every 3 days. Desensitization was successful in only five children, who were ultimately able to tolerate 1.5-3.0 g of sulfasalazine daily again. In the rest (six of 11 patients), oral 5-ASA (Asacol) was administered, and three could not tolerate it. One of these three with intolerance to Asacol required colectomy. One did not tolerate Asacol or Dipentum. Our findings suggest that sulfasalazine desensitization should be attempted in all patients developing hypersensitivity reactions before trying alternative therapy.     

Recent advances in the management of distal ulcerative colitis

The most frequent localization of ulcerative colitis (UC) is the distal colon. In treating patients with active distal UC, efficacy and targeting of the drug to the distal colon are key priorities. Oral and rectal 5-aminosalicylic acid (5-ASA) preparations represent the first line therapy of mild-to-moderate distal UC for both induction and maintenance treatment. It has been reported that many UC patients are not adherent to therapy and that non-compliant patients had a 5-fold risk of experiencing a relapse. These findings led to the introduction of once-daily oral regimens of 5-ASA as better therapeutic options in clinical practice due to improved adherence. New formulations of mesalazine, including the multi-matrix delivery system, and mesalazine granules, which allow once-daily administration, have been developed. They have been demonstrated to be efficacious in inducing and maintaining remission in mild-to-moderate distal UC in large clinical trials. However, existing data for distal UC are rather insufficient to make a comparison between new and classical 5-ASA formulations. It seems that the new formulations are at least as effective as classical oral 5-ASA formulations. Other treatment options, in the case that 5-ASA therapy is not effective, include systemic corticosteroids, thiopurines (azathioprine or 6-mercaptopurine), cyclosporine, infliximab and surgery. The combination of a prompt diagnostic work-up, a correct therapeutic approach and an appropriate follow-up schedule is important in the management of patients with distal UC. This approach can shorten the duration of symptoms, induce a prolonged remission, improve patient's quality of life, and optimize the use of health resources.     

5-ASA in ulcerative colitis： Improving treatment compliance

5-aminosalicylic acid （5-ASA） compounds are a highly effective treatment for ulcerative colitis （UC）. While UC patient compliance in clinical studies is over 90%, only 40% of patients in every day life take their prescribed therapy. Adherence to medication has been emphasized recently by a Cochrane meta-analysis that has suggested that future trials of 5-ASA in UC should look at patient compliance rather than drug efficacy. Better compliance can be obtained by reducing the number of tablets and times of administration. Given that the 5-ASA formulations have different delivery systems that split the active moiety in various regions of the intestine, it is particularly important that an adequate dose of the drug arrives at the inflamed part of the colon. 5-ASA Multi matrix （MMx） is a novel, high strength （1.2 g）, oral formulation designed for oncedaily dosing. It releases the active moiety throughout the colon. Different studies with this compound have shown that it is as effective as 5-ASA enema in the treatment of mild-to-moderate, left-sided UC, and is comparable to a pH-dependent, delayed release 5-ASA （Asacol）, even if given once daily. Recently, the effectiveness in the acute phase of UC has been confirmed also in maintenance. In conclusion, at present, 5-ASA MMx seems theoretically the best agent for maintaining patient compliance, and consequently, treatment effectiveness.     

Disposition of 5-aminosalicylic acid from 5-aminosalicylic acid-delivering drugs during accelerated intestinal transit in healthy volunteers

In eight healthy volunteers accelerated intestinal transit time was induced with bisacodyl, and urinary and faecal excretion of sulphasalazine, olsalazine, 5-aminosalicylic acid (5-ASA), and acetyl-5-ASA was studied after a single oral dose of 3.3 mmol sulphasalazine, olsalazine, Pentasa, and Salofalk and 2.6 mmol of Asacol. The faecal and urinary excretion of acetyl-5-ASA was lowest after intake of sulphasalazine and olsalazine and highest after intake of Pentasa and Salofalk. The figures for Asacol were intermediate. This indicates insufficient release of 5-ASA from sulphasalazine and olsalazine. When the results of this study are compared with those of a previous study without accelerated transit time, the disposition of 5-ASA from all the 5-ASA-delivering drugs is influenced unfavourably by an accelerated gut transit but most pronounced in the case of sulphasalazine, olsalazine, and Asacol. The impaired release from the azo compounds sulphasalazine and olsalazine is a result of far less complete splitting of the diazo bond.     

Disposition of 5-aminosalicylic acid by 5-aminosalicylic acid-delivering compounds

The disposition of 5-aminosalicylic acid (5-ASA) from 5-ASA-delivering drugs was studied in eight healthy volunteers. Time-related urinary excretion and faecal excretion of 5-ASA and acetyl-5-ASA were measured after a single oral dose of the azo compounds sulphasalazine and olsalazine, of the slow-release compounds Pentasa, Asacol, and Salofalk, and of plain 5-ASA. Plain 5-ASA was rapidly excreted into urine and had a low faecal recovery, indicating fast absorption proximally in the intestine and little availability to the colon. After ingestion of both azo compounds and slow-release compounds, urinary excretion of 5-ASA was markedly delayed and reduced, and faecal excretion was enhanced. At all points of time there was a significant but not very marked difference in urinary excretion of 5-ASA after ingestion of the azo compounds and the slow-release compounds, in favour of the azo compounds. A significantly larger proportion of the ingested 5-ASA, moreover, was excreted in faeces after intake of azo compounds as compared with slow-release compounds.     

Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications

BACKGROUND: Sulfasalazine, consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, was first used for treatment of ulcerative colitis in the early 1940s and later found effective in placebo-controlled trials for acute disease and for long-term maintenance of remission. Later studies found that the active moiety is 5-ASA (mesalazine, mesalamine) and the sulfapyridine moiety acts as a carrier molecule but causes many of the symptomatic adverse reactions. METHODS: Review of the literature. RESULTS: The finding that 5-ASA in the active motility led to the development of mesalazine prodrugs, olsalazine (Dipentum) and balsalazide (Colazide, Colazal), and targeted release mesalazine preparations, such as Asacol, Pentasa, and Salofalk, as well as enemas and suppository preparations for distal disease. Most patients with adverse effects from sulfasalazine will tolerate mesalazine. Mesalazine has been shown equivalent or superior to sulfasalazine, and superior to placebo, with a dose-response benefit, in inducing remission of acute disease. and comparable to sulfasalazine and superior to placebo for long-term maintenance of remission. Better tolerance of mesalazine and the ability to use higher doses favor its use in patients intolerant of sulfasalazine and in patients failing to respond to usual doses of sulfasalazine. Adverse effects from mesalazine are uncommon, but include idiosyncratic worsening of the colitis symptoms and renal toxicity. Mesalazine is safe to use during pregnancy and for nursing mothers. As maintenance therapy, mesalazine may reduce the risk of developing colorectal carcinoma. CONCLUSION: Mesalazine represents effective and well-tolerated first-line therapy for mildly to moderately acute disease as well as for the long-term maintenance treatment in the patient with ulcerative colitis.     

Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of Crohn's disease. The Italian IBD Study Group.

A randomized, placebo-controlled multicenter trial was conducted to evaluate the efficacy and safety of a delayed-release formulation of 5-aminosalicylic acid (5-ASA) (Asacol; Giuliani & Bracco, Milan, Italy) for prevention of clinical relapse in 125 patients with inactive Crohn's disease. Patients in remission [Crohn's Disease Activity Index (CDAI) less than 150] between 3 months and 2 years were randomly allocated to receive either 800 mg 5-ASA three times daily (n = 64) or placebo (n = 61) for up to 12 months or until relapse of symptoms. Relapse was defined by a CDAI greater than 150, with a minimum increase of 100 points over the baseline value. The cumulative relapse rates were 12% in the 5-ASA group and 22% in the placebo group at 3 months [95% confidence interval (CI) for the difference, -4 to 24]; 28% and 41%, respectively, at 6 months (95% CI, -4 to 30); and 34% and 55%, respectively, at 12 months (95% CI, 3-39; P = 0.02, log rank test). Significant decrease in the risk of relapse was found in patients with ileitis, in those with previous bowel resection and, in those with prolonged prestudy remission. Eight patients (5 on 5-ASA, 3 on placebo) withdrew from the study because of adverse reactions, but no major clinical or laboratory adverse effect was observed. It is concluded that oral 5-ASA coated with Eudragit S (Rohn Pharma GmbH, Wieterstadt, Germany), 2.4 g daily, is safe and seems superior to placebo in preventing or delaying clinical relapse in Crohn's disease, especially in milder cases and in ileal disease.     

Aminosalicylates and steroids in the treatment ot chronic inflammatory bowel diseases--consensus paper of the Working Group for Chronic Inflammatory Bowel Diseases of the OGGH

5-aminosalicylates (5-ASA) and steroids constitute a cornerstone of medical therapy in patients with inflammatory bowel diseases (IBD). Whereas the efficacy of 5-ASA in Crohn's disease (CD) is equivocal, ulcerative colitis (UC) is the main indication for this drug. In UC, 5-ASA is effective in the treatment of mild to moderate acute disease and in maintenance of remission. Furthermore, 5-ASA topical therapy is an important treatment option in patients with mild to moderate proctitis and/or left-sided UC and shows additive efficacy to oral therapy. From retrospective data a chemo-preventative activity of long-term 5-ASA therapy in UC is delineated. Steroids are treatment of first choice for moderate to severe cases of CD and UC. Budesonide, a modified steroid with less side effects, plays a major role in the treatment of ileocolonic CD +/- involvement of the right colon and is used as treatment of choice in mild-to-moderate cases. In case of acute, severe disease conventional steroids are superior compared to budesonide and therefore budesonide should only be used after considerable improvement of disease activity. The necessity to apply steroids in a given patient represents a negative prognostic indicator for the course of disease and should incite the early introduction of immunosuppressive therapy in this case. Steroids are only effective as short term therapy of IBD and are to be avoided for maintenance treatment. In all cases of steroid therapy an osteoporosis prophylaxis with calcium and vitamin D is recommended. Topical steroid treatment is less effective in left-sided UC compared to 5-ASA.     

Standard treatment of ulcerative colitis

Ulcerative colitis (UC) is an idiopathic, chronic inflammation of the colon which may present with a range of mild to severe symptoms. The disease may be localized to the rectum or can be more extensive and involve the left side of the colon or the whole colon. Treatment in UC is directed towards inducing and maintaining remission of symptoms and mucosal inflammation. The key parameters to be assessed for the most appropriate treatment are the severity and extent of the inflammation. Meta-analyses of published trials have shown that topical treatment with 5-aminosalicylic acid (5-ASA) is the treatment of choice in active distal mild-to-moderate UC. Oral aminosalicylates are effective in both distal and extensive mild-to-moderate disease, but in distal disease, the rates of remission are lower than those obtained with topical 5-ASA. New steroids, such as budesonide and beclomethasone dipropionate (BDP), administered as enemas, constitute an alternative to 5-ASA therapy. In some studies, these have been shown to be as effective as conventional steroids but with significantly lower inhibition of plasma cortisol levels. Patients with unresponsive disease or those with more severe presentation will require oral corticosteroids and sometimes intravenous therapy. Approximately 10% of patients with unresponsive UC have severe attacks requiring hospitalization. Patients with severe disease should be managed jointly by a medical and surgical team, and intensive intravenous treatment should be started with high-dose steroids. Early recognition of failure of therapy will allow the introduction of immunosuppressive therapy with intravenous cyclosporine. Patients who respond are shifted to oral cyclosporine associated with azathioprine/6-mercaptopurine, whereas those who fail will require proctocolectomy. Oral aminosalicylates are the first-line therapy in maintenance of remission. Topical 5-ASA may play a role in distal disease. Patients who are steroid dependent can be started on azathioprine or 6-mercaptopurine although it may take up to 3 months for the treatment to become effective. They may have reversible immediate side effects, such as pancreatitis or bone marrow suppression, which disappear upon discontinuation of therapy. Close monitoring of these hematologic and biochemical parameters will improve safety. The use of biologic therapy with infliximab in more severe disease has not been established.     

Comparative, open, randomized trial of the efficacy and tolerance of slow-release 5-ASA suppositories once daily versus conventional 5-ASA suppositories twice daily in the treatment of active cryptogenic proctitis: French Pentasa Study Group

OBJECTIVE: The efficacy and tolerance of slow-release 5-ASA suppositories (Pentasa 1 g/day) were compared with those of conventional 5-ASA suppositories (Rowasa 0.5 g b.i.d.). METHODS: Two hundred and fifty-one (251) patients presenting with an exacerbation of cryptogenic proctitis were randomized. Clinical activity and rectal lesions were measured at days 1 and 14 (and at day 21 for patients not in remission at day 14), and each patient had to fill out a daily diary card (checklist). RESULTS: Results are given for slow-release and classical suppositories, respectively. The reduction in symptoms and lesions was identical in both groups. Treatment was continued until day 21 in 36% versus 33% of the patients, and minor or moderate side effects occurred in 5.6% versus 6.3% (NS). The tolerance of the suppositories was rated as satisfactory every day by 77% versus 54% (p = 0.001), and early suppository expulsion occurred in 0.5% versus 3.4% (p = 0.001). CONCLUSIONS: The treatments were equally effective and both were well tolerated. However, the advantages of the slow-release suppositories were that patients exhibited greater tolerance and early expulsion was less frequent.     

5-Aminosalicylic acid in the treatment of Crohn's disease. A 16-week double-blind, placebo-controlled, multicentre study with Pentasa

The response to 5-aminosalicylic acid (5-ASA) in mild and moderately active Crohn's disease localized in the small bowel was studied in a randomized, double-blind, placebo-controlled trial in four centres. Sixty-seven patients were included, of whom 30 were treated with 1500 mg slow-release 5-ASA/day (Pentasa) for a scheduled period of 16 weeks. In the 5-ASA group 40% of the patients improved, versus 30% of the placebo-treated group ('intent to treat' basis; p greater than 0.1). Four of the patients treated with 5-ASA left the study owing to disease deterioration, versus 10 of the placebo-treated patients (p greater than 0.2). Seventeen patients were secondarily excluded, and the remaining 50 patients (23 receiving 5-ASA) were reevaluated in greater detail. No statistically significant differences in outcome were shown. Three patients (one given 5-ASA) were withdrawn from the study because of presumed side effects, but no serious adverse reactions were recorded. The present results indicate that 5-ASA, at least in the dosage used, is not superior to placebo. Nevertheless, trends towards a beneficial effect in Crohn's disease in the small bowel justify further clinical trials with a larger dosage of 5-ASA.     

A dynamic model of once-daily 5-aminosalicylic acid predicts clinical efficacy

New once daily mesalamine formulations may improve adherence to medication usage.Response to Asacol and other forms of 5-aminosalicyclic acid(5-ASA)is better correlated with tissue concentrations and best predicted by concentrations of the drug within the lumen of the colon.Our group used computer simulation to predict colonic 5-ASA levels after Asacol administration.In our study,the model simulated Asacol distribution in the healthy colon,and during quiescent and active ulcerative colitis.An Asacol dosage ...     

Ulcerative colitis therapy: importance of delivery mechanisms

Since the initial observation that mesalamine or 5-aminosalicylate (5-ASA) has an anti-inflammatory effect on ulcerative colitis, investigators have been trying to improve on the delivery mechanisms of this compound. As it is believed that the anti-inflammatory effect of 5-ASAs is mediated topically, current formulations are designed to release 5-ASA in the small intestine and colon, or predominantly in the colon. A dose-response curve is seen with some preparations of mesalamine but not all. In general, 5-ASAs are effective in patients with ulcerative colitis and much less effective in Crohn's disease. Evidence demonstrates that 5-ASAs are effective for induction of remission and maintenance of remission. Preparations that deliver 5-ASA in a pH-dependent manner are most affected by variability in luminal pH, whereas those that depend on bacterial cleavage for release of the active 5-ASA are most affected by transit time. Most studies have not compared different preparations of mesalamine and examined differences in colonic delivery. Depending on the endpoint examined in the studies, efficacy of the various 5-ASA products appears similar at the most optimal doses. For a given patient, however, it may be necessary to experiment with more than one preparation if an initial trial results in a suboptimal response.     

Anastomotic configuration and mucosal 5-aminosalicyclic acid (5-ASA) concentrations in patients with Crohn's disease: a GISC study. Gruppo Italiano per lo Studio del Colon e del Retto

OBJECTIVE: Recurrence of Crohn's disease quite inevitably occurs after resection of distal small bowel and proximal colon, involving the neoterminal ileum close to the anastomosis. Oral 5-aminosalicylic acid (5-ASA) administered soon after surgery delays recurrence and reduces its severity. We recently observed that in operated patients submitted to prophylactic treatment with oral 5-ASA the rate of recurrence was significantly higher in those with end-to-end anastomosis than in those with other types of anastomosis (end-to-side, side-to-side). The hypothesis investigated in the present study was that patients with end-to-side or side-to-side anastomosis would benefit from a higher mucosal concentration of 5-ASA with respect to patients with end-to-end anastomosis. Therefore, the mucosal 5-ASA concentration was measured in the perianastomotic area of both groups. METHODS: The study was carried out in 19 patients submitted to radical surgery for Crohn's ileitis or ileocolitis, under oral prophylactic treatment with 5-ASA (Asacol). All patients were on regular endoscopic follow-up and were free of recurrence. Two biopsies were collected 3 cm from the anastomosis, in the neoterminal ileum, and two biopsies were collected at the colonic site 3 cm below the anastomosis. 5-ASA concentrations (ng/mg) were measured in tissue homogenates by high-performance liquid chromatography (HPLC) with electrochemical detection. RESULTS: The mucosal concentration of 5-ASA in the neoterminal ileum was significantly lower in patients with end-to-end anastomosis than in those with other types of anastomosis (median values: 29.4 ng/mg vs 92.9 ng/mg respectively; p < 0.001). Six of 10 patients (60%) with end-to-end anastomosis, but none of the nine patients with other types of anastomosis, showed 5-ASA mucosal concentrations <40 ng/mg at the neoterminal ileum. On the contrary, no patients with end-to-end anastomosis showed mucosal concentrations of 5-ASA >90 ng/mg, compared with the 57% of patients in the group with other types of anastomosis. No differences were observed for colonic biopsies. CONCLUSIONS: The different mucosal concentrations in these two groups may be explained by the difference in segmental transit time induced by the different anastomotic configurations. A slower preanastomotic transit time, demonstrated in patients with end-to-side or side-to-side anastomosis, could offer a prolonged contact time between the intestinal content and the mucosa, resulting in an increase in drug absorption.     

Disposition of mesalazine from mesalazine-delivering drugs in patients with inflammatory bowel disease, with and without diarrhoea.

The disposition of mesalazine from the azo compounds sulphasalazine and olsalazine (Dipentum) and from the slow-release mesalazine drugs Pentasa, Asacol, and Salofalk was studied in 20 patients with inflammatory bowel disease. Ten of them had diarrhoea, and 10 had normal stools. On the last 2 days of a 7-day maintenance treatment with each of the study drugs urine and faeces were collected for determination of mesalazine, acetyl-mesalazine, and unsplit azo compound. In patients with and without diarrhoea the urinary and the faecal excretion of acetyl-mesalazine was lowest during treatment with olsalazine. The proportion of acetyl-mesalazine in faeces was highest during treatment with Pentasa in both groups. The presence of diarrhoea was associated with a decrease in the proportion of acetyl-mesalazine in faeces during treatment with all drugs, not significant only for Pentasa. The proportion of unsplit azo compound in faeces increased in the case of diarrhoea to almost 50%. It is concluded that in patients with inflammatory bowel disease diarrhoea substantially influences the disposition from all these drugs except Pentasa.