Pharmacology and pharmacokinetics of 5-aminosalicylic acid

There is accumulating clinical evidence that 5-aminosalicylic acid (5-ASA), a primary metabolite of sulfasalazine (SAS), represents the therapeutic active moiety of the azo-compound SAS in the treatment of chronic inflammatory bowel disease (IBD). Since it is presumed that 5-ASA acts from the lumen of the intestine, it is important to know how much 5-ASA is released from its special galenic formulations. After liberation of 5-ASA in the terminal ileum (only slow release oral preparations of 5-ASA) and colon (5-ASA suppositories and enemas), 5-ASA is only partly absorbed. A major part of this 5-ASA is presystemically eliminated, eg, N-acetylated during its first passage through the intestinal mucosa and liver. Mean steady state plasma levels of unchanged 5-ASA are rather low (range 0.02 to 1.2 μg/ml) whereas those of Ac-5-ASA are always higher (range 0.1 to 2.9 μg/ml). This is due to the rapid elimination of 5-ASA (t1/2=0.4 to 2.4h) and the slightly slower renal excretion of the Ac-5-ASA (t1/2=6 to 9h, renal clearance=200 to 300 ml/min). The knowledge of the pharmacokinetic properties of 5-ASA from different drug formulations might contribute to a better understanding of its mode of action in IBD.     

Oral mesalazine for the treatment of Crohn's disease: clinical efficacy with respect to pharmacokinetic properties

The release of 5-ASA from various preparations depends on the presence of bacterial azoreductases (sulphasalazine, olsalazine, balsalazide) or the pharmacokinetic properties of the mesalazine-containing pharmaceutical preparations. The differences of the 5-ASA release from the various preparations account for the different anatomic sites of actions. In this regard, a close relationship between the regional intraluminal concentrations of 5-ASA and the clinical response can be assumed. The aim of the present paper is to survey clinical trials in Crohn's disease with special respect to the pharmacokinetic properties of the used mesalazine containing preparations. There are clear differences between the different coated 5-ASA formulas in respect to 5-ASA release and in respect to their pharmacokinetic properties leading to a different therapeutic efficacy in Crohn's disease. The detailed analysis indicates that higher doses of 5-ASA (> 3 g/d) are required for the acute phase treatment. 4.5 g Eudragit-L-coated 5-ASA tablets are almost equally as potent as glucocorticosteroids for the treatment of active Crohn's disease. Clinical efficacy has been demonstrated for Eudragit-L-coated tablets even at a low dose of 1-1.5 g 5-ASA/day in the maintenance treatment of remission of Crohn's disease. This has also been shown for Eudragit-S-coated tablets at a dose of 2.4 g 5-ASA/day, while even 3 g 5-ASA of an Eudragit-L/S formula as well as the ethylcellulose-coated formulas up to 4 g 5-ASA/day were ineffective, except for a high risk group. On the basis of the published trials, there is clear evidence that post-operative prophylaxis with 5-ASA requires daily doses higher than 1.5 g. Ethylcellulose-coated 5-ASA has only been effective in Crohn's disease limited to the small bowel and should not be given to patients with ileo-colonic or colonic disease. Moreover, Eudragit-L-coated 5-ASA preparations have shown to be effective in both ileal and colonic disease concerning their clinical efficacy in post-operative prophylaxis. In contrast, endoscopic efficacy has been demonstrated for ethylcellulose as well as Eudragit-S-coated formulas. Treatment of Crohn's disease with orally administered 5-ASA can generally be regarded as an effective and well-tolerated therapy. However, the distinct therapeutic goal (acute phase treatment, maintenance therapy or post-operative prophylaxis), the involved areas of the gut and the specific release of the drug administered have to be considered.     

Tolerance of 4-aminosalicylic acid enemas in patients with inflammatory bowel disease and 5-aminosalicylic-induced acute pancreatitis

Derivatives of 5-aminosalicylic acid (5-ASA) used for the treatment of inflammatory bowel disease may induce acute pancreatitis of immunoallergic origin. 4-aminosalicylic acid (4-ASA) differs from its 5-ASA counterpart by the position of the NH2 group and has shown efficacy in ulcerative colitis. The risk of cross intolerance reaction between 5-ASA and 4-ASA has currently never been evaluated. We report three cases of 5-ASA-induced pancreatitis, with no recurrence of pancreatitis during subsequent treatment with 4-ASA enemas. We conclude that 4-ASA enemas are a safe and well-tolerated therapeutic alternative whenever 5-ASA-induced pancreatitis occurs.     

Oral 5-ASA therapy in ulcerative colitis: what are the implications of the new formulations?

5-aminosalicylic acid (5-ASA) is the standard first-line treatment for mild-to-moderate ulcerative colitis. A variety of 5-ASA delivery systems are available and in development, including both oral and rectal formulations; all of which aim to deliver the active drug to the colon while minimizing systemic absorption. Because the efficacy of most oral 5-ASA therapies is broadly similar, the appropriate selection of a given formulation often relies on other factors. This article explores the differences between oral 5-ASA formulations in terms of their delivery system, reviews the available data on oral 5-ASA treatment efficacy and tolerability, and examines the rationale for changing from one 5-ASA formulation to another if a patient does not respond to, or worsens on, their existing agent.     

5-Aminosalicylic acid concentration in mucosal interstitium of cat small and large intestine

Uncertainty regarding the concentration of 5-ASA within the mucosal interstitium has been a major limitation of defining the protective mechanisms of 5-ASA in intestinal inflammation. Therefore, we measured the concentration of 5-ASA in intestinal lymph and venous plasma during luminal perfusion of the cat small and large intestine with 10 mM 5-ASA. Blood and lymph flows were measured in each segment. 5-ASA and N-acetyl-5-ASA were extracted from plasma and lymph and quantified using fluorescence spectroscopy. Luminal perfusion of the terminal ileum with 5-ASA resulted in the following concentration profile: intestinal venous plasma (143 +/- 30 micrograms/ml) much greater than lymph (43 +/- 17 micrograms/ml) = systemic arterial plasma (40 +/- 11 micrograms/ml). In the colon the local venous plasma concentration of 5-ASA was 20 +/- 6 micrograms/ml compared to 2.0 +/- 1.0 micrograms/ml in systemic arterial plasma. N-Acetyl-5-ASA was found to comprise less than 5% of the total metabolite concentration in both ileum and colon. We also found that 58% of luminal 5-ASA was absorbed per minute in the terminal ileum, whereas only 3%/min was absorbed from the colon. The results of this study suggest that: (1) the mucosal interstitial concentration of 5-ASA in the terminal ileum and colon are approximately 100 micrograms/ml (654 microM) and 20 micrograms/ml (164 microM), respectively; and (2) the rate of 5-ASA absorption in the terminal ileum is approximately seven times greater than that in the colon.     

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)     

Steady-state pharmacokinetics of a new 4-gram 5-aminosalicylic acid retention enema in patients with ulcerative colitis in remission.

The pharmacokinetic profile of a new 4-g 5-aminosalicyclic acid (5-ASA) retention enema, Mesasal, was investigated. Nine patients with ulcerative colitis in remission and one patient with mild disease activity received one enema for seven consecutive nights. They were admitted to hospital for administration of the eighth enema. Plasma concentration and urinary excretion of 5-ASA and acetyl-5-aminosalicyclic acid (Ac-5-ASA) were studied for 45 h and faecal excretion for 24 h after administration of the last enema. The median peak plasma concentration of 5-ASA was 0.92 (range, 0.59-1.87) micrograms/ml at a median of 11 h after administration, and of Ac-5-ASA 1.62 (range, 1.03-4.36) micrograms/ml at a median of 12 h after administration. On average, the plasma concentration of Ac-5-ASA was almost twice that of 5-ASA at each sampling period. At 24 h after administration the median plasma concentration for 5-ASA was 0.12 (range, 0-0.77) micrograms/ml and for Ac-5-ASA 0.36 (range, 0.01-1.6) micrograms/ml. At 45 h after administration low levels of both 5-ASA (less than 0.2 micrograms/ml) and Ac-5-ASA (less than 0.3 microgram/ml) were noted in two patients, low levels of only Ac-5-ASA (less than 0.1 microgram/ml) in two patients, and neither 5-ASA nor Ac-5-ASA in the other six patients. All patients had detectable urinary levels of both 5-ASA and Ac-5-ASA during the first 4 h after administration. Median urinary recovery during 45 h was 12.6% (range, 5.6-22.2%), indicating a low absorption at steady-state conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytoprotection against neutrophil derived hypochlorous acid: a potential mechanism for the therapeutic action of 5-aminosalicylic acid in ulcerative colitis.

The aim of the present study was to investigate the effects of 5-aminosalicyclic acid (5-ASA) on the cell injury mediated by activated neutrophils. We used a system constituted of neutrophils, triggered with phorbol myristate acetate, and 51Cr-labelled Daudi cells as targets. The results show that 5-ASA is capable of efficiently preventing neutrophil-mediated lysis. 5-ASA was up to 10-fold more effective than taurine, which acts as an hypochlorous acid scavenger. Moreover, 5-ASA was found to compete with taurine for the neutrophil derived hypochlorous acid. The results are consistent with the conclusion that 5-ASA is capable of limiting the neutrophil mediated cell damage by scavenging the generated hypochlorous acid. This may represent a potential mechanism for the therapeutic action of 5-ASA in ulcerative colitis.     

Putting rectal 5-aminosalicylic acid in its place: the role in distal ulcerative colitis

Oral aminosalicylates such as sulfasalazine and mesalamine are widely prescribed for the treatment of mild or moderately active distal ulcerative colitis. However, a critical review of the literature demonstrates that rectal 5-aminosalicylic acid (5-ASA) is the optimal therapy for this disease. Meta-analyses of published trials show that rectally delivered 5-ASA is superior to placebo and to conventional rectal corticosteroids in inducing remission of distal ulcerative colitis, whereas the combination of rectal 5-ASA with a rectal corticosteroid or oral aminosalicylate is superior to rectal 5-ASA alone. For maintaining remission of distal ulcerative colitis, rectal 5-ASA is significantly better than placebo and at least as effective as oral 5-ASA. The dosage forms available for rectal delivery include suppositories, foams, and liquid enemas, and selection among these preparations should be guided by the proximal extent of disease and patient preference. The efficacy of rectal 5-ASA is complemented by its low rate of reported adverse effects, which may reflect its reduced potential for systemic absorption. This review summarizes the evidence supporting the role of rectal 5-ASA as a first-line therapy for mild or moderately active distal ulcerative colitis, and offers guidelines for its use.     

Measurement of colonic mucosal concentrations of 5-aminosalicylic acid is useful for estimating its therapeutic efficacy in distal ulcerative colitis: comparison of orally administered mesalamine and sulfasalazine

OBJECTIVES: Oral 5-aminosalicylic acid (5-ASA) preparations have been used frequently in the treatment of ulcerative colitis. However, there have been few reports investigating the relationship between colonic mucosal concentrations of 5-ASA and its clinical efficacy when oral sulfasalazine or 5-ASA compounds were administered. The aim of this study is to compare the mucosal concentrations of 5-ASA ensured by sulfasalazine or mesalamine, and to define the clinical significance of the measurement of 5-ASA concentrations in the treatment of distal ulcerative colitis. MATERIALS AND METHODS: Biopsies were taken from the rectum and sigmoid colon of the oral sulfasalazine group (n = 13) and the slow-release 5-ASA (mesalamine) group with (n = 5) or without (n = 11) rectal administration of 5-ASA. High-pressure liquid chromatography was used to measure the tissue concentrations of 5-ASA and its metabolites. We compared the 5-ASA concentrations of the sulfasalazine group with the mesalamine group. Furthermore, we analyzed the relationship between tissue 5-ASA concentrations and the Disease Activity Index (DAI). RESULTS: The concentrations of 5-ASA and acetyl-5-ASA in the sulfasalazine group were higher than those in the group taking oral mesalamine alone (p < 0.01). The concentration of 5-ASA was much higher in the patients who received oral and rectal mesalamine in an enema than in the patients who had oral mesalamine alone. There was a significant inverse correlation between the DAI and concentrations of 5-ASA in the rectum (r = 0.712, p < 0.001). CONCLUSIONS: We demonstrated that the colonic mucosal concentration of 5-ASA was significantly higher in the sulfasalazine group than in the mesalamine group. Furthermore, the concentrations of mucosal 5-ASA may be a good marker for the estimation of its efficacy in the treatment of ulcerative colitis.     

Therapeutic efficacy of 5-ASA molecules in idiopathic intestinal inflammatory diseases: critical review]

Sulfasalazine has been the most widely prescribed drug for patients with inflammatory bowel disease. Clinical trials have established its usefulness in treating patients with active ulcerative colitis and Crohn colitis and its important role in maintaining remissions in patients with ulcerative colitis. Despite its widespread acceptance, the usefulness of sulfasalazine has been limited by the occurrence of adverse reactions in about 10 to 20% of the patients. Now the aminosalicylates are emerging as a treatment for both ulcerative colitis and Crohn disease. We have critically reviewed the clinical trials assessing the efficacy of 5-ASA molecules. Therapeutic efficacy of 5-ASA appears to be as good as sulfasalazine but causing less adverse effects. In mild to moderate ulcerative colitis relapse, 2g 5-ASA is active while 1 g 5-ASA seems equivalent to 2g sulfasalazine for maintaining remission. 5-ASA enema in the treatment of distal ulcerative colitis is helpful and can replace topical cortisone administration. Administration of 1g 5-ASA enema a day seems to be the best regimen. In case of Crohn's disease, preliminary studies are encouraging but more date are required to define the indications as well as the regimen.     

Effect of weekend 5-aminosalicylic acid (mesalazine) enema as maintenance therapy for ulcerative colitis: results from a randomized controlled study

BACKGROUND: 5-aminosalicylic acid (5-ASA) is known to be effective in the treatment of active ulcerative colitis (UC). The aim of the current study was to investigate the effect of 5-ASA enemas, as a maintenance therapy for UC, when administered twice weekly as a weekend treatment regimen, compared to daily oral 5-ASA alone. We hypothesized that the weekend enema therapy would be better tolerated by patients who worked or attended school. METHODS: Between January 2004 and August 2005, patients with UC, in whom remission of the condition had just been induced, were randomly assigned to either: the weekend 5-ASA enema group (n=11), who received 1 g 5-ASA enemas twice a week on Saturday and Sunday plus oral 5-ASA 3 g/day for 7 days, or to the daily oral 5-ASA use only group (n=13), who received only oral 5-ASA 3 g/day for 7 days. The primary endpoint of the study was defined as the incidence of relapse. The study was stopped after 24 patients had been enrolled because an interim analysis showed a significant benefit of the weekend 5-ASA enema group. RESULTS: In the weekend enema group, 2 patients (18.2%) had relapses compared with 10 (76.9%) in the oral 5-ASA only group. The multivariate hazard ratio of relapse associated with weekend 5-ASA enema, relative to the oral alone group, was 0.19 (95% confidence interval, 0.04-0.94). CONCLUSIONS: This study demonstrated the beneficial effects of adding weekend 1 g 5-ASA enema to daily 3 g oral 5-ASA as maintenance therapy for UC.     

Oroileal transit of slow release 5-aminosalicylic acid.

The predominant active anti-inflammatory moiety in chronic inflammatory bowel disease is 5-aminosalicylic acid (5-ASA). As unprotected 5-ASA is rapidly absorbed in the upper gastrointestinal tract several slow release preparations have been developed to permit passage of 5-ASA to the lower small bowel and to the colon. To investigate luminal kinetics and extent of the release of 5-ASA intraluminal concentrations and loads of this compound together with that of its main metabolite acetyl-5-aminosalicylic acid (ac-5-ASA) were studied, over 15 hours after giving the slow release preparation Salofalk at a dose of 500 mg orally together with a test meal. Plasma concentrations and urinary excretion were also measured. Six healthy volunteers swallowed an 11 lumen oroileal tube, which allowed marker perfusion, aspiration of luminal content from the duodenum, mid-jejunum, and ileum, and recording of intestinal motility. Emptying of 5-ASA into the duodenum started after emptying of the meal, together with the first phase III of interdigestive motility. Mean luminal concentrations of 5-ASA and ac-5-ASA increased continuously from duodenum (both: 15 to 30 micrograms/ml) to ileum (60 to 110 micrograms/ml and 80 to 150 micrograms/ml respectively) over three hours and decreased over the next three hours. During 10 hours after eating, 30% of the total dose passed the ileum in solution and another 10% were excreted in urine. Thus about 60% reached the colon unreleased from tablets and another 30% were in solution. The ratio of 5-ASA and ac-5-ASA in solution was about 1:1 in the duodenum and 1:1.5 to 1:2 in the more distal small intestine. The data suggest that the large quantities of intraluminal ac-5-ASA are generated in the intestinal mucosa and reach the lumen by back diffusion. The results show that most of the 5-ASA from this slow release preparation is delivered into the colon, which explains its effectiveness in ulcerative colitis. The considerable luminal concentrations already present in the distal ileum might justify therapeutic trials in Crohn's disease.     

Mesalamine promotes intestinal epithelial wound healing in vitro through a TGF-beta-independent mechanism

OBJECTIVE: Treatment with 5-aminosalicylic acid (5-ASA) derivatives is one of the main principles in the therapy of uncomplicated mild to moderate inflammatory bowel diseases (IBD). The beneficial effect of 5-ASA in the treatment of IBD is attributed to its anti-inflammatory and anti-oxidant properties within the inflamed gut. The aim of this study was to investigate whether 5-ASA also modulates intestinal epithelial wound repair in vitro. MATERIAL AND METHODS: The effects of 5-ASA on cell migration and proliferation, two key processes in mucosal healing, were studied in the non-transformed small-intestinal epithelial cell line IEC-6 using an in vitro wounding model and colorimetric MTT assays. Furthermore, the effects of 5-ASA on epithelial cell viability were determined by Trypan blue exclusion and flow cytometry-based cell cycle analysis. RESULTS: Clinically relevant concentrations of 5-ASA caused a significant dose-dependent enhancement of epithelial cell migration and proliferation in vitro. An about 2-fold enhancement of intestinal epithelial cell proliferation and migration was observed for pharmacological doses of 100 microg/ml 5-ASA. Neutralizing antibodies against TGFbeta did not modulate 5-ASA effects on IEC-6 cell proliferation and migration, indicating that the effects of 5-ASA were TGFbeta independent. Trypan blue viability tests and cell cycle analysis did not reveal any toxic or apoptotic effects of pharmacological 5-ASA concentrations on IEC-6 cells. CONCLUSIONS: 5-ASA promotes the rapid re-establishment of mucosal integrity in vitro by enhancing epithelial restitution and proliferation, suggesting that 5-ASA in addition to the well-characterized effects on the intestinal inflammatory cascade may also directly stimulate epithelial wound healing.     

Colon-specific drug delivery systems based on cyclodextrin prodrugs： In vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates

AIM: To investigate the release of cyclodextrin-5-amino-salicylic acid (CyD-5-ASA) in cecum and colon. METHODS: An anti-inflammatory drug 5-ASA was conjugated onto the hydroxyl groups of α-,β- and γ-cyclodextrins (CyDs) through an ester linkage, and the in vivo drug release behavior of these prodrugs in rat' s gastrointestinal tract after the oral administration was investigated. RESULTS: The 5-ASA concentration in the rat's stomach and small intestine after the oral administration of CyD-5-ASA conjugate was much lower than that after the oral administration of 5-ASA alone. The lower concentration was attributable to the passage of the conjugate through the stomach and small intestine without significant degradation or absorption, followed by the degradation of the conjugate site-specific in the cecum and colon. The oral administration of CyD-5-ASA resulted in lower plasma and urine concentration of 5-ASA than that of 5-ASA alone. CONCLUSION: CyD-5-ASA conjugates may be used as prodrugs for colon-specific drug delivery system.     

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.     

Lupus-like syndrome caused by 5-aminosalicylic acid in patients with inflammatory bowel disease.

BACKGROUND: Although 5-aminosalicylic acid (5-ASA) preparations used to treat inflammatory bowel disease are reported to have fewer side effects than sulphasalazine, increased clinical use of these compounds has resulted in increased reports of significant side effects. OBJECTIVE: To report four patients with antinuclear antibody-positive migratory arthralgias and acute inflammation unrelated to the underlying inflammatory bowel disease, fulfilling the criteria of a drug-induced lupus-like syndrome. SETTING: A university-affiliated teaching hospital. INTERVENTION: Cessation of treatment with 5-ASA compounds. RESULTS: The cases described constitute a drug-induced lupus-like syndrome. All patients improved rapidly after discontinuation of 5-ASA compounds. CONCLUSIONS: Reversible lupus-like syndrome appears to be a rare but significant side effect of 5-ASA compounds. Patients treated with 5-ASA compounds who experience acute inflammatory symptoms or clinical deterioration not related to their gastrointestinal disease should be screened to rule out a lupus-like reaction.     

Dose-dependent influence of 5-aminosalicylates on thiopurine metabolism

INTRODUCTION: Studies indicated that 5-aminosalicylates (5-ASA) may influence the metabolism of thiopurines; however, conclusions were restricted as a result of number of patients or study design. AIM: To determine the influence of 5-ASA on thiopurine metabolism, we performed a prospective multicenter pharmacokinetic interaction study of two different 5-ASA dosages (2 g daily followed by 4 g daily) in 26 inflammatory bowel disease (IBD) patients during steady-state AZA or 6-MP therapy. RESULTS: The 4-wk coadministration of 2 g 5-ASA daily, followed by a 4-wk period of 4 g 5-ASA daily, led to a statistical significant increase of 40% (absolute 84 pmol/8x10(8) RBC) and 70% (absolute 154 pmol/8x10(8) RBC) in 6-thioguaninenucleotide levels (6-TGN), respectively. A rise in 6-TGN levels was observed in 100% of patients after a 4-wk period of 4 g 5-ASA daily. The 6-methylmercaptopurine-ribonucleotide levels did not change. Signs of myelotoxicity were observed in 7.7% of patients (N=2). CONCLUSIONS: The level of the pharmacologically active 6-TGN significantly increases in a dose-dependent manner during 5-ASA coadministration. IBD patients who are unresponsive or refractory to standard thiopurine therapy may benefit from the coadministration of 5-ASA, leading to an increase in 6-TGN levels.     

5-Aminosalicylic acid dependency in Crohn's disease: A Danish Crohn Colitis Database study

Background and aimsThe role of 5-aminosalicylic acid (5-ASA) in Crohn's disease is unclear. The outcome of the first course of 5-ASA monotherapy with emphasis on 5-ASA dependency was retrospectively assessed in consecutive cohort of 537 Crohn's disease patients diagnosed 1953–2007.MethodsFollowing outcome definitions were used: Immediate outcome (30 days after 5–ASA start) defined as complete/partial response (total regression/improvement of symptoms) and no response (no regression of symptoms with a need of corticosteroids, immunomodulator or surgery). Long-term outcome defined as prolonged response (still in complete/partial response 1 year after induction of response); 5-ASA dependency (relapse on stable/reduced dose of 5-ASA requiring dose escalation to regain response or relapse ≤ 1 year after 5-ASA cessation regaining response after 5-ASA re-introduction).ResultsOne hundred sixty-five (31%) patients had monotherapy with 5-ASA. In 50% 5-ASA monotherapy was initiated ≤ 1 year after diagnosis (range 0–49 years). Complete/partial response was obtained in 75% and no response in 25% of patients. Thirty-six percent had prolonged response, 23% developed 5-ASA dependency and 38% were non-responders in long-term outcome. Female gender had higher probability to develop prolonged response or 5-ASA dependency (OR 2.89, 95%CI: 1.08–7.75, p = 0.04). The median duration (range) of 5-ASA monotherapy was 34 months (1–304) in prolonged responders, 63 (6–336) in 5-ASA dependent and 2 (0–10) in non-responders.ConclusionsA selected phenotype of Crohn's disease patients may profit from 5-ASA. Fifty-nine percent of patients obtained long-term benefit with 23% becoming 5-ASA dependent. Prospective studies are warranted to assess the role of 5-ASA in Crohn's disease.