Oral Delayed-Release Mesalazine

Abstract

Oral delayed-release mesalazine is an enteric-coated formulation which releases mesalazine in the terminal ileum and colon. Up to 74% of patients with mild to moderately active ulcerative colitis experience endoscopic or symptomatic improvement (including remission) or both when treated with oral delayed-release mesalazine 2.4 to 4.8 g/day. There is a trend towards a better response in patients receiving higher daily dosages of oral delayed-release mesalazine, especially in patients with active distal disease. In patients with left-sided ulcerative colitis, oral balsalazide 6.75 g/day appears to be more effective than oral delayed-release mesalazine 2.4 g/day, but a higher dosage of oral delayed-release mesalazine 4.8 g/day may provide additional benefit in these patients. Oral delayed-release mesalazine 0.8 to 4.4 g/day appears to be as effective as sulfasalazine 2 to 4 g/day, prolonged-release mesalazine 1.5 g/day or balsalazide 3 g/day in maintaining remission in patients with ulcerative colitis. The optimal dosage of oral delayed-release mesalazine for the maintenance of remission is unclear. However, oral delayed-release mesalazine 1.6 g/day with rectal mesalazine 4g, administered twice weekly, was more effective than oral drug alone in maintaining remission in patients at high risk of relapse. In patients with left-sided or distal disease oral olsalazine 1 g/day appeared to be superior to oral delayedrelease mesalazine 1.2 g/day for maintenance of symptomatic remission. Limited data in patients with Crohn’s disease have shown oral delayed-release mesalazine 0.4 to 4.8 g/day to be an effective therapy for active disease (remission in up to 45% of patients) and for quiescent disease (relapse in 34% of recipients over a duration of up to 12 months). Preliminary data indicate that oral delayedrelease mesalazine 2.4 g/day is effective in preventing postoperative recurrence of Crohn’s disease. Oral delayed-release mesalazine is effective and well tolerated in sulfasalazine-intolerant patients with ulcerative colitis or Crohn’s disease. Conclusions: Oral delayed-release mesalazine is effective in patients with mild to moderately active or quiescent ulcerative colitis. Available data suggest that patients with left-sided or distal ulcerative colitis are likely to require higher daily dosages of oral delayed-release mesalazine or supplementation with rectal mesalazine. Oral delayed-release mesalazine also appears to be effective in active and quiescent Crohn’s disease. The drug is well tolerated and it appears to be effective in sulfasalazine-intolerant patients. Delayed-release mesalazine is coated with an 80 to 130μm layer of Eudragit® S, which dissolves at pH ≥7 and releases the active drug in the terminal ileum and colon. Although the exact mechanism of action of mesalazine in patients with ulcerative colitis and Crohn’s disease is not known, in vitro studies have indicated various possible ways in which the drug may provide benefit in these patients. These include inhibition of eicosanoids, inhibition of cytokines and modulation of their effects and protection against oxygen-derived free radicals. Most studies have shown that mesalazine concentration-dependently inhibits in vitro leukotriene (LT)B₄ production in colonic mucosal cells from biopsy specimens from patients with inflammatory bowel disease and from patients with healthy colons, and in peripheral mononuclear leucocytes from healthy volunteers. Mesalazine did not affect in vitro prostaglandin (PG)E₂ production in biopsy specimens from healthy volunteers but tended to normalise the increased PGE₂ levels in biopsy specimens from patients with active ulcerative colitis. Other in vitro studies indicate that mesalazine may also decrease levels of LTC₄, PGD₂, 5-hydroxyeicosatetraenoic acid (HETE) and 11-, 12- and 15-HETE. Mesalazine showed concentration-dependent inhibition of oxygen-derived free radical generation and concentration-dependent protection against oxidant-induced injury in various in vitro models. Interferon (IFN)-γ binding and IFNγ-induced effects, such as expression of major histocompatibility gene complex D-related (HLA-DR) and increased cellular permeability, are also inhibited by mesalazine in cultures of standard colonic epithelial cell lines. Mesalazine may also decrease interleukin (IL)-1/1β and IL-2 production and reduce IL-2 receptor expression. Orally administered delayed-release mesalazine acts locally from within the lumen of the inflamed bowel and is partly absorbed into the systemic circulation. Mean steady-state mesalazine concentrations of 298.5 ng/mg wet tissue weight were found in ileocolonic biopsy specimen homogenates from patients with irritable bowel syndrome after 7 days’ treatment with oral delayed-release mesalazine 1.2 g/day. After 7 days’ treatment with other mesalazine formulations or prodrugs, containing nearly equal amounts of mesalazine, the tissue concentrations were 3-to 1000-fold lower than with oral delayed-release mesalazine. Rectal mucosal mesalazine concentrations increased dose-dependently after oral delayed-release mesalazine. Mesalazine is primarily acetylated, to its major metabolite N-acetyl-5-aminosalicylic acid (Ac-5-ASA), in the gut wall and the liver. After oral administration of delayed-release mesalazine, up to 44% of the administered dose is excreted in the faeces as mesalazine or Ac-5-ASA. Renal excretion of mesalazine and Ac-5-ASA accounts for up to 35.6% of the administered dose. The release of mesalazine after administration of oral delayed-release mesalazine does not appear to be affected by diarrhoea or by concurrent administration of omeprazole, famotidine or a high fibre diet with ispaghula husk. Oral delayed-release mesalazine ≥2.4 g/day is generally effective in patients with mild to...