ABSTRACT
Randomized trials support the use of the thiopurines and anti-TNF monoclonal antibodies in treating Crohn disease. New therapeutic approaches and laboratory assays have helped optimize the use of these agents. Thiopurine methyltransferase activity should always be determined to avoid thiopurines in individuals with absent enzyme activity. The role of metabolite-adjusted dosing when initiating thiopurines is not settled. Measuring metabolites helps guide management in patients failing therapy. Loss of response to anti-TNF therapy is mitigated by maintenance therapy and concomitant immunomodulators. When loss of response to infliximab occurs, management is guided by the serum concentrations of infliximab and antibodies to infliximab.
Subject(s)
Crohn Disease/drug therapy , Immunosuppressive Agents/therapeutic use , Mercaptopurine/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Crohn Disease/enzymology , Humans , Methyltransferases/metabolismABSTRACT
BACKGROUND & AIMS: The practice of dosing mesalamines in divided doses for the treatment of ulcerative colitis (UC) began with sulfasalazine and was driven by sulfapyridine toxicity. This convention and the assumption that dosing multiple times a day is necessary to treat UC had not been challenged until recently. This study was conducted to determine the efficacy and safety of once-daily dosing of delayed-release mesalamine (Asacol 400-mg tablets) compared with twice-daily dosing for maintaining remission in UC patients. METHODS: A multicenter, randomized, investigator-blinded, 12-month, active-control trial was conducted to assess the noninferiority of delayed-release mesalamine 1.6-2.4 g/day administered once daily compared with twice daily in patients with mild-to-moderate UC currently in clinical remission. The primary end point was maintenance of clinical remission at month 6. RESULTS: A total of 1023 patients were randomized and dosed. The primary objective of noninferiority was met. At month 6, 90.5% of patients receiving once-daily dosing had maintained clinical remission, compared with 91.8% of patients receiving twice-daily dosing (95% confidence interval for twice daily - once daily, -2.3 to 4.9). At month 12, 85.4% of patients receiving once-daily dosing had maintained clinical remission, compared with 85.4% of patients receiving twice-daily dosing (95% confidence interval for twice daily - once daily, -4.6 to 4.7). Both regimens had low rates of withdrawals as a result of adverse events and serious adverse events. CONCLUSIONS: Once-daily dosing of delayed-release mesalamine at doses of 1.6-2.4 g/day was shown to be as effective as twice-daily dosing for maintenance of clinical remission in patients with UC.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Colitis, Ulcerative/drug therapy , Mesalamine/administration & dosage , Administration, Oral , Adult , Aged , Delayed-Action Preparations , Drug Administration Schedule , Female , Humans , Male , Mesalamine/adverse effects , Middle AgedABSTRACT
Iron contributes significantly to the formation of reactive oxygen species via the Fenton reaction. Therefore, we assessed whether a series of desferrithiocin analogs, both carboxylic acids and hydroxamates, could (1) either promote or diminish the iron-mediated oxidation of ascorbate, (2) quench a model radical species, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), and (3) when applied topically, prevent acetic acid-induced colitis in rats. Surprisingly, most of the desferrithiocin analogs inhibited the Fenton reaction to an approximately equivalent degree; however, substantial differences were observed in the capacity of the analogs to scavenge the model radical cation. Four carboxylic acid desferrithiocin analogs and their respective N-methylhydroxamates were tested along with desferrioxamine and Rowasa, a currently accepted topical therapeutic agent for inflammatory bowel disease (IBD), in a rodent model of acetic acid-induced colitis. The colonic damage was quantitated by two independent measurements. Although neither radical scavenging nor prevention of Fenton chemistry was a definitive predictor of in vivo efficacy, the overall trend is that desferrithiocin analogs substituted with an N-methylhydroxamate in the place of the carboxylic acid are both better free radical scavengers and more active against acetic acid-induced colitis. These results represent an intriguing alternative avenue to the development of improved IBD therapeutic agents.
