Ulcerative Colitis: Isaacs KL

Isaacs KL, Lewis JD, Sandborn WJ, Sands BE, Targan SR. · University of North Carolina, Chapel Hill, North Carolina, USA. · Inflamm Bowel Dis. · Pubmed #16254481 No free full text.

Abstract: Inflammatory bowel diseases (IBD) encompass Crohn's disease and ulcerative colitis, which are diseases characterized by chronic intestinal inflammation. IBD is believed to result from predisposing genetic and environmental factors (specific antigens and pathogen-associated molecular patterns) acting on the immunoregulatory system and causing inflammation of the gastrointestinal mucosa. IBD may be the result of an imbalance of effector (proinflammatory) and regulatory T-cell responses. Three scenarios indicative of the outcome of this balance exist in animal models: balanced effector and regulatory T cells resulting in a normal controlled inflammation; overactive effector T cells resulting in inflammation and disease; and an absence of regulatory T cells resulting in uncontrolled inflammation and severe, aggressive disease. The number of products under study for the treatment of IBD has increased from 3 products and 1 target in 1993 to more than 30 products and more than 10 targets in 2005. The number of products under development and continued investigations into the pathogenesis of IBD emphasize the need to expand clinical research efforts in IBD.

Isaacs KL, Sartor RB. · Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, 27599-7080, USA. · Gastroenterol Clin North Am. · Pubmed #15177542 No free full text.

Abstract: Although antibiotics are clearly recognized as having a role in treating the infectious complications of inflammatory bowel diseases (IBD), their impact in the primary treatment of IBD has long been an area of speculation. Over the past decade there is increasing evidence that luminal gut bacteria play a role in the pathogenesis of IBD, particularly Crohn's disease. Compelling evidence that normal commensal bacteria induce chronic intestinal inflammation in susceptible rodents provides an excellent rationale for treatment of human IBD with antibiotics. This article summarizes published studies of antibiotics in IBD patients and reviews available data for the use of antibiotic therapy in Crohn's disease and ulcerative colitis.

Schreiber S, Keshavarzian A, Isaacs KL, Schollenberger J, Guzman JP, Orlandi C, Hanauer SB. · Department of General Internal Medicine, Christian-Albrechts University, Schittenhelmstrasse 12, Kiel Schleswig-Holstein 24105, Germany. · Gastroenterology. · Pubmed #17241861 No free full text.

Abstract: BACKGROUND & AIMS: Tetomilast (OPC-6535), a novel thiazole compound, inhibits phosphodiesterase-4 and proinflammatory functions of leukocytes including superoxide production and cytokine release. METHODS: One hundred eighty-six patients with mildly to moderately active ulcerative colitis (Disease Activity Index [DAI] 4-11 points) from 35 centers were randomized to receive an oral, once-daily dose of placebo or tetomilast 25 mg or 50 mg for 8 weeks. RESULTS: Percentages of patients reaching the primary end point (improvement as defined by reduction in DAI > or =3 at week 8) were not significantly different between placebo (35%) and either the 25 mg tetomilast (52%) or the 50 mg tetomilast (39%) groups (intent-to-treat population). Remission rates (DAI 0-1) were 7%, 16%, and 21%, respectively (not significant). Mean reduction in DAI at week 8 was greater in the 25-mg group than under placebo (2.8 +/- 0.4 vs 1.7 +/- 0.36, respectively, P = .041) and approached statistical significance in the 50-mg group (2.8 +/- 0.46, P = .056). A post hoc analysis focusing on patients with high activity scores (baseline DAI 7-11) suggested differences between tetomilast and placebo that will require further investigation. No significant safety concerns were raised. Main adverse effects included gastrointestinal problems (nausea, vomiting) and were preferentially seen in the 50-mg tetomilast group. CONCLUSIONS: This phase II trial of tetomilast in ulcerative colitis did not achieve statistical significance for the primary end point. Secondary end points indicate a potential clinical activity of tetomilast. The post hoc analysis suggests that further clinical development should focus on patients with objective parameters of inflammation.

Sandborn WJ, Sands BE, Wolf DC, Valentine JF, Safdi M, Katz S, Isaacs KL, Wruble LD, Katz J, Present DH, Loftus EV, Graeme-Cook F, Odenheimer DJ, Hanauer SB. · Mayo Clinic, Rochester, MN, USA. · Aliment Pharmacol Ther. · Pubmed #12786629 links to  free full text

Abstract: BACKGROUND: Repifermin (keratinocyte growth factor-2) has been shown to reduce inflammation in animal models of colitis. AIM: To evaluate repifermin for the treatment of active ulcerative colitis. METHODS: Eighty-eight patients with active ulcerative colitis were enrolled in a 6-week, double-blind trial. Patients were randomized to receive treatment for five consecutive days with intravenous repifermin at a dose of 1, 5, 10, 25 or 50 microg/kg, or placebo. The primary objective of the study was to evaluate the safety of repifermin. The primary efficacy outcome was clinical remission at week 4, defined as a score of zero on the endoscopic appearance and stool blood components of the Mayo score and a score of zero or unity on the stool frequency and physician's global assessment components. RESULTS: At week 4, the rates of clinical remission in the 1, 5, 10, 25 and 50 microg/kg repifermin groups were 19%, 9%, 0%, 0% and 0%, respectively, and 11% for the placebo group (P = 0.32 for repifermin vs. placebo). The frequencies of commonly occurring adverse events and severe adverse events were similar in both groups. CONCLUSIONS: Intravenous repifermin at a dose of 1-50 microg/kg was very well tolerated, but there was no evidence that repifermin was effective for the treatment of active ulcerative colitis at these doses. An additional study to determine the efficacy of repifermin at doses of > 50 microg/kg or for a longer treatment duration may be warranted, as the maximally tolerated dose was not reached in the present study.