(Taken from application) Crohn's disease (CD) is a chronic idiopathic inflammatory bowel disease (IBD) characterized by transmural infiltration of the intestine with T-cells, B-cells, and macrophages. These immunologically active cells cause tissue destruction, which results in symptoms such as abdominal pain, diarrhea and weight loss. The factors responsible for the initiation and perpetuation of this damaging immune response are unknown, but cytokines, soluble mediators of inflammation, are known to play a central role in the modulation of intestinal inflammation. Experimental data have shown that the proinflammatory cytokine tumor necrosis factor alpha (TNF-a) is elevated in patients with active CD. Recently, treatment with monoclonal antibodies to TNF-a has produced dramatic improvement in the clinical symptoms and endoscopic appearance of CD patients. These results argue for a central role of TNF-a in the pathophysiology of intestinal inflammation in CD and support modulation of TNF-a activity as a viable therapeutic strategy. Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown in both animal and human studies to significantly decrease TNF-a expression at both the protein and messenger RNA level. In IBD, our preliminary studies have shown that PTX improves clinical symptoms in CD patients, and others have shown that PTX improves symptoms in patients with ulcerative colitis (UC). The goal of this investigation is to study the efficacy of PTX as a novel pharmacologic agent for CD patients. The central hypothesis of this proposal is that PTX improves clinical symptoms by selectively decreasing TNF-a levels in the intestinal mucosa. This hypothesis will be tested by the following specific aims: 1) Investigate the efficacy and safety of PTX 400 mg p.o. QID in the treatment of CD. This will be a prospective pilot study with reduction in clinical symptoms and improvement in health-related quality of life as the outcome measures. Improvement in clinical symptoms will be correlated with changes in endoscopic and histologic disease activity, and 2) Measure mucosal production of TNF-a before and after treatment with PTX. This will define the effects of PTX on mucosal proinflammatory cytokines and specifically correlate changes in clinical symptoms with mucosal TNF-a levels. Although therapy exists for CD, current treatments are not always effective, have side-effects, and may be poorly tolerated. Support of this project with a Small Grant for Clinical Trials in Digestive and Nutritional Disorders will allow for the thorough evaluation of a new approach to the pharmacologic modulation of intestinal inflammation and ultimately help CD patients.
| Soweid, A M; Chak, A; Katz, J A et al. (1999) Catheter probe assisted endoluminal US in inflammatory bowel disease. Gastrointest Endosc 50:41-6 |
