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1 1-Anti-integrin



FIGURE 38-1 Proposed pathogenesis of inflammatory bowel disease and target sites for pharmacological intervention. Shown are the interactions among bacterial antigens in the intestinal lumen and immune cells in the intestinal wall. If the endothelial barrier is impaired, bacterial antigens (dark circles) can gain access to antigen-presenting cells (APCs) in the lamina propria. These cells then present the antigen(s) to CD4+ lymphocytes and also secrete IL-12, thereby inducing the differentiation of TH1 cells in Crohn's disease (or type 2 helper T cells in ulcerative colitis). The Th1 cells produce a characteristic array of lymphokines, including IFN-y, which in turn activates macrophages. Macrophages positively regulate TH1 cells by secreting additional IL-12 and TNF-a. In addition to general immunosuppressants that affect multiple sites of inflammation (e.g., glucocorticoids, thioguanine derivatives, methotrexate, and cyclosporine), more specific sites for therapeutic intervention involve the intestinal bacteria (antibiotics and probiotics) and therapy directed at TNF-a (see text for further details).

groups: prodrugs and coated drugs. Prodrugs contain the same azo bond as sulfasalazine but replace the linked sulfapyridine with either another 5-ASA (olsalazine, dipentum) or an inert compound (balsalazide, colazide). Thus, these compounds act at similar sites along the GI tract as does sulfasalazine. The alternative approaches employ either a delayed-release formulation (pentasa) or a pH-sensitive coating (asacol). Delayed-release mesalamine is released throughout the small intestine and colon, whereas pH-sensitive mesalamine is released in the terminal ileum and colon. These different distributions of drug delivery have potential therapeutic implications (see Figure 38-2).

Oral sulfasalazine is of proven value in patients with mild or moderately active ulcerative colitis, with response rates of60-80%. The usual dose is 4 g/day in four divided doses with food; to avoid adverse effects, the dose is increased gradually from an initial dose of500 mg twice a day. Doses as high as 6 g/day can be used but cause an increased incidence of side effects. For patients with severe colitis, sulfasalazine is of less certain value, even though it is often added as an adjunct to

systemic glucocorticoids. Regardless of disease severity, the drug plays a useful role in preventing relapses once remission has been achieved. Because they lack the dose-related side effects of sulfapyridine, the newer formulations can be used to provide higher doses of mesalamine with some improvement in disease control. The usual doses to treat active disease are 800 mg three times a day for asacol and 1 g four times a day for pentasa. Lower doses are used for maintenance (e.g., asacol, 800 mg twice a day).

The efficacy of 5-ASA preparations (e.g., sulfasalazine) in Crohn's disease is less striking, with modest benefit at best. Sulfasalazine has not been shown to be effective in maintaining remission and has been replaced by newer 5-ASA preparations. Some studies have reported that both asacol and pentasa are more effective than placebo in inducing remission in patients with Crohn's disease (particularly colitis), although higher doses than those typically used in ulcerative colitis are required. The role of mesalamine in maintenance therapy for Crohn's disease is controversial, and there is no clear benefit of continued 5-ASA therapy in patients who achieve medical remission. Because they largely bypass the small intestine, the second-generation 5-ASA prodrugs such as olsalazine and balsalazide do not have a significant effect in small bowel Crohn's disease.

Topical preparations of mesalamine suspended in a wax matrix suppository (rowassa) or in a suspension enema (canassa) are effective in active proctitis and distal ulcerative colitis, respectively. They appear to be superior to topical hydrocortisone in this setting, with response rates of 75—90%. Mesalamine enemas (4 g/60 mL) should be used at bedtime and retained for at least 8 hours; the suppository (500 mg) should be used two to three times a day with the objective of retaining it for at least 3 hours. Response to local therapy with mesalamine may occur within 3—21 days; however, the usual course of therapy is from 3-6 weeks. Once remission has occurred, lower doses are used for maintenance.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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