Inflammatory bowel disease activation

Glucocorticoids are commonly used in the treatment of patients with moderate to severe active inflammatory bowel disease. Active disease is commonly treated with an initial oral dosage of 40-60 mg/d of prednisone or prednisolone. Higher doses have not been shown to be more efficacious but have significantly greater adverse effects. Once a patient responds to initial therapy (usually within 1-2 weeks), the dosage is tapered to minimize development of adverse effects. In severely ill patients, the drugs are usually administered intravenously. 

KC706 stabilizes the inactive conformation of the mitogen-activated protein kinase p38a, a protein kinase involved in inflammatory reactions and cardiovascular functions. KC706 therefore holds the potential to treat conditions such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and cardiovascular disease. This compound is currently being tested in phase II clinical trials with patients suffering from rheumatoid arthritis. 

Human tumor necrosis factor (TNF) (Fig. 1) is a hormone-like proinflammatory peptide belonging to the group of cytokines. It is mainly produced by cells of the immune system in response to infection, inflammation, or cell damage. Disregulated TNF is an important factor in many pathological situations, like sqDsis, rheumatoid arthritis, inflammatory bowel disease (Crohn s disease), and Cachexia. The cytotoxic activity of TNF is of interest in development of new antitumoral strategies. 

Burdelski, M., Oellericch, M., Pippenger, C.E., Meng, X., Rodeck, B., Latta, A. and Kucher, K. (1990). Free radical scavenging enzyme activities in erythrocytes of paediatric patients with Crohn s disease. In Trends in Inflammatory Bowel Disease Therapy (ed. C. J. Williams), pp. 453-454. Kluwer Academic Publishers, Lancaster. 

Mahida, Y.R., Wu, K.C. and Jewell, D.P. (1989). Respiratory burst activity of intestinal macrophages in normal and inflammatory bowel disease. Gut 30, 1362-1370. 

Pippenger, C.E., Meng, X., Stolfi, V, McGonagle, B. and Fazio, V.W. (1991). Free radical scavenging activities and trace element concentrations in erythrocytes and plasma of adult patients with inflammatory bowel disease. In Inflammatory Bowel Diseases. Progress in Basic Research and Clinical Implications (eds. H. Gocbell, K. Ewe, H. Malchow and Ch. Koelbel) p. 33. Kluwer Academic Publishers, Lancaster. 

Verspaget, H.W., Elmgreen, J., Weterman, I.T., Pena, A.S., Riis, P. and Earners, C.B.H.W. (1986). Impaired activation of the neutrophil oxidative metabolism in chronic inflammatory bowel disease. Scand. J. Gastroenterol. 21, 1124-1130. 

Duchman R, Kaiser I, Hermann E, Mayet W, Ewe K, Meyer zum Buschenfelde KH Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin Exp Immunol 1995 102 448-455. 

The same strategy was applied in colon-specific delivery of two corticosteroids used to treat inflammatory bowel disease [20][21], Indeed, budeso-nide /3-D-glucuronide and dexamethasone /3-D-glucuronide underwent ready hydrolysis in the luminal contents of rat colon and caecum. Rat mucosal homogenates were less active, and hydrolysis in human fecal samples was quite low. Based on these and other studies, the prodrugs were found to be suitable candidates for delivery of corticosteroids to the large intestine. 

As a consequence of their immunosuppressive activity, Tregs may function as a cellular therapeutic agent that ameliorates allergies and autoimmune diseases. This has been proven in several disease models including asthma, inflammatory bowel disease, multiple sclerosis and CHS reactions. Others and we have studied the effects of in vivo applied Tregs as a possible therapeutical means to curb... 

Fig. 13.3 Clinical response, adverse effects, and hematological parameters were determined and correlated with thiopurine methyl transferase (TPMT) enzyme activity and genotype in 106 patients with inflammatory bowel disease. The odds of achieving complete remission (CR) to azathioprine is approx, five times lower if TPMT is greater than 14 units/mL red blood cells (RBCs). (Reproduced from ref 39.)...

Ansari, A., Hassan, C., Duley, J., et al. (2002) Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment. Pharmacol. Ther. 16, 1743-1750. 

Importantly, knowledge of intestinal bile acid transport and metabolism, coupled with increased understanding of the mechanistic basis of the pro-tumorigenic activity of bile acids against CRC cells in vitro, has recently led to development and testing of bile acid-based treatment and prevention strategies for sporadic and inflammatory bowel-disease-associated CRC. Existing evidence that manipulation of the luminal secondary bile acid pool and/or therapy with ursodeoxycholic acid (UDCA) may have promise for prevention of CRC will be assessed. 

Is the development of two formulations to proceed in parallel or sequentially The size of the programme may be doubled if a second formulation is aimed at a different target group. On the other hand, it may be more cost-effective to carry out a larger programme than to come back at a later date. Por example, in the development of a new agent to treat inflammatory bowel disease it may be inappropriate to use an orally active... 

Indications for glucocorticosteroids include adrenal insufficiency and inflammatory, non-infectious processes of all sorts such as various types of arthritis, auto-immune diseases, asthma, inflammatory bowel diseases, especially Crohn s disease but also ulcerative colitis and further many skin diseases and some diseases of the eye. Their antimitotic activity is used in various anti-cancer chemotherapeutic regimens. They still have an important place... 

Sulfasalazine has been used for the management of RA and ankylosing spondylitis with apparently similar effectiveness as penicillamine and with less toxicity. While 5-aminosalicylic acid is the active agent in inflammatory bowel disease, it is believed that sulfapyridine is mostly responsible for the antirheumatoid effects. Gastrointestinal complaints, dizziness and photosensitivity are the most frequently observed adverse events. With levamisole and also with sulfasalazine and olsalazine a delay of 2-3 months is to be expected before positive responses will be observed. 

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