Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Budesonide-beta-D-glucuronide is a potentially useful orally administered prodrug for the treatment of colonic inflammatory bowel disease. Budesonide is a topically active glucocorticosteroid that exhibits low oral bioavailability (15%) in humans and laboratory animals. Oral delivery of budesonide to the inflamed tissues of the large intestine as its glucuronide prodrug should lead to locally high concentrations of active drug. Following liberation and absorption of the active drug, a large portion should be inactivated due to hepatic metabolism. Budesonide-beta-D-glucuronide was chemically stable in solutions at pHs of 1.5, 4.5, 6.5, and 7.4 at 37 degrees C. The enzymatic lability of the prodrug was assessed in luminal contents and mucosa obtained from conventional, germ-free, and colitic rats under in vitro conditions. There was a substantial change in glycosidase activity between the small intestine (proximal and distal portions) and the cecum in both conventional and colitic rat luminal contents. Luminal hydrolytic activity was low along the entire rat gastrointestinal tract of germ-free rats. Mucosal glycosidase activity was relatively low along the entire gastrointestinal tract of all three types of rats. The hydrolysis of prodrugs budesonide-beta-D-glucuronide and dexamethasone-beta-D-glucuronide in human fecal samples from patients with ulcerative colitis and normal volunteers was also measured. There were no statistically significant differences between the normal and colitic fecal samples for hydrolysis of the either prodrug or between the relative rates of hydrolysis of the two prodrugs. Hydrolysis rates of the prodrugs were about two orders of magnitude less in human fecal samples compared with those in cecal and colonic contents from the rat.
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PMID:Budesonide-beta-D-glucuronide: a potential prodrug for treatment of ulcerative colitis. 756 3

Budesonide is a glucocorticoid with high topical activity, but low systemic bio-availability which results in reduced systemic effects in comparison with other glucocorticoids. To date, it has been evaluated for use in patients with inflammatory bowel disease when administered either orally as a controlled ileal release formulation or rectally as an enema. In comparative trials, daily treatment with budesonide enema 2 mg/100ml for 4 weeks produced endoscopic remission or improvement in 46 to 84% of patients with active distal ulcerative colitis and/or proctitis and histological remission or improvement in 45 to 68%. In general, this regimen was effective as regimens of hydrocortisone, methylprednisolone, prednisolone or mesalazine (5-amino-salicylic acid, mesalamine) enemas, but caused less suppression of plasma cortisol levels than the other glucocorticoids. Oral treatment with controlled release budesonide 9 mg/day for 8 weeks produces clinical remission in 42 to 67% of patients with active Crohn's disease of the ileum, ileocaecal region and/or ascending colon and significantly reduces Crohn's disease activity index scores compared with baseline and placebo. Results of a quality-of-life questionnaire reflected these clinical improvements. Budesonide has similar efficacy to prednisolone. Response to budesonide is maintained after dosage tapering at 8 weeks. Compared with placebo, maintenance treatment with oral budesonide 3 or 6 mg/day increases the duration of remission in patients with Crohn's disease, but does not appear to affect the 1-year relapse rate. Thus, budesonide, administered rectally to patients with distal ulcerative colitis or proctitis or orally to patients with Crohn's disease of the ileum, ileocaecal region and/or ascending colon, is a favourable option for the treatment of acute exacerbations of inflammatory bowel disease. Because of the low incidence of adverse glucocorticoid-related effects associated with oral budesonide, it may also be a useful agent for longer term maintenance therapy if further clinical trials confirm its efficacy in this indication.
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PMID:Budesonide. A review of its pharmacological properties and therapeutic efficacy in inflammatory bowel disease. 858 30

Due to its immunomodulatory and anti-inflammatory properties glucocorticosteroids have proved to be highly efficacious in patients with inflammatory bowel disease. However, because of the risk of side-effects, the dose and duration of therapy with systemically acting glucocorticosteroids have to be restricted. Recently the use of topically acting glucocorticosteroids has attracted great interest. Among the various topically acting glucocorticosteroids budesonide has emerged as the most promising. Budesonide is highly potent, is readily water-soluble and has low systemic bioavailability, thus reducing the risk of corticosteroid-related side-effects. When given as enema to patients with proctitis or proctosigmoiditis, the efficacy of budesonide is greater than that of placebo and equal to that of prednisolone or 5-aminosalicylic acid enemas. In an enteric-coated formulation budesonide is more effective than placebo in achieving and maintaining remission in patients with ileocecal Crohn's disease. Although corticosteroid-related side-effects are rare, some suppression of the hypothalamic-pituitary-adrenal axis may occur.
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PMID:Budesonide in inflammatory bowel disease. 881 1

This review focuses on current developments in the major categories of therapy used in the management of inflammatory bowel disease (IBD). Conventional corticosteroids, although a mainstay of the acute treatment of IBD for many years, have many drawbacks, including a variety of side effects--particularly with chronic use. Budesonide appears to be relatively safe and at least moderately effective in inducing remission in active distal ulcerative colitis (UC) and Crohn's disease. Aminosalicylates, both oral and topical, have proven useful in managing mild-to-moderate active UC and mild active Crohn's disease, as well as in maintaining remission. Data from recent trials suggest that higher doses of mesalamine are generally more efficacious than lower doses. In addition, a combination of oral and rectal formulations may succeed when one route, alone, is not successful. The immunomodulatory agents azathioprine, 6-mercaptopurine, and methotrexate have been shown to be effective in the treatment of IBD and are now widely accepted as valuable parts of the therapeutic armamentarium. Cyclosporine, although effective, is associated with many toxicities, and patients must be monitored closely in centers experienced with this agent. Clinical trials of IL-10, IL-11, and anti-TNFalpha have also shown promise. Antibiotics have been used empirically for many years in the treatment of IBD. Larger clinical trials are warranted to explore the potential efficacy of antibiotic therapy. This has been accomplished with metronidazole in Crohn's disease, and other antibiotic trials are underway at this time. The investigational agents acemannan, heparin, and transdermal nicotine have also shown variable degrees of promise as possible therapies for IBD. Despite the variety of agents available for the treatment of IBD, none is ideal or universally accepted. Ongoing research into the well-established therapeutic agents, as well as novel drugs with more precise targets, may contribute to the design of a more nearly optimal regimen for IBD in the not-too-distant future.
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PMID:Optimizing therapy for inflammatory bowel disease. 939 47

The use of non-specific anti-inflammatory drugs such as the glucocorticoids is the foundation of medical therapy for inflammatory bowel disease. Although conventional steroid drugs are highly effective, their use is associated with the adverse effects of Cushing's syndrome. However, the therapeutic index of these drugs can be improved by chemical modification of the steroid nucleus and the use of new drug delivery systems that target the bowel wall as the pharmacokinetic compartment of interest. Budesonide is a novel glucocorticoid compound that illustrates the potential of this approach to identify effective and safe new treatments. Regional therapy for inflammatory bowel disease is an important pharmacological concept for the future development of the new glucocorticoids and other classes of drugs.
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PMID:Review article: Drug development in inflammatory bowel disease: budesonide--a model of targeted therapy. 946 84

Budesonide, a beta-adreno-receptor agonist, is comparable to corticosteroid in the treatment of patients with inflammatory bowel disease with the advantage of minimal side effect. Although the immunomodulatory effects of budesonide on the circulatory and respiratory mucosal immune system have been reported, its effect on the human gut immune system has not been published. In this study, the effect of budesonide on the human gut immune system was compared to methyl-prednisolone. The cellular immune function was measured in-vitro by DNA synthesis, ornithine decarboxylase (ODC) activity and TNFalpha secretion. We found that both drugs have a comparable inhibitory effect on DNA synthesis, ODC activity and suppression of TNFalpha secretion. Exogenous addition of IL-2, did not restore the antiproliferative effect of both drugs. We conclude that budesonide has a comparative suppressive effect to methyl-prednisolone on the gut immune system which is not related to IL-2 secretion. The antiproliferative response may explain the therapeutic effect of budesonide on patients with inflammatory bowel disease.
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PMID:Immunosuppressive effect of budesonide on human lamina propria lymphocytes. 950 28

Glucocorticosteroids (GCS) are effective in treatment of inflammatory bowel disease (IBD), but also have unwanted systemic side effects. Here, we describe the effects of budesonide and dexamethasone on acute experimental colitis and on T cells in thymus and spleen, as well as the effect of budesonide treatment on relapsing colitis. Acute colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in ethanol, and a relapse was induced by an intraperitoneal booster of TNBS. GCS were administered intrarectally on days 1, 4, and 6 after induction of acute colitis or a relapse. Inflammatory cells in the colon were studied on day 7, and in acute colitis also on days 13 and 16. Budesonide treatment in acute and relapsing colitis resulted in reduction of macroscopic damage and decreased the numbers of macrophages and neutrophils in the colon. Dexamethasone was less effective. Dexamethasone, but not budesonide, reduced the number of T cells in the thymus. It is concluded that local budesonide is more effective in treatment of acute experimental colitis than dexamethasone and, in contrast to dexamethasone, did not cause a general suppression of T cells. Although budesonide was very effective in the treatment of relapsing colitis, this effect was not accomplished by affecting the number of T cells in the colon.
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PMID:Effects of local budesonide treatment on the cell-mediated immune response in acute and relapsing colitis in rats. 982 45

Inflammatory bowel disease therapy can be considered in several subcategories, and this review is designed to provide selective updates for some of the most important therapeutic entities currently marketed or soon to be available for the medical management of IBD. Although conventional corticosteroids have been a major component of acute inflammatory bowel disease management, steroids have many serious disadvantages; and toxicity is heightened with chronic steroid therapy. Newer corticosteroids, particularly budesonide, may be less toxic than older agents such as prednisone. Budesonide may be used as an enema in active distal ulcerative colitis (UC) or as delayed release tablets in Crohn's disease (CD). However, budesonide is not completely free from steroid side effects, and may share in some of the toxicity of older corticosteroids, particularly when high dose budesonide is administered. Topical and oral aminosalicylates are widely utilized for the treatment of mild to moderate active UC and mild active CD, and they also are efficacious for maintenance of IBD remission. Recent data continue to support the concept that higher doses and prolonged use of mesalamine-based drugs are therapeutically superior to lower doses and short term treatment. In addition, the combination of oral and rectal aminosalicylate formulations often succeeds in patients refractory to either used alone. The immunomodulatory drugs azathioprine and 6-mercaptopurine are particularly effective in treating both CD and UC, and methotrexate has also shown some promise in CD therapy. Immunosuppressive therapy for inflammatory bowel disease initially met with strong physician resistance. However, views have shifted in response to positive data on the utility of immunosuppressive agents in many cases of IBD. Although cyclosporine may be used as a 'rescue' medication in some severe IBD cases, it has been associated with severe toxic reactions. Possible candidates for cyclosporine treatment should be offered such therapy only in academic centers highly experienced with the nuances of this modality. Clinical trials of the newer entities IL-10, IL-11, tacrolimus, and anti-TNFalpha, have demonstrated variable efficacy in refractory IBD patients. Anti-TNFalpha has been very impressive, particularly in the presence of fistulizing Crohn's disease. Many physicians have utilized various antibiotics empirically as part of their 'general' management of IBD. Only metronidazole has been adequately studied in controlled CD trials, but other antibiotic studies are pending. Further exploration of antimicrobial treatment for IBD is clearly warranted. Many other investigational agents in disparate pharmaceutical categories have been employed in IBD therapy; and some of these also show varying degrees of promise, including the aloe vera derivative acemannan, several formulations of heparin, and both transdermal and intra-rectal nicotine. Despite the growing list of medications and formulations promoted for the treatment of IBD, no single drug or recognized combination has yet been confirmed as dependably clinically effective. Many additional investigations of IBD medical therapy are needed, including permutations of conventional medications, along with newer agents that may be more precisely targeted to specific aspects of IBD pathophysiology. All physicians who care for UC and CD patients enthusiastically await more optimal regimens for these challenging disorders.
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PMID:Medical therapy of inflammatory bowel disease for the 21st century. 1002 72

A groundswell of therapeutic modalities is presently sweeping through the field of inflammatory bowel disease (IBD), revolutionising the treatment and management of these disorders. At the forefront of newer agents are biological therapies, also referred to as 'biologics'. These include infliximab (cA2), CDP 571, rhIL-10, ICAM-1 antisense oligonucleotide (ISIS 2302) and opreleukin (rhIL-11). Among these, infliximab and CDP 571 are perhaps the most promising, particularly in Crohn's disease. Both are anti-TNF alpha monoclonal antibody formulations with proven efficacy at doses of 5 mg/kg for inducing remission in patients with moderate to severe refractory Crohn's disease. Infliximab is beneficial in the treatment of fistulous Crohn's disease as well. Anti-inflammatory cytokines such as rhIL-10 and opreleukin (rhIL-11) in early reports appear efficacious in Crohn's disease but not in ulcerative colitis. Budesonide, a second generation glucocorticoid, in an oral controlled ileal release capsule, is an attractive alternative to prednisone for treating active Crohn's disease of the distal ileum and proximal colon. Also available as an enema, budesonide's efficacy approximates that of prednisolone for inducing remission in active distal ulcerative colitis. Postoperative recurrences of Crohn's disease are a common clinical scenario. Recently, mesalazine, metronidazole and mercaptopurine have been re-evaluated in the postoperative setting. In the largest postoperative prophylaxis trial, mercaptopurine was superior to both placebo and mesalazine in preventing clinical, endoscopic and radiographic relapses. Finally, miscellaneous therapies such as transdermal nicotine, nicotine tartrate enemas and topical lidocaine used in pilot studies for ulcerative colitis have shown promise. Case reports of thalidomide and tacrolimus (FK 506) have reported beneficial effects in treating complicated, refractory Crohn's disease.
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PMID:Promising new agents for the treatment of inflammatory bowel disorders. 1056 35

Our aims were to assess the impact on health-related quality of life (HRQOL) of a controlled ileal release (CIR) formulation of budesonide in active Crohn's disease (CD) and further define the role of HRQOL, using the Inflammatory Bowel Disease Questionnaire (IBDQ), in assessing outcome in CD. A randomized trial was conducted in 258 patients with active ileal or ileocecal CD. Budesonide CIR 1.5 mg, 4.5 mg, 7.5 mg, or placebo was given b.i.d. for 8 weeks. IBDQ score changes were compared among groups. Correlations for IBDQ and Crohn's Disease Activity Index (CDAI) scores were calculated. Mean IBDQ scores improved significantly over placebo by 2 weeks in budesonide 15 mg (155+/-38; p = 0.006) and 9 mg groups (157+/-33; p = 0.0002). Bowel, systemic, social, and emotional subscores were also significantly better (p < 0.002) at 2 and 8 weeks in the 9 mg group. Improved HRQOL scores correlated well with decreased CDAI (-0.8 < r < -0.4). Average per item change in IBDQ at remission was 1.17 to 1.48. Prior surgery (p < 0.005) or current smoker (p < 0.05) status predicted poorer initial HRQOL but not response. Budesonide CIR 9 or 15 mg/day rapidly and significantly improved HRQOL in active CD.
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PMID:Quality of life rapidly improves with budesonide therapy for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group. 1096 90


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