Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intramucosal 5-aminosalicylic acid (5-ASA) and acetylated 5-ASA (Ac-5-ASA) concentrations were determined in ileocolonic biopsy specimens from 61 patients with irritable bowel syndrome treated for one week with near equimolar doses of different slow release preparations of 5-ASA (Claversal, Asacol, or Pentasa) or azo-bound drugs (Salazopyrin, Dipentum). The transit time in these patients was accelerated by a laxative, metoclopramide, and colonic lavage. The presence of 5-ASA in the mucosa was confirmed by autofluorescence. The highest concentrations of 5-ASA were obtained after Asacol (mean (SEM), 298.5 (37.3) ng/mg wet wt), followed by Claversal 500 mg (108.8 (11.7) ng/mg wet wt) and Pentasa (25.7 (2.2) ng/mg wet wt). Very low concentrations only were observed after Claversal 250 mg (0.3 (0.03) ng/mg wet wt), Salazopyrine (1.2 (0.1) ng/mg wet wt), and Dipentum (11.0 (3.2) ng/mg wet wt). The results for Ac-5-ASA were similar but the concentrations were generally lower. Serum concentration-time curves over eight hours were obtained from 34 healthy volunteers after a single oral dose of 400 to 500 mg of the different drugs. For the slow release forms, an apparently inverse relationship was found between the area under the curve of the serum concentrations and the intramucosal concentrations, supporting the importance of the local availability of the drug. This inverse relationship was absent for the azo-bound drugs. Colonic washout induced mechanical removal of intraluminal 5-ASA with a secondary disturbance in absorption resulting in a rapid decline in the serum concentrations. However, only for Dipentum did this result in significantly lower 5-ASA mucosal concentrations. This is the first reported attempt to evaluate the mucosal availability of 5-ASA after different oral preparations. It shows that where transit time is accelerated higher mucosal concentrations occur after slow release preparations (except for Claversal 250 mg) than after azo-bound drugs. Additional studies are necessary to correlate these concentrations with clinical effects.
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PMID:Concentrations of 5-ASA and Ac-5-ASA in human ileocolonic biopsy homogenates after oral 5-ASA preparations. 850 78

The etiologic factors responsible for IBD remain only speculative. It does appear that the inappropriate activation of the immune system, whether by immune complex deposition, infectious agents or vascular impairment, is important in the pathogenesis of these diseases. Interaction of certain cytokines known to be produced in human IBD with specific immune cells such as neutrophils and macrophages results in the induction of the enzyme NO. synthase with the concomitant release of large amounts of NO.. Nitric oxide is known to mediate many of the pathophysiological alterations associated with IBD including cell injury, intestinal hyperemia and intestinal smooth muscle dysfunction. In addition, NO. is known to decompose in solution to yield potent N-nitrosating agents which will N-nitrosate certain amines to yield potent carcinogenic nitrosamines. Because antioxidants (including 5-ASA) are potent inhibitors of nitrosamine formation, they may prove useful in attenuating the formation of potentially carcinogenic agents in vivo.
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PMID:Neutrophils, nitrogen oxides, and inflammatory bowel disease. 145 43

There is a growing body of experimental data to suggest that the chronically inflamed intestine and/or colon may be subjected to considerable oxidative stress. The most probable sources of these oxidants are the phagocytic leukocytes since these cells are known to be present in large numbers in the inflamed mucosa and are known to produce significant amounts of reactive oxygen species in response to certain inflammatory stimuli. Because the colonic mucosa contains relatively small amounts of antioxidant enzymes (e.g. SOD, catalase, GSH peroxidase) it is possible that the gut mucosa may be overwhelmed during times of active inflammation which could result in intestinal injury. If reactive oxygen species play an important role in mediating mucosal injury in IBD then it should be possible to attenuate this injury by the use of antioxidants. One such drug is the sulfasalazine metabolite 5-ASA. It may not be coincidence that this potent antiinflammatory metabolite is a potent antioxidant that possesses multiple mechanisms of action including nitrogen, carbon and oxygen-centered free radical scavenging properties as well as the ability to decompose HOCl and scavenge hemoprotein-associated oxidants. In addition 5-ASA has the additional property of being able to chelate iron and render it poorly redox active. The reason that 5-ASA is so effective in vivo may be due to this multitude of antioxidant properties. This would also suggest that other, more potent antioxidants may prove beneficial in the treatment of IBD.
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PMID:Role of neutrophil-derived oxidants in the pathogenesis of intestinal inflammation. 166 88

Fertility in women is normal in ulcerative colitis but impaired in Crohn's disease. In men fertility can be decreased during treatment with sulphasalazine and after proctectomy. In the case of drug-induced (SASP) infertility, withdrawal of the drug or substitution by one of the new 5-ASA drugs will normalize the fertility. Pregnancy has no adverse effect on the course of UC or CD and there is no place for a therapeutic abortion. Moreover, therapeutic abortion does not influence the activity of the disease. In general, the outcome of pregnancy in women with IBD is good, particularly when the disease is inactive at the time of conception. When at the start of pregnancy the disease is active, the risk of spontaneous abortion or premature delivery is increased and the patient has a considerable chance of having symptoms throughout pregnancy despite medical treatment. Therefore the patient should be advised to plan pregnancy when the disease is in remission. Medical treatment of pregnant patients should be the same as in non-pregnant patients with active disease with the exception of the drugs azathioprine, 6-MP and metronidazole. The majority of the patients will respond to medical treatment and surgical intervention is rarely necessary. However, when there is an indication for surgery, there should be no delay, despite the risk to the fetus.
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PMID:Fertility and pregnancy in inflammatory bowel disease. 270 15

The armamentarium for the treatment of IBD has grown considerably within the last decade. Sulfasalazine and corticosteroids, the two cornerstones of past therapy, are now joined by the 5-ASA drugs, antibiotics, immunosuppressive agents, and newer corticosteroids. In addition, several novel therapies with promising initial results are being investigated. As the mechanisms by which these agents work are elucidated, further insight into the pathogenesis of IBD will be gained. Based on the nature and extent of disease, physicians and patients will be able to select the optimal agent or therapeutic combination for control of this enigmatic and morbid disease.
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PMID:Inflammatory bowel disease therapy: an update. 766 41

In search of new therapies in IBD, the introduction of 4-aminosalicylic acid (4-ASA) has been proposed based on the longstanding, positive clinical experience in tuberculosis, the expected similar modes of action due to the close structural analogy to 5-aminosalicylic acid (5-ASA), an established therapy in IBD, and its inexpensiveness. To better understand the mechanisms of action of aminosalicylates, the intestinal inflammatory response and to develop new, more effective and cost saving drugs it is important to compare 4-ASA with 5-ASA with respect to their pharmacology, mechanisms of action and clinical efficacy. The inhibition of the upregulation of the initial local immune response, the inhibition of the production of inflammatory mediators, e.g. leukotrienes and the direct scavenging of toxic oxygen metabolites are important common antiinflammatory mechanisms. As the clinical experience with 4-ASA is promising, but still limited, 4-ASA currently cannot yet be recommended outside clinical trials. As the costs of 4-ASA are significantly lower compared to 5-ASA, 4-ASA may replace 5-ASA in the near future provided further trials will confirm the therapeutic and pharmacologic equivalency.
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PMID:[Recent therapeutic modalities in chronic inflammatory bowel diseases: 4- or 5-aminosalicylic acid?]. 788 75

The IBD patient should be optimistic about a potential pregnancy. Inactive IBD is not associated with decreased fertility. Inactive IBD does not affect the course of pregnancy; however, IBD has been associated with increased preterm deliveries. Active IBD during pregnancy is associated with increased stillbirths and spontaneous abortions but not with increased congenital abnormalities. Pregnancy does not cause exacerbation of previously quiescent IBD. If the disease is active at conception, it remains active or worsens in approximately two thirds of patients. Corticosteroids, sulfasalazine, and 5-ASA drugs are safe and should be used to maintain or induce remission. Antimetabolites may possibly be proved safe in the future during pregnancy but cannot yet be recommended. Both enteral nutrition and total parenteral nutrition can and should be used safely and effectively during pregnancy. Radiographs are to be used in diagnosis if an emergent condition, such as perforation or toxic megacolon, is suspected. The chance of an offspring developing IBD is about 9% but rises to 34% if both parents have IBD.
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PMID:Pregnancy and nursing. 880 43

Improvement and standardization of the conservative therapy of inflammatory bowel disease has lead to a better prognosis for the patients. During the acute flare of Crohn's disease steroids are still the standard therapy, whereas 5-aminosalicylic acid (5-ASA) preparations are used for maintenance therapy during remission. In contrast ulcerative colitis may be treated with 5-ASA also for acute exacerbations. The development of new drugs as for example the topical steroids helps to improve life quality of the patients by reducing adverse side effects. Potent immunosuppressants as azathioprine and methotrexate are useful in chronic active and refractory disease. Cyclosporin A plays a role in severe steroid refractory colitis. In the future immunomodulation by application of antiinflammatory cytokines or antibodies to inflammatory cytokines may have its place in the treatment of IBD patients. In some cases, however, the conservative therapy reaches its limits. Mistakes in the therapy are made, when these limits are not recognized and complications are not discovered in time.
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PMID:[Standards, perspectives and limits of conservative therapy of chronic inflammatory bowel diseases]. 962 88

Corticosteroids and 5-amino salicylic acid (5-ASA) are established therapies in the induction of remission and in maintenance of remission in patients with ulcerative colitis. 5-ASA exists in different delivery systems, however, clinical studies directly comparing these preparations exist only in very limited numbers. When analyzing placebo-controlled or comparative studies it is clearly evident that 5-ASA is superior to placebo in both induction of remission and maintenance therapy. In maintenance therapy prodrug compounds (sulfasalazine, SASP) seem to be marginally better compared to 5-ASA slow release preparations. Direct comparison of the newer 5-ASA preparations is not possible because of limited data. Theoretical considerations based on the different principles of slow release are also questionable since the intraluminal pH or intestinal motility may be disturbed in IBD.
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PMID:[Consequences of galenic considerations and clinical results for therapy of ulcerative colitis]. 1019 48

The incidence and prevalence of IBD increase in our Western populations. Standard therapy with glucocorticosteroids and 5-ASA formulations allow control in only about half of the patients with substantial toxicity for the former drug. Since it became apparent that both UC and Crohn's disease are disorders mediated through abnormalities in the mucosal immune system immunosuppression and immunomodulation have become current practice in the treatment of refractory IBD. In UC cyclosporin is the main immunosuppressive agent. In Crohn's disease azathioprine is the mainstay of therapy for refractory disease. Recently anti-TNF strategies have been developed which hold great promise for the treatment of Crohn's disease.
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PMID:New strategies in the management of inflammatory bowel disease. 1055 85


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