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)

The in vitro synthesis of leukotriene B4 (LTB4) was evaluated in colorectal biopsy specimens and resection tissue from patients with inflammatory bowel disease. The in vitro formation of LTB4 from biopsy tissues stimulated with calcium ionophore A23187 correlated with the degree of mucosal inflammation assessed at sigmoidoscopy, and with neutrophil infiltration measured as myeloperoxidase activity. Biopsy specimens from patients taking prednisolone formed less LTB4 than those from patients not on prednisolone, with comparable levels of inflammation seen at sigmoidoscopy. The formation of LTB4 was reduced dose-dependently by the acetohydroxamic acid 5-lipoxygenase inhibitor BWA4C, with no significant inhibition of prostaglandin E2 or thromboxane B2 synthesis. In inflamed colonic resection tissue from colitic patients, the IC50 for inhibition of LTB4 formation by BWA4C was 0.03 mumol/l, compared with an IC50 of 0.8 mumol/l for NDGA. Thus, BWA4C is a potent and selective inhibitor of LTB4 synthesis in colonic tissue from patients with ulcerative colitis. Acetohydroxamic acid 5-lipoxygenase inhibitors, exemplified by BWA4C, may be useful to evaluate the clinical importance of LTB4 in ulcerative colitis, and offer a novel therapy for the disease.
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PMID:Colorectal leukotriene B4 synthesis in vitro in inflammatory bowel disease: inhibition by the selective 5-lipoxygenase inhibitor BWA4C. 131 5

A model of inflammatory bowel disease in guinea-pigs involving a 14 day initial treatment with formalin-killed Bacteroides vulgatus subcutaneously and oral carrageenin plus live B. vulgatus for 10 days was used to determine the effects of sulphasalazine 100 mg kg-1 day-1 b.i.d., p.o. given for 4, 7 and 10 days after cessation of the bacterial/carrageenin treatment on the morphological and histological states of the established disease and on the production of the principal 5-lipoxygenase products, 5-hydroxyeicosatetraenoic acid and leukotriene B4. The drug treatment did not cause any significant changes in this established disease as measured by these parameters.
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PMID:Sulphasalazine fails to prevent development of mucosal ulceration and 5-lipoxygenase activity in guinea-pigs with chronic inflammatory bowel disease induced by combined bacterial immunization and oral carrageenin. 135 81

Whatever initiates inflammation, the final message mediating cellular invasion is chemical. This consideration allows rational development of anti-inflammatory treatments. Two main classes of chemotactic mediator are recognised. Water-soluble peptides, e.g. cytokines derived from macrophages and other cells, play an important integrating part in the early recruitment of neutrophils and mononuclear cells, and in the amplification of immune responses. Lipid-soluble mediators, of which leukotriene B4 is the most highly chemotactic for neutrophils, are important in secondary amplification. In inflammatory bowel disease, we have shown evidence of increased synthesis of cytokines interleukin 1, 6 and 8. These are associated with activation of circulating monocytes in active Crohn's disease, of lamina propria macrophages in relapse of both ulcerative colitis and Crohn's disease, and development of adhesion molecules on vascular endothelium. Our studies show that interleukin 6 is selectively increased in Crohn's disease, whilst preliminary findings suggest that enhanced synthesis of interleukin 8 is particularly characteristic of ulcerative colitis. Patterns of cytokine synthesis may, therefore, be of diagnostic value. They also offer the potential for therapeutic strategies since cytokine antagonists are becoming available. We have also demonstrated increased synthesis of leukotrienes in active inflammatory bowel disease. Since leukotriene B4 is quantitatively the main chemotactic signal in the mucosa in inflammatory bowel disease during relapse, we investigated the therapeutic effect of suppressing leukotriene B4 synthesis by treating patients with fish oil (as Hi-EPA), giving 4.5 g daily of eicosapentaenoic acid. This competes for the 5-lipoxygenase enzymes, inhibiting leukotriene B4 and promoting synthesis of the less chemotactic product, LTB5.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Therapeutic interventions in gastrointestinal disease based on an understanding of inflammatory mediators. 135 43

The unique role of the enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes (LTs) makes it a likely target for biochemical manipulation. The rationale for using 5-LO inhibitors for the treatment of inflammatory bowel disease (IBD) is based on the increased generation of LTs in the inflamed mucosa, LTB4 being the most potent chemotactic and chemokinetic metabolite of arachidonic acid. Furthermore, conventional drugs, such as corticosteroids, sulphasalazine, and 5-aminosalicylic acid, inhibit LT production and specific 5-LO inhibition accelerates healing in animal models of acute colitis. The compounds identified as 5-LO inhibitors can be divided into antioxidants, substrate-analogous, and a large miscellaneous group of inhibitors, where hydroxamic acids are potent and more selective inhibitors of 5-LO. The benzothiophene hydroxyurea, zileuton, is the first selective 5-LO inhibitor evaluated for the treatment of patients with IBD. An 800-mg oral dose of zileuton was shown to reduce LTB4, but not prostaglandin E2, concentrations by 75-85% in rectal dialysates from patients with active ulcerative colitis. The clinical efficacy of zileuton 800 mg b.i.d. has also been tested in a randomized, double-blind, placebo-controlled trial in similar patients. Zileuton significantly improved the symptom scores and the histology score, but not the sigmoidoscopy score, compared to pretreatment conditions and with response to placebo, the beneficial effects being most pronounced in patients not receiving concomitant sulphasalazine treatment. The mean inhibition of LTB4 in the target tissue of inflammation was 70%. The proof that any putative 5-LO inhibitor is blocking LT production is an important stage in assessing any such drug. The main disadvantage of existing new LT inhibitors relates to the high potency of LTs, and unless a higher level of inhibition can be achieved, endogenous LTs may still be present in sufficient amounts to produce their effects.
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PMID:5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. 135 45

It has recently been suggested that the sulfidopeptide leukotriene C4 (LTC4), a 5-lipoxygenase product of the arachidonic acid metabolism and one of the most potent mediators of vascular permeability, might be involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). Subsequently, 20 guinea pigs with EAE were treated with sulfasalazine, a substance with a proved leukotriene inhibiting effect, which has previously been described as exerting beneficial effects in patients with inflammatory bowel disease and rheumatoid arthritis. The sulfasalazine-treated guinea pigs showed a significantly better clinical outcome, as well as a significantly lower histological inflammation score compared with 19 controls.
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PMID:Suppression of experimental autoimmune encephalomyelitis by sulfasalazine. 168 88

The leukotrienes constitute a group of 5-lipoxygenase catalyzed metabolites of arachidonic acid, the cellular effects of which may be divided into two broad categories. Leukotriene B4 is predominantly a leukocyte stimulant, and has recently been observed to represent the inflammatory cell component of a mutual activation mechanism between inflammatory cells and the immune system. It is thus anticipated that LTB4 acts as an inflammatory mediator and immune regulator in a variety of immune-mediated disorders. The presence of LTB4 in inflamed tissues from patients with psoriasis, rheumatoid arthritis and chronic inflammatory bowel disease renders it probable that the novel class of 5-lipoxygenase inhibitors and LTB4 antagonists will be capable of influencing the clinical course of these diseases. The other main group is comprised of leukotrienes C4, D4 and E4, collectively known as slow reacting substance of anaphylaxis leukotrienes, and has been identified primarily in immediate hypersensitivity conditions, e.g. bronchial asthma in which the smooth muscle contractile and permeability increasing properties of SRS-A appears to contribute to the early bronchoconstrictor phase. Leukotriene D4, however, may also be involved in the late reaction mediated by inflammatory cells, since it has the ability to immobilize neutrophils attracted by LTB4 to the inflammatory focus. The ultimate elucidation of the importance of leukotrienes in different diseases awaits the outcome of clinical trials with the newly developed highly potent and specific 5-lipoxygenase inhibitors and leukotriene antagonists.
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PMID:[Leukotrienes. A review of the significance for disease in man and the possibilities for therapeutic intervention]. 199 35

Since the early recognition that leukotrienes are generated in response to allergen exposure, a role for these multipurpose mediators has been sought. The pharmacologic actions of the leukotrienes and their cell sources were strong evidence that they should contribute to allergic airway disease. That promise is now being fulfilled. Potent leukotriene receptor antagonists and enzyme inhibitors of leukotriene generation are now being investigated. With the availability of these new compounds, not only will greater insight to leukotrienes in asthma become apparent, but possibly newer, more effective therapeutics. Of additional interest and relevance is the potential role of leukotrienes in other nonrespiratory inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis. Therefore, the role of leukotrienes in inflammation is not limited to the respiratory system but are more universal in their ability to cause tissue injury. Consequently, studies that have shown benefit from inhibition of leukotriene synthesis and antagonism of the LTD4 receptor in respiratory diseases are suggestive that such an approach will also be beneficial in other inflammatory diseases. For example, a study of 72 patients with A-64077 (zileuton) has demonstrated that 5-lipoxygenase inhibitors are efficacious in the treatment of inflammatory bowel disease. Therefore, the contribution of leukotrienes to inflammation is likely to be a global phenomenon, and the introduction of leukotriene antagonists and 5-lipoxygenase inhibitors may represent the beginning of a new era for the treatment of many inflammatory diseases.
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PMID:The role of leukotriene antagonists and inhibitors in the treatment of airway disease. 201 49

Serum interferon (IFN) of alpha-class was studied in 64 consecutive patients, 26 with Crohn's disease, 38 with ulcerative colitis, and in 34 healthy volunteers. Detectable IFN-alpha in 10 patients was associated with a moderate to severe activity of chronic inflammatory bowel disease (CIBD). However, 19 of 28 patients (68%) with activity in their disease did not have elevated IFN-alpha levels. The three groups, ulcerative colitis, Crohn's disease, and healthy volunteers did not reveal any statistically significant difference in serum IFN-alpha, as four of 34 healthy controls without intercurrent infections had elevated levels as well. Possible effects of alpha, beta, and gamma classes of IFN on endogenous arachidonic acid (AA) release and metabolism in human neutrophils was investigated in a substudy. IFN-alpha caused a dose-dependent release of AA from phospholipids and metabolism of a modest fraction of leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE) at doses reaching a maximum of 100 IU/ml. IFN of the beta and gamma classes did not exert such effects. Addition of complement 5a to cells activated by IFN-alpha caused induction of increased 5-lipoxygenase activity with unchanged release of AA. As only 16% of all CIBD patients had elevated IFN-alpha levels as compared to 12% among the group of healthy volunteers, IFN-alpha does not seem to be of importance for the perpetuation of the inflammatory reaction in ulcerative colitis or Crohn's disease, and other factors may therefore be responsible for activation of the inflammatory cells to production of LTB4 and 5-HETE.
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PMID:Serum interferon activity in inflammatory bowel disease. Arachidonic acid release and lipoxygenation activated by alpha-class interferon in human neutrophils. 283 22

Despite the extensive use of sulfasalazine (SAS) and/or 5-aminosalicylic acid (5-ASA) in patients with inflammatory bowel disease and, more recently, rheumatoid arthritis, their mode of action has not been elucidated so far. None of the numerous pharmacological and biochemical effects described, including immunosuppressive, antifolate, and modulatory actions on lymphocyte and leukocyte functions, could be defined unequivocally as mediating their beneficial activity. Recently, interest has focused on actions of SAS and 5-ASA on the various enzymes of the arachidonic acid cascade. Mucosa of patients with inflammatory bowel disease generates excessive amounts of cyclooxygenase products such as prostaglandins (PG) as well as 5-lipoxygenase products such as leukotriene (LT) B4 and sulfidopeptide-LT. Both PG and LT exert proinflammatory actions and are potentially important mediators of mucosal inflammation. SAS and 5-ASA, however, have been found to inhibit PG synthesis under certain experimental conditions only, while increasing PG formation under other conditions. While SAS was found to inhibit colonic LTB4 synthesis, 5-ASA was reported to selectively affect the cyclooxygenase pathway of arachidonate metabolism in this tissue. Our results demonstrate that, like the parent compound, the metabolite 5-ASA in a dose-dependent manner inhibits release of LTB4 and sulfidopeptide-LT from normal human colonic mucosa (IC50 3.5 and 3.7 mmol/liter, respectively). Indomethacin, which has no efficacy in the treatment of patients with inflammatory bowel disease, on the other hand, selectively inhibited PGE2 formation in normal and inflamed colonic mucosa (IC50 1.7 and 1.0 mmol/liter, respectively) without reducing synthesis of LTB4 or sulfidopeptide-LT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible mode of action of 5-aminosalicylic acid. 289 68

5-Aminosalicylic acid seems to be the active moiety of sulfasalazine in the treatment of chronic inflammatory bowel disease. Even if the precise mode of action is obscure, it is assumed that two of the main mechanisms are inhibitory effects on the lipoxygenation of arachidonic acid and interaction with free radicals. As 4-aminosalicylic acid has been claimed to be beneficial in the topical treatment of ulcerative colitis, it was tested whether this drug possesses any influence on the 5-lipoxygenase activity in human neutrophils in vitro or whether it acts as a radical scavenger. The change of the amino residue from carbon-5 to carbon-4 abolished the effect in the two systems tested. The reported clinical observations on 4-aminosalicylic acid in the treatment of chronic inflammatory bowel disease remain to be confirmed and cannot be explained by interference with arachidonic acid metabolism or free oxygen radicals.
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PMID:4-Aminosalicylic acid, in contrast to 5-aminosalicylic acid, has no effect on arachidonic acid metabolism in human neutrophils, or on the free radical 1,1-diphenyl-2-picrylhydrazyl. 313 49


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