Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:017444 (TNF)
 61,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advancement of genome analysis might give great impact to the treatment of inflammatory bowel diseases(IBD). IBD patients are treated by sulfadrugs, steroids and anti-immune drugs. For difficult cases, leukocytapheresis, beclomethasone dipropionate, anti-TNF therapy, anti-LTB4 therapy and other new methods are applied. Developing epoch-making drugs will be achieved by finding new molecular targets. Histologic identification of dysplasia is important in the surveillance of long-standing ulcerative colitis. The molecular diagnosis is required for the distinction of dysplasia from the regenerative inflammatory changes. P53 immunostaining have been proved useful. Various molecular targets will be taken into discussion as additional procedures. Recent genome analysis have revealed some genetic factors contribute to pathogenesis of IBD, which are HLA, IL4, MUC3, IBD1 locus, IBD2 locus and so on. More information about genes concerning IBD will be provided by analyzing dense SNP map using DNA tip. They will open the way to the tailored therapy.
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PMID:[Post-genome challenges against inflammatory bowel diseases]. 1119 52

Inflammatory bowel diseases are multifactorial polygenic diseases. The author has worked on the characterisation of the mucosal immuno-inflammatory reaction, on genetic predisposition and on potential clinical application of blood immuno-inflammatory markers in these diseases. This paper summarizes some aspects of this work, focusing on TNF. Following points are developed: production of TNF by inflamed mucosa, genetic control of TNF production, TNF gene polymorphim in inflammatory bowel disease, and evaluation of serum TNF as a marker of disease activity or evolutivity.
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PMID:The immuno-inflammatory reaction in Crohn's disease and ulcerative colitis: characterisation, genetics and clinical application. Focus on TNF alpha. 1132 60

Corticosteroids are considered a drug of choice for the treatment of patients with moderately to severely active Crohn's disease (CD), an inflammatory bowel disease characterized by chronic recurrent flares of disease activity. However, among patients receiving corticosteroid therapy for induction of remission, 20% have corticosteroid-refractory disease and 36% of those with an initial response develop corticosteroid dependency within 1 year. Chronic corticosteroid exposure in patients who are corticosteroid dependent increases the risk for serious drug-related adverse effects. Withdrawal or reduction of corticosteroid therapy without exacerbation of symptoms is therefore recognized as an important goal of treatment. Therapies that have been shown to facilitate "steroid sparing' include the immunomodulators azathioprine/6-mercaptopurine and methotrexate and the antitumor necrosis factor-alpha monoclonal antibody infliximab. In corticosteroid-dependent patients, budesonide may be substituted for conventional corticosteroid therapy without loss of response and with less risk for toxicity, but its long-term efficacy requires further evaluation. A preliminary controlled study suggests that the investigational anti-TNF monoclonal antibody CDP-571 may also be clinically beneficial as a corticosteroid-sparing agent. This review summarizes the clinical evidence that supports consideration of these agents as alternatives in patients with CD who are dependent on, refractory to, or intolerant of conventional corticosteroid therapy.
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PMID:Approach to corticosteroid-dependent and corticosteroid-refractory Crohn's disease. 1138 40

Tumor necrosis factor alpha (TNF alpha) is an important mediator of inflammatory and autoimmune diseases. The analysis of its pathophysiologic roles has been difficult because low concentrations of TNF alpha, including those in healthy controls, cannot be measured by existing methods. We developed a sensitive Immuno-PCR assay for the detection of TNF alpha in human serum. The DNA label was generated by PCR amplification using biotinylated primer and was bound by streptavidin to the biotinylated third antibody. TNF alpha sandwiched by antibodies was detected by amplification of the DNA label using PCR. The limit of detection of the assay was 0.001 pg/ml, an approximately 5 x 10(4)-fold improvement compared with conventional ELISA. The mean serum TNF alpha concentration in Duchenne muscular dystrophy patients (27.8 pg/ml) was approximately 1,000 times higher than that in healthy subjects (0.027 pg/ml). The mean value in inflammatory bowel disease patients was approximately 2,000 times that in healthy subjects (mean excess for UC, 1,100 times; for CD, 7,700 times). These findings suggest that measuring the serum concentration using a highly sensitive Immuno-PCR assay may be useful for analyzing the clinical significance of TNF alpha in various diseases.
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PMID:[Clinical significance of measurement of circulating tumor necrosis factor alpha]. 1168 66

The treatment of patients with ulcerative colitis and Crohn's disease is a huge challenge to the clinician mainly because the etiology of IBD is still completely unknown. Pathogenetic mechanisms, in constrast, have partly been elucidated thanks to immunohistochemical investigation of the tissue in IBD and the study of experimental animal models of gut inflammation. There is extensive evidence that at least in Crohn's disease tolerance for commensal bacteria is lost which leads to uncontrolled inflammation mediated by a T-helper 1 response and to tissue destruction of the gut epithelium with inadequate repair. Genetic factors are probably responsible for increased susceptibility and may define disease phenotypes. These insights have led to a dramatic improvement of our therapeutic means with the development of the chimeric monoclonal antibody to TNF. The pathogenetic mechanisms are less clear in UC. The hypothesis is that UC is a T-helper 2 mediated disease. We have a very attractive way to study the early onset of Crohn's disease in the postoperative Crohn's situation. Newer therapeutic approaches should aim at preventing recurrence of Crohn's lesions in the normal postoperative bowel. Such model is also available for UC since there is increasing evidence that pouchitis is recurrent ulcerative colitis in the small bowel. Cooperation between clinicians and basic scientists is the best way to achieve fast progress in understanding IBD.
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PMID:Understanding inflammatory bowel disease--the clinician's perspective. 1171 29

p38 mitogen-activated protein kinase (MAPK) (p38/p38-alpha/CSBP2/RK) has been implicated in the regulation of many proinflammatory pathways. Because of this, it has received much attention as a potential drug target for controlling diseases such as rheumatoid arthritis, endotoxic shock, inflammatory bowel disease, osteoporosis, and many others. A number of small molecule inhibitors of this kinase have been described, and in this paper we have used surface plasmon resonance to directly measure and quantitate their binding to p38. Despite the relatively low molecular mass (approximately 400 Da) of these inhibitors, specific binding can be observed. For the two most potent inhibitors studied, SB 203580 and RWJ 67657, dissociation constants, K(d)'s, of 22 and 10 nm, respectively, were obtained. These values closely match the IC(5)0 values observed in a cell-based TNF alpha release assay implying that p38 plays a major role in TNF alpha release. The association and dissociation rates for the binding of these inhibitors to p38 have also been quantitated. SB 203580 and RWJ 67657 have very similar association rates of around 8 x 10(5) m(-1) x s(-1), and the differences in affinity are determined by different dissociation rates. The weaker binding compounds have dissociation rates similar to SB 203580, but the association rates vary by an order of magnitude or more. The direct measurement of compounds binding to p38 may help in understanding the difference between potency and efficacy for these inhibitors. This in turn may yield clues on how to develop better inhibitors.
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PMID:Kinetics of small molecule inhibitor binding to p38 kinase. 1172 59

Therapy of inflammatory bowel disease (IBD) is rapidly changing with the advent of new discoveries in disease pathogenesis. The need for targeted therapies against the uncontrolled immuno-inflammatory reaction in IBD together with a prerequisite for minimal side effects is driving improvement in old medicines and is leading to the development of new drugs. This review introduces emerging changes in IBD treatment, such as improvements in conventional IBD medications or their use. Balsalazide, budesonide and changes in the use of 5-aminosalicylate (5-ASA) products and purine analogues, such as azathioprine, are discussed. Additionally, studies examining the role of drugs newly introduced into IBD therapy, such as mycophenolate mofetil (MMF), thalidomide and heparin, are stated. Emerging biological therapies, such as therapies against TNF, therapies to enhance anti-inflammatory cytokines, therapeutic manoeuvres to disrupt immune cell trafficking, anti-oxidant therapies, as well as non-conventional treatments, such as diet therapies, prebiotics and probiotics, and helminth therapies are discussed.
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PMID:New developments in the treatment of inflammatory bowel disease. 1186 66

The only therapy in inflammatory bowel disease (IBD), which up to the mid-1990s was disease modifying, was immunosuppression with azathioprine. Other 'standard' therapies in IBD were merely symptomatic. With the advent of biological therapies, especially the chimeric monoclonal anti-TNF antibody infliximab, we start to target specific pathogenic disease mechanisms, which allow thorough suppression of the disease process and healing of the bowel in the long term. Moreover, infliximab is the only drug up to the present that allows short-term healing of fistulizing Crohn's disease. This therapy is, however, associated with problems of immunogenicity. The formation of antibodies to infliximab jeopardizes the efficacy and is associated with infusion reactions. Optimization of anti-TNF strategies will occur in the coming years. Another promising therapy is antagonization of alpha4 integrins and hence, of migration of inflammatory cells to the intestine. It can be expected that more simple therapies using small molecules that inhibit the key cytokines or pro-inflammatory processes will take over in the next decade. In the current and future approach to IBD therapy immunosuppression with azathioprine or 6-MP and methotrexate play a central role. At the present time, the combination of infliximab with azathioprine or methotrexate can be regarded as the new standard for the therapy of refractory Crohn's disease. In ulcerative colitis (UC) much less progress has been made and the value of biological therapy as well as of long-term management with immunosuppression remains controversial. Probiotics are an attractive treatment option for IBD but studies so far are small and data are not yet convincing.
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PMID:A critical assessment of new therapies in inflammatory bowel disease. 1200 Jun 4

In inflammatory diseases such as Crohn's disease (CD) and ulcerative colitis (UC), one would expect that TNF or IL-6 stimulates the hypothalamus, which activates the hypothalamus-autonomic nervous system (HANS) axis and the hypothalamic-pituitary-adrenal (HPA) axis in a parallel fashion. The study was initiated in order to investigate the parallelism of the HANS and HPA axes. We measured a typical marker of the HANS axis (neuropeptide Y, NPY) and of the HPA axis (serum cortisol). Plasma NPY was positively correlated with serum cortisol in control subjects (R(Rank)=0.259, p=0.026), which is a sign for the parallel activation of the two axes in healthy subjects. However, serum cortisol was not correlated with plasma NPY in CD or UC patients. In the active CD or UC, inclusion of patients with and without prior prednisolone therapy revealed a negative correlation between the serum cortisol and plasma NPY (CD: R(Rank)=-0.285, p<0.05; UC: R(Rank)=-0.510, p<0.01). This study demonstrates that the two stress axes seem to act in a parallel fashion in control subjects but are uncoupled in IBD patients. Uncoupling of these two axes may be partly due to prior corticosteroid therapy, whereas inverse coupling is a result of simultaneous corticosteroid therapy. It is discussed how the uncoupling of the two anti-inflammatory stress axes can appear.
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PMID:Uncoupling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in inflammatory bowel disease? 1202 Sep 63

Most patients with inflammatory bowel disease can be managed with conventional immunosuppressive therapy. The choice of agents to prevent relapses of inflammatory bowel disease must be based on efficacy, toxicity and cost. Studies in animal models of inflammatory bowel disease indicate that chronic intestinal inflammation results from enhanced immune responses to bacteria that are present normally in the lumen. Loss of tolerance, an abnormal function or defective healing of the mucosal barrier may all give raise to chronic intestinal inflammation. This hypothesis is the basis of new therapies aimed at either decreasing the levels of luminal bacterial antigens and/or selectively blocking detrimental mucosal immune responses. Anti-TNF is an example of this novel approach that is very effective in Crohn's disease. The use of biological therapy is costly, however, and the long-term complications are not yet known. The recent increase of tuberculosis in patients treated with anti-TNF indicates that careful monitoring is necessary. It is clear that the new forms of treatment may play an important role in tailoring the appropriate drug to a specific group of patients. However, for the time being, fine-tuning in the use of conventional immunosuppression is necessary. New knowledge in the pharmacogenetics of these compounds allows improvements to be made in their use. It is to be hoped that a critical approach in the use of current and future drugs, taking into account the advances in the aetiopathogenesis of inflammatory bowel disease, will contribute to the quality of life of patients with inflammatory bowel disease.
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PMID:Review article: a critical approach to new forms of treatment of Crohn's disease and ulcerative colitis. 1204 61


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