Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serious and unexpected adverse events, such as heart failure and drug-induced lupus, have been reported in patients receiving TNF inhibitor therapy. These events generally are easily recognizable, although they cannot be predicted nor avoided, other than by drug avoidance altogether Many patients have great benefit from anti-TNF therapies. Their intelligent use requires a firm understanding of these rare toxicities, so as to minimize the morbidity associated with their uncommon occurrence.
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PMID:Unusual toxicities with TNF inhibition: heart failure and drug-induced lupus. 1555 28

Tumor necrosis factor a (TNF-alpha) is a proinflammatory cytokine that is produced by activated macrophages. It has been shown to stimulate the release of endothelial cytokines and NO, increase vascular permeability, decrease contractility, and induce a prothrombotic state. The most studied TNF-a gene mutation in heart disease is a gamma to alpha substitution, which occurs when 308 nucleotides move upstream from the transcription initiation site in the TNF promoter and has been associated with elevated levels of TNF-alpha. The TNF1 allele (wild type) contains gamma at this site, while the TNF2 allele has an alpha substitution at the site. The TNF2 allele is a more powerful transcriptional activator, therefore leading to higher TNF-alpha levels. Most of the studies to date have failed to conclusively show any link between the polymorphism and heart disease, both coronary artery disease and cardiomyopathy/heart failure.
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PMID:Tumor necrosis factor alpha polymorphism in heart failure/cardiomyopathy. 1559 43

Acute myocardial infarction (AMI) is a myocardial necrosis occurring due to persistent coronary ischemia, in which inflammation plays an important role and heart failure is a common complication. The present work was undertaken to clarify the role of Tumor Necrosis Factor Alpha (TNF-alpha) in acute myocardial infarction (AMI). The study was conducted on 20 newly diagnosed AMI patients and 10 healthy age and sex matched controls. Sequential estimation of plasma TNF alpha level was carried out at admission, 24 and 48 hours post admission using ELISA. AMI patients showed a significant increase of plasma TNF-alpha level on admission, and 24 hours post admission but not after 48 hours. However, a significant increase was still seen at 48 hours post admission in patients with signs of heart failure but not in those without signs of heart failure. A significant positive correlation was found between plasma TNF-alpha level and CPK level at admission. On the other hand a significant negative correlation was found between these 2 parameters at 24 and 48 hours post admission. It is concluded that TNF-alpha may be an early marker of myocardial damage because of the early increase of its level after ischemic injury instead of being late consequence of extensive tissue necrosis. TNF-alpha level may be an important indicator of the severity of AMI and the occurrence of heart failure.
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PMID:Tumor necrosis factor alpha in patients with acute myocardial infarction. 1572 84

In recent years we have noticed the arrival of biological drugs for the treatment of rheumatoid arthritis (RA), Crohn's disease (CD), psoriasis, and other chronic inflammatory diseases. Those drugs are produced with biotechnology methods and are defined as biologicals because of they work on the immune system. Different cellular groups and inflammation mediators participate in the inflammatory process, all of them susceptible of a therapeutic approach; they are so-called biological targets. Inhibition of TNF and interleukina 1 (IL-1) has proven effective for the control of inflammation in diseases as RA or CD. At present we have two types of inhibitors of TNF, specific monoclonal antibodies (infliximab, adalimumab) and cellular receptors (etanercept) and an IL-1 inhibitor (anakinra). The use of TNF inhibitors has given rise to a substantial change in the treatment of RA and CD because of its effectiveness. Together with this beneficial effect, an increase of infections (some of them severe) has occurred, especially tuberculosis. Other side effects that can be considered infrequent include demyelinization, heart failure, blood dyscrasias and lymphomas, which means that a thorough knowledge of these drugs is necessary for their use. Other potential biological drugs still in investigational phase are mentioned.
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PMID:[Applications of monoclonal antibodies and biotechnology products in the treatment of chronic inflammatory diseases]. 1581 Dec 82

Cardiovascular disease (CVD) is responsible for 35-50% of rheumatoid arthritis (RA) deaths, whereas, in the general UK adult population, coronary heart disease is responsible for 1/4 deaths in males and 1/5 deaths in female. This increased risk may be attributable to RA-specific risk factors such as hyperhomocysteinemia, disease-related dyslipidemia or vascular inflammation, or to morbidity related to medications and high levels of tumor necrosis factor-alpha (TNF-alpha). The possible roles of TNF-alpha in the development of atherosclerosis include the recruitment of inflammatory cells to the site of injury or the promotion of adverse vascular smooth muscle cell remodelling. TNF-alpha may also act as a proinflammatory factor in plaque rupture. Anticytokine therapy could prove beneficial in the treatment of patients with heart failure. While early studies supported this hypothesis, anti-TNF strategies have not demonstrated salutary benefits in large multicenter randomized and placebo-controlled clinical trials in patients with symptomatic heart failure. There is a variety of possible explanations for the failure of anti-TNF therapy: (1) TNF antagonism has untoward effects in the setting of heart failure; (2) the biological agents used in the trials were intrinsically toxic; (3) sex and race may have important implications in the outcome after anticytokine therapy; (4) the TNF-alpha protein contains a polymorphism, and, in fact, genoma plays a role in modifying the pharmacologic response to anticytokines; (5) anti-TNF-alpha approaches could have had pharmacodynamic interactions with other heart failure medications; and (6) the patients in these trials may have been inappropriately selected. These disappointing results may determine controversial attitude in the long-term treatment with anti-TNF agents in RA or Crohn's disease. The effects of TNF-alpha blockers on incident cases of congestive heart failure (CHF) in RA are controversial. The available published data suggest the following: (a) RA patients with history of CHF and a concomitant indication for the use of TNF-alpha blockers do not need a baseline cardiac evaluation to screen for heart failure; (b) patients with well-compensated mild CHF New York Heart Association (NYHA) classes I and II and a concomitant indication for the use of TNF-alpha blockers should be evaluated at baseline and then be closely monitored for any clinical signs of worsening heart failure; and (c) patients with (NYHA) class III or IV heart failure should not be treated with TNF-alpha blockers in any case.
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PMID:TNF-alpha, rheumatoid arthritis, and heart failure: a rheumatological dilemma. 1582 1

The immune system of higher vertebrates consists of two components: the innate and adaptive immunity. While the adaptive immune system relies on somatically generated and clonally selected antigen receptors, the innate immune system detects the presence of pathogens by their evolutionarily highly conserved, relatively invariant structural motifs. Interestingly, recent data suggest that activation of the innate immune system could play an important role in various diseases without the direct involvement of infectious pathogens. For example, a number of inflammatory cytokines, including TNF (tumor necrosis factor), IL (interleukin)-1beta, IL-6 and IL-8, as well as iNOS (inducible nitric oxide synthase), all components of innate immunity, are also implicated in ischemia/reperfusion injury, and in the abnormal myocardial remodeling characteristic of chronic heart failure. Understanding of the regulation and activation of the innate immune system in diseases not obviously related to an immune response to specific pathogen could provide new therapeutic targets for cardiovascular diseases. Thus, in this review, we provide a general overview of the components of innate immunity with a focus on humoral factors, their role in the response to foreign pathogens, and their potential role in the response to tissue injury (i.e., the "Expanded Self-Non-Self" and the "Danger" theories of immune activation).
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PMID:Innate immunity and the heart. 1585 84

Accumulating evidence indicates that inflammatory mediators are important in the pathogenesis of chronic heart failure (CHF), contributing to cardiac remodeling and peripheral vascular disturbances. Several studies have shown increased levels of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 in patients with CHF in both plasma and circulating leukocytes as well as in the failing myocardium itself. Importantly, this increase in inflammatory mediators does not seem to be accompanied by a corresponding increase in anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta, resulting in an inflammatory imbalance in the cytokine network. Traditional cardiovascular drugs seem to have little influence on the cytokine network in patients with CHF, and immunomodulatory therapy in addition to "optimal" cardiovascular treatment regimens has emerged as an option. Thus, several animal studies as well as some clinical pilot trials have suggested that downregulation of inflammatory cytokines may improve cardiac performance. On the other hand, preliminary results from placebo-controlled anti-TNF studies suggest no effect, or even an adverse effect of anti-TNF therapy on mortality and hospitalization. Although somewhat disappointing, these negative results do not necessarily argue against the cytokine hypothesis. These studies only underscore the difficulties and challenges in developing treatment modalities that can modulate the cytokine network in patients with CHF, resulting in anti-inflammatory and beneficial net effects. Further research in this area will have to more precisely identify the most important "actors" in the immunopathogenesis of CHF to improve the immunomodulatory treatment regimens in this disorder.
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PMID:Review of trials in chronic heart failure showing broad-spectrum anti-inflammatory approaches. 1592 60

Evidence from both experimental and clinical trials indicates that inflammatory mediators are important in the pathogenesis of chronic heart failure (HF), contributing to cardiac remodelling and peripheral vascular disturbances. Several studies have shown raised levels of inflammatory cytokines such as TNF-alpha, IL-1beta and -6 in HF patients in plasma, circulating leukocytes, atherosclerotic lesions, and in the failing myocardium itself. Importantly, this rise in inflammatory mediators does not seem to be accompanied by a corresponding increase in anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta; thus resulting in an inflammatory imbalance in the cytokine network. Traditional cardiovascular drugs have little influence on the cytokine network in HF patients. Results from randomised, placebo-controlled anti-TNF studies suggest lack of effect of such therapy. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'; these studies just underscore the challenges in understanding the complex cytokine network in order to develop effective treatment modalities in HF patients. More general immunmodulating treatments, such as pentoxyfylline, intravenous immunoglobulin, thalidomide and statins, have shown promising results in smaller studies, which need to be confirmed in larger studies with hospitalisations and death as the end points. In addition, further research in this area will have to be more precise in identifying the most important 'actors' in the immunopathogenesis of chronic HF.
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PMID:Agents targeting inflammation in heart failure. 1592 63

Human tumor necrosis factor alpha (hTNF-alpha) is one of the most important inflammatory cytokines that acts as a mediator in inflammatory and immune response and plays a key role in host defense against infection. The over expression of hTNF-alpha is associated with serious consequences, such as shock, hypotension, thrombus, septicemia and even death. It has been implicated in many autoimmune and inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, chronic heart failure and septic shock. Inhibiting the bio-activity of hTNF-alpha is one of the strategy for the treatment of these diseases. Compared with traditional recombinant protein drugs, small molecule drugs have many advantages, such as high affinity, low immunogenecity and low cost. Systematic evolution of ligands by exponential enrichment (SELEX) is a powerful method for the selection of oligonucleotides that bind with high affinity and specificity to target proteins. Such oligonucleotides are called aptamers, and are potential therapeutics for blocking the activity of pathologically relevant proteins. To obtain oligonucleotide aptamers specifically binding to TNF, a 40nt random DNA combinatorial library flanked by 31nt fixed sequences was chemically synthesized. The random library was amplified with PCR and subjected to selection by SELEX protocol against hTNFalpha. After incubation of the library with hTNFalpha, the mixture was blotted onto Immobilon-NC transfer membrane. The no-specific binding was washed away and the hTNFa binding aptamers were eluted and detached from the target protein. The eluted oligo nucleotides were amplified with PCR and served as the DNA library for the next round selection. After 12 rounds of such selection, the selected aptamers were cloned to pGEM-T vector. Positive clones were identified by restriction enzyme digestion and DNA sequencing. Oligo DNA were synthesized according to the sequence data and tested for their activities. Binding activity of the aptamers to hTNFalpha were detected by ELISA and dot blot with biotin-streptavidin-horseradish peroxidase system. Mouse L929 cells were used to test the anti-hTNFa activity of the DNA aptamers. The aptamers were incubated with hTNFalpha and added to the L929 cells. The results were read under microscope and with MTT staining. It was shown that these DNA aptamers bound to hTNFalpha with high affinity, and can inhibit the cytotoxicity of hTNFalpha on cell culture. The affinity of these aptamers are different and may related to their structure. These ssDNA aptamers are potential for the treatment and diagnosis of hTNFalpha related diseases.
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PMID:[Screening and characterization of DNA aptamers with hTNF-alpha binding and neutralizing activity]. 1597 88

The nonviral gene delivery systems are usually not very effective in transferring gene into target cells, and the intensity and duration of the gene expression is very poor. The EBNA1/oriP maintain EBNA1/oriP-based plasmids as episome, contribute to nuclear transport of the plasmid and transcriptional up-regulation of target gene. The EBNA1/oriP based plasmid enhances the transfection rate as well as magnitude and longevity of gene expression. This article reviews recent preclinical gene therapy studies with the EBV plasmid vectors conducted against various diseases. For gene therapy against malignancies, the EBNA1/ oriP based plasmid encoding the HSV1-TK suicide gene was combined with a cationic polymer to transfer into HCC cell line. The expression level of TK gene was 100- to 1000-fold higher than the conventional plasmid. The sensitivity of HCC to ganciclovir (GCV) elevated several hundred-fold. The EBNA1/oriP based plasmid equipped with tumor specific promoter, such as CEA promoter, enabled targeted killing of CEA-positive tumor cell. Transfection of EBNA1/oriP based plasmid carrying IL-12 and IL-18 gene either locally, or systemically, induced therapeufic antitumor immune responses including augmentation of the cytotoxic T lymphocyte and natural killer activities and growth retardation of tumors. For gene therapy of congenital diseases and chronic diseases, the EBNA1/oriP based plasmid encoding the adenosine deaminase gene was transfered into human hematopoietic progenitor cells. The ADA activity was elevated 1.5-to 2-fold. Intracardiomuscrlar transfer of the EBNA1/oriP based plasmid encoding the beta-AR gene may be useful for the treatment of severe heart failure. Human tumor necrosis factoralpha (hTNFalpha) is one of the most important inflammatory cytokines. It has been implicated in many autoimmune and inflammatory diseases. sTNFR can efficiently neutralize the bioactivities of hTNFalpha. In primary study we cloned the chimeric protein sTNFR II-IgG Fc and expect to use it in the gene therapy of the inflammatory disease relative to TNF. In summary, The EBNA1/oriP based plasmid shows advantage in gene therapy of cancer, congenital and inflammatory diseases. Moreover, the EBNA1/oriP element may greatly contribute to the engineering of a human artificial chromosome, the ultimate device for controllable gene therapy.
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PMID:[Progress of EBNA1/oriP-based plasmid applied in gene therapy]. 1610 85


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