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)

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

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

Cachexia, usually defined as the loss of >5% of an individual's baseline bodyweight over 2-6 months, occurs with a number of diseases that includes not only AIDS and advanced cancer but also chronic heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease, Crohn disease, and renal failure. Anorexia is considered a key component of the anorexia-cachexia syndrome. Progestogens, particularly megestrol acetate, are commonly used to treat anorexia-cachexia. The mechanism of action of megestrol is believed to involve stimulation of appetite by both direct and indirect pathways and antagonism of the metabolic effects of the principal catabolic cytokines. Because the bioavailability of megestrol acetate directly affects its efficacy and safety, the formulation was refined to enhance its pharmacokinetics. Such efforts yielded megestrol acetate in a tablet form, followed by a concentrated oral suspension form, and an oral suspension form developed using nanocrystal technology. Nanocrystal technology was designed specifically to optimize drug delivery and enhance the bioavailability of drugs that have poor solubility in water. Megestrol acetate nanocrystal oral suspension is currently under review by the US FDA for the treatment of cachexia in patients with AIDS. Preclinical pharmacokinetic data suggest that the new megestrol acetate formulation has the potential to significantly shorten the time to clinical response and thus may improve outcomes in patients with anorexia-cachexia.
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PMID:The science of megestrol acetate delivery: potential to improve outcomes in cachexia. 1598 2

Infliximab (Remicade) is a chimeric monoclonal antibody against tumour necrosis factor (TNF)-alpha that has shown efficacy in Crohn's disease and rheumatoid arthritis with a disease-modifying activity and rapid onset of action. It is administered intravenously, generally in a schedule with initial infusions at 0, 2 and 6 weeks, followed by administration once every 8 weeks. Infliximab is effective in the treatment of patients with moderately to severely active Crohn's disease with an inadequate response to other treatment options or those with fistulising disease. In combination with methotrexate, infliximab reduced signs and symptoms and delayed disease progression in patients with active, methotrexate-refractory rheumatoid arthritis and in those with early disease. The drug was generally well tolerated. Recrudescence of tuberculosis infection and worsening of heart failure and demyelinating disease are among some of the concerns with anti-TNFalpha therapy, requiring cautious use of these agents in high-risk patients. Current data suggest that infliximab may be cost effective, especially when long-term clinical outcomes and burden of the diseases are taken into account. More robust, prospective pharmaco-economic studies are required to better ascertain the cost effectiveness of infliximab. Direct head-to-head comparative trials of infliximab with other biological agents are not yet available and would be helpful in determining with greater certainty the place of infliximab in the management of these diseases. Nonetheless, infliximab, like other biological agents, is a valuable treatment option in patients with moderately to severely active Crohn's disease (including fistulising disease) or rheumatoid arthritis (including early disease).
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PMID:Infliximab: a review of its use in Crohn's disease and rheumatoid arthritis. 1622 77

Infliximab (Remicade) is a chimeric monoclonal antibody against tumor necrosis factor (TNF)-alpha that has shown efficacy in Crohn disease and rheumatoid arthritis with a disease-modifying activity and rapid onset of action. It is administered intravenously, generally in a schedule with initial infusions at 0, 2, and 6 weeks, followed by administration once every 8 weeks. Infliximab is effective in the treatment of patients with moderately to severely active Crohn disease with an inadequate response to other treatment options or those with fistulizing disease. In combination with methotrexate, infliximab reduced signs and symptoms and delayed disease progression in patients with active, methotrexate-refractory rheumatoid arthritis and in those with early disease. The drug was generally well tolerated. Recrudescence of tuberculosis infection and worsening of heart failure and demyelinating disease are among some of the concerns with anti-TNFalpha therapy, requiring cautious use of these agents in high-risk patients. Current data suggest that infliximab may be cost effective, especially when long-term clinical outcomes and burden of the diseases are taken into account. More robust, prospective pharmacoeconomic studies are required to better ascertain the cost effectiveness of infliximab. Direct head-to-head comparative trials of infliximab with other biological agents are not yet available and would be helpful in determining with greater certainty the place of infliximab in the management of these diseases. Nonetheless, infliximab, like other biological agents, is a valuable treatment option in patients with moderately to severely active Crohn disease (including fistulizing disease) or rheumatoid arthritis (including early disease).
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PMID:Spotlight on infliximab in Crohn disease and rheumatoid arthritis. 1657 54

Ever since the first embryonic stem cells were isolated in the 1990s scientists and clinicians as well as the general public have followed the development of the field with great attention. As unspecialized cells capable of dividing, renewing and differentiating into specialized cells, stem cells hold great promise as a therapeutic strategy for many diseases, especially those of degenerative nature. In 2006, stem cells were actively investigated in preclinical and clinical settings to manage heart failure, amyotrophic lateral sclerosis, spinal cord injury, stroke, hematologic disorders, renal cell carcinoma, solid tumor cancer, Crohn's disease and cirrhosis, among other disorders. Likewise, biotech and pharmaceutical industry highlighted stem cells and associated products and technologies as useful tools for drug discovery that provide relevant clinical models and ensure efficacious transition of investigational compounds into preclinical testing.
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PMID:Stem cells: therapeutic present and future. 1744 Jun 35

Changing of the distant finger phalanges into the form of a drumstick or fingernails into the form of a watch-glass (hippocratic fingers--HF) presents a well-known clinical phenomenon that suggests the presence of various diseases, especially those associated with hypoxia, i.e. manifested by respiratory and/or heart failure, as well as malignant tumors and subacute infective endocarditis. At the same time, the fact that this clinical phenomenon can accompany other diseases (Crohn's disease, HIV-infection) should be taken into consideration as well. HF often appear ahead of more specific symptoms. In this connection, correct interpretation of this clinical sign, augmented with laboratory tests, allows for early and valid diagnosis.
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PMID:[Hippocratic fingers: clinical importance and differential diagnosis]. 1766 9

Tumor necrosis factor-alpha (TNFalpha) antagonists including antibodies and soluble receptors have shown remarkable efficacy in various immune-mediated inflammatory diseases (IMID). As experience with these agents has matured, there is an emerging need to integrate and critically assess the utility of these agents across disease states and clinical sub-specialties. Their remarkable efficacy in reducing chronic damage in Crohn's disease and rheumatoid arthritis has led many investigators to propose a new, 'top down' paradigm for treating patients initially with aggressive regimens to quickly control disease. Intriguingly, in diseases such as rheumatoid arthritis and asthma, anti-TNFalpha agents appear to more profoundly benefit patients with more chronic stages of disease but have a relatively weaker or little effect in early disease. While the spectrum of therapeutic efficacy of TNFalpha antagonists widens to include diseases such as recalcitrant uveitis and vasculitis, these agents have failed or even exacerbated diseases such as heart failure and multiple sclerosis. Increasing use of these agents has also led to recognition of new toxicities as well as to understanding of their excellent long-term tolerability. Disconcertingly, new cases of active tuberculosis still occur in patients treated with all TNFalpha antagonists due to lack of compliance with recommendations to prevent reactivation of latent tuberculosis infection. These safety issues as well as guidelines to prevent treatment-associated complications are reviewed in detail in this article. New data on mechanisms of action and development of newer TNFalpha antagonists are discussed in a subsequent article in the Journal. It is hoped that these two review articles will stimulate a fresh assessment of the priorities for research and clinical innovation to improve and extend therapeutic use and safety of TNFalpha antagonism.
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PMID:TNFalpha blockade in human diseases: an overview of efficacy and safety. 1791 45

Ever since the first embryonic stem cells were isolated in the 1990s scientists and clinicians as well as the general public have followed the development of the field with great attention. As unspecialized cells capable of dividing, renewing and differentiating into specialized cells, stem cells hold great promise as a therapeutic strategy for many diseases, especially those of degenerative nature. In 2006, stem cells were actively investigated in preclinical and clinical settings to manage heart failure, amyotrophic lateral sclerosis, spinal cord injury, stroke, hematologic disorders, renal cell carcinoma, solid tumor cancer, Crohn's disease and cirrhosis, among other disorders. Likewise, biotech and pharmaceutical industry highlighted stem cells and associated products and technologies as useful tools for drug discovery that provide relevant clinical models and ensure efficacious transition of investigational compounds into preclinical testing.
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PMID:Stem cells: therapeutic present and future. 1829 42


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