Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue factor (TF) plays a crucial role in the pathogenesis of thrombotic, vascular and inflammatory disorders. Thus, the inhibition of this membrane protein provides a unique therapeutic approach for prophylaxis and/or treatment of various diseases. Tissue factor pathway inhibitor (TFPI), the only endogenous inhibitor of the TF/Factor VIIa (FVIIa) complex, has recently been characterised biochemically and pharmacologically. Studies in patients demonstrated that both TF and TFPI may be indicators for the course and the outcome of cardiovascular and other diseases. Based on experimental and clinical data, TFPI might become an important drug for several clinical indications. TFPI is expected to inhibit the development of post-injury intimal hyperplasia and thrombotic occlusion in atherosclerotic vessels as well as to be effective in acute coronary syndromes, such as unstable angina and myocardial infarction. Of special interest is the inhibition of TF-mediated processes in sepsis and disseminated intravascular coagulation (DIC), which are associated with the activation of various inflammatory pathways as well as of the coagulation system. A Phase II trial of the efficacy of TFPI in patients with severe sepsis showed a mortality reduction in TFPI- compared to placebo-treated patients and an improvement of organ dysfunctions. TFPI can be administered exogenously in high doses to suppress TF-mediated effects, alternatively high amounts of TFPI can be released from intravascular stores by other drugs, such as heparin and low molecular weight heparins (LMWH). Using this method high concentrations of the inhibitor are provided at sites of tissue damage and ongoing thrombosis. At present, clinical studies with TFPI are rather limited so that the clinical potential of the drug cannot be assessed properly. However, TFPI and its variants are expected to undergo further development and to find indications in various clinical states.
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PMID:Tissue factor pathway inhibitor: an update of potential implications in the treatment of cardiovascular disorders. 1177 96

Despite advances in supportive care, sepsis and septic shock continue to be major causes of morbidity and mortality in critically ill patients. The lack of efficacy of anti-inflammatory drugs in patients with sepsis has shifted interest toward developing alternative treatments. The observation that clotting system activation may in part underlie the physiological derangements of sepsis has resulted in efforts to target the clotting cascade as a therapeutic strategy. Anticoagulants have been shown to ameliorate physiological derangements and improve survival in animal sepsis models. Three agents have undergone extensive study in humans: recombinant human activated protein C (rhAPC, drotrecogin-alpha), antithrombin III (ATIII) and tissue factor pathway inhibitor (TFPI). While a recent Phase III study of rhAPC suggests a survival benefit in patients with sepsis, major concerns about this trial include the manner in which the study was conducted, the potential toxicity of rhAPC and the questionable efficacy of this agent in patients with low mortality risk. Further clinical testing of rhAPC appears to be necessary to better define the target population most appropriate for its use. In contrast, a large Phase III study of high dose ATIII in patients with sepsis failed to show a treatment benefit with this agent. Finally, while TFPI has undergone extensive preclinical and Phase II testing, the results of Phase III studies have not been published. In summary, while coagulation inhibitors may ultimately have a therapeutic role in selected subgroups of patients with sepsis, the efficacy and safety of this class of agents remain to be proven.
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PMID:Coagulation inhibitors in the treatment of sepsis. 1177 22

Derangements in coagulation and fibrinolysis are frequent complications of systemic infection, and septic shock is the most common recognized cause of disseminated intravascular coagulation. Anticoagulant therapy has been used as a treatment strategy for severe sepsis for several decades without compelling evidence of efficacy until the 2001 publication of the phase III trial with recombinant human activated protein C. Major phase III international trials with antithrombin and tissue factor pathway inhibitor also have been completed recently. The molecular mechanisms by which the clotting system interacts with the innate immune response have greatly facilitated the understanding of coagulation and the pathophysiology of septic shock. Anticoagulants such as recombinant human activated protein C and related agents may become the mainstay of adjuvant therapies for severe sepsis in the near future.
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PMID:Clinical impact of novel anticoagulation strategies in sepsis. 1180 32

Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) are critically involved in activation of the coagulation system in sepsis, leading to disseminated intravascular coagulation (DIC). Natural anticoagulants such as antithrombin (AT) and activated protein C (APC) regulate the coagulation system by inhibiting thrombin generation. In addition to these anticoagulant effects, both AT and APC have been shown to attenuate inflammatory responses induced by various noxious stimuli in rats such as lipopolysaccharide (LPS) challenge. AT promotes the endothelial release of prostacyclin, a potent anti-inflammatory prostaglandin that inhibits the monocytic production of TNF-alpha, by interacting with cell-surface heparin-like substances. APC directly inhibits the production of TNF-alpha by inhibiting the activation of both nudear factor kappaB (NFkappaB) and activator protein-1 in monocytes stimulated with LPS. Thrombomodulin, an endothelial membranous integral protein that binds thrombin, exerts anti-inflammatory effects by generating APC. Furthermore, tissue factor pathway inhibitor, a natural anticoagulant for the extrinsic pathway of the coagulation system, also attenuates LPS-induced inflammatory responses in rats by inhibiting TNF-alpha production by monocytes. These findings strongly suggest that natural anticoagulants could regulate inflammatory responses as well as the coagulation system in rats by inhibiting the monocytic production of TNF-alpha. Such anti-inflammatory properties of natural anticoagulants are potentially important for their replacement in patients with sepsis who frequently develop DIC and organ failure as inflammatory responses.
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PMID:Regulation of inflammatory responses by natural anticoagulants. 1191 84

Sepsis can be defined as a phenomenon related to the host's response to infection. Sepsis is considered an uncontrolled, unregulated, and self-sustaining intravascular inflammation, resulting from an imbalance between systemic proinflammatory reaction and excessive anti-inflammatory response. Microcirculatory dysfunction lies at the center of sepsis pathogenesis and involves all three elements of the microcirculation: arterioles, capillaries, and venules. Endothelium plays a pivotal role in the pathogenesis of sepsis, not only because it modulates the inflammatory response but also because endothelial cells activated with excessive amounts of inflammatory mediators become dysfunctional. In response to various stimuli, the endothelium exhibits a wide range of responses that may lead to local as well as systemic changes, giving rise to the phenotypic heterogeneity seen in sepsis. Therapeutic approaches, such as targeting the coagulation system, nitric oxide synthesis or intracellular signal transduction, have been considered. The administration of activated protein C has been associated with a dramatic reduction in mortality and ongoing studies with tissue factor pathway inhibitor seem promising. Glucocorticoids also seem promising for use in sepsis as a result of their anti-inflammatory effects.
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PMID:Microvascular responses to sepsis: clinical significance. 1203 45

Following on the heels of multiple failed clinical trials of adjunctive therapeutic agents in sepsis, the positive outcome of a recent phase III study using activated protein C (APC) has led to a renewed optimism in targeted biotherapies for this syndrome. A growing body of data (both preclinical and clinical) suggests that the protection against death afforded by APC cannot be solely explained by its antithrombotic activity but rather is likely explained by its associated anti-inflammatory and profibrinolytic effects. Although a recent phase III study failed to demonstrate any protective effect of another important antithrombotic molecule, antithrombin, it is premature to conclude that the benefit observed with APC is unique among inhibitors of the coagulation system. The result of a third phase III study examining the effect of tissue factor pathway inhibitor (TFPI) in sepsis is currently awaited, and the possibility that other antithrombotic agents--and combinations thereof--have a place in the therapeutic armamentarium will undoubtedly be the topic of future studies.
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PMID:Coagulation inhibition for sepsis. 1217 60

Sepsis is associated with the activation of several inflammatory cascades, including the cytokine network and the coagulation system, but it can also be associated with an immunodepressed state. This can lead to a situation in which the septic patient becomes more susceptible to secondary infections. In animal experiments, inhibition of the cytokine cascade by administration of tumour necrosis factor alpha (TNF alpha)-receptors or anti-TNF alpha antibodies has led to reduced mortality, but this has not been confirmed in clinical trials. After the data were pooled, there was a statistically significant decrease in mortality of 3-5%. Treatment with endotoxin antibodies, corticosteroids in high doses, other anti-inflammatory agents and agents designed to eliminate immunodepression generally also did not produce a convincing decrease in mortality. Research on antithrombotic agents has yielded, along with disappointing results with antithrombin III and 'tissue factor pathway inhibitor', one study with a positive result. In septic patients with organ failure who were treated with activated protein C, a coagulation inhibitor, the mortality decreased from 30.8 to 24.7%.
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PMID:[Immunomodulating strategies in the treatment of sepsis]. 1253 64

Although coagulation abnormalities may partly underlie the physiologic derangements of the sepsis syndrome, anticoagulant therapies have produced mixed results on survival in clinical studies. We hypothesized that a meta-analysis of clinical trials of anticoagulants in sepsis may provide insight as to the therapeutic utility of targeting the clotting cascade in this syndrome. We searched electronic databases and reviewed bibliographies of pertinent articles to identify controlled clinical studies in which anticoagulants had been administered as adjunctive therapy to patients with sepsis. After establishing statistical homogeneity, odds ratios (OR; with 95% confidence intervals [CI]) for effect of these agents on mortality and bleeding complications were determined using Mantel-Haenszel methodology. Potential for publication bias was assessed by the use of a statistical test of funnel plot asymmetry. Weighted linear regression was performed to examine the effect of control group mortality rate on treatment efficacy. We identified 11 studies that satisfied our inclusion criteria. Collectively, these studies enrolled 4690 patients (range of 29-2314) and examined three agents: antithrombin III (2659 patients), tissue factor pathway inhibitor (210 patients), and activated protein C (1821 patients). After establishing statistical homogeneity (P > 0.10, chi-square), we found that the OR (with 95% CI) for effect on mortality for these agents, relative to control treatment, was 0.8692 (0.7519-1.006). Weighted linear regression analysis was consistent with a control group mortality dependent effect for these agents (P = 0.02). Only five of the studies reported bleeding complications. Pooling the results of these five studies (4376 patients) resulted in an OR (with 95% CI) of 1.70 (1.40-2.07) relative to control treatment for bleeding risk. Anticoagulants as adjuvant therapy do not appear to improve outcome in sepsis and are associated with a significant risk of bleeding complications. To the extent that their treatment effect is dependent upon disease severity, the safety and efficacy of these agents may be enhanced by refinement in techniques of clinical stratification.
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PMID:A meta-analysis of controlled trials of anticoagulant therapies in patients with sepsis. 1462 85

Tifacogin is a recombinant tissue factor pathway inhibitor (rTFPI) under development by Pharmacia Corp (formerly GD Searle) and Chiron as a potential treatment for sepsis. The product is in phase III trials [406208]. In July 2000, Pharmacia anticipated regulatory filings in 2002 [374505]. Chiron and Searle conducted research on TFPI independently in the early 1990s and entered an agreement to collaborate on the development, manufacturing and marketing of the compound in 1994, granting each other licenses on the patents concerned with TFPI [224098]. Searle (Monsanto Co) first disclosed recombinant TFPI in the associated patent, US-05212091. Unlike natural TFPI, however, it possessed an N-terminal alanine and the expression method using E coli did not always yield entirely homologous protein. A method for expressing genuine TFPI in yeast is disclosed in Chiron's patent WO-09604377. Patents for methods of treating sepsis with TFPI were claimed independently in two patents from Cetus Oncology (Chiron; WO-09324143) and Searle (WO-09325230). The discovery research of TFPI was conducted by Searle in collaboration with Washington University [224098]. Washington University holds two patents, EP-00563023 and WO-09604378, which claim the use of TFPI for the inhibition of microvascular thrombosis and reperfusion injury, respectively. Analysts at Lehman Brothers predicted in December 2001, that there was a 50% probability of the drug making it to market, with peak sales potential of 500 million US dollars in 2003 [434768].
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PMID:Tifacogin (Chiron Corp/Pharmacia Corp). 1286 83

This review describes disseminated intravascular coagulation (DIC) as a syndrome in which hemostatic factors are activated. The syndrome ranges in severity from a decompensated coagulopathy (overt-DIC) to the subclinical compensated activation of hemostatic factors (nonovert DIC). The first part of this review emphasizes two points. First, activation of the hemostatic system is controlled by a vast network of capillaries and venules through anticoagulant and anti-inflammatory regulatory factors that operate from the endothelium (e.g., protein C and thrombomodulin, tissue factor pathway inhibitor). These hemostatic regulators can be overridden by procoagulant disorders such as amniotic fluid embolism or degraded by proinflammatory disorders such as sepsis. Second, because this link between the microvascular endothelium and circulating hemostatic factors is so close, even a relatively mild disturbance of the microvasculature targeted by the inflammatory process may be reflected systemically by changes in molecular biomarkers of hemostatic activity. Therefore, application of criteria for the diagnosis of nonovert DIC should be of value in detecting a compensated response to inflammatory stress of the microvasculature in patients who are at risk before they develop an uncompensated over DIC response and organ failure. The second part of this review covers the recent experience investigators have had in diagnosing and following the response of patients to treatment with biomarkers.
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PMID:The diagnosis and management of disseminated intravascular coagulation. 1290 Nov 23


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