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)

Natural inhibitors of coagulation, in other words, antithrombin (AT), the protein C system, and tissue factor pathway inhibitor (TFPI), play an important role in controlling the activation of coagulation during disseminated intravascular coagulation (DIC). Furthermore, they may not only influence coagulation but also attenuate inflammatory responses during sepsis. Low circulating levels of AT and protein C have been associated with poor outcome. Replacement therapy with AT, activated protein C (APC), and TFPI has been shown to attenuate thrombin generation and to reduce mortality in experimental sepsis models. Experience with AT and APC in patients is promising. Data from large phase III trials of AT and APC as treatment of patients with severe sepsis will soon be available. Recombinant TFPI is currently in phase II clinical trials for severe sepsis.
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PMID:Anticoagulant factor concentrates in disseminated intravascular coagulation: rationale for use and clinical experience. 1174 Jun 90

Multiple organ failure (MOV) still represents the leading medical and economical problem in the care of the critically ill surgical patient. Although the incidence of MOF has tended to decrease over the last several years reflecting improved surgical and supportive therapy in the ICU, prognosis still remains serious when MOF develops. MOF seems to reflect a dysregulation of host-defence systems, such as innate immune, coagulation and complement systems, which are likely to reflect a more general dysregulation of cellular and subcellular functions, such as signal transduction and stress gene expression. Besides complexity and redundancy of the mediator systems involved, their beneficial local reparative as opposed to detrimental systemic effects may have contributed to the disappointing results of anti-mediator strategies in the treatment of MOF and sepsis. Although treatment of the underlying disease remains the cornerstone of the care of the critically ill patient to prevent MOF, recent results indicating a decreased mortality in severely septic patients receiving activated protein C as a supportive treatment suggest that modulation of the mediator cascades of sepsis and MOF remains a generally promising therapeutic strategy.
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PMID:[Multiple organ failure. Mechanisms, clinical manifestations and treatment strategies]. 1176 Apr 77

The underlying principles of sepsis therapy have remained unchanged for decades. These include: prompt institution of antimicrobial agents aimed at the inciting pathogen, source control directed at removal of the infection nidus whenever possible, and support of organ dysfunction. Despite advances in antibiotics, surgical techniques and organ support technology, the morbidity and mortality from sepsis-related diseases have remained substantially unchanged (30 - 50%). Immunomodulation of the inflammatory cascade has been suggested as a crucial but inadequately addressed element in the treatment of sepsis. The list of potential therapeutic targets has been growing as more and more mediators are identified in the pathogenesis of sepsis. To date, numerous anti-inflammatory agents, found to have favourable effects in animal models of septic shock, have been tested in a number of clinical trials on thousands of patients. In this first of a three part series, we go through some of the background and current strategies in sepsis therapy. In this review, we include the two novel therapies that have shown clear survival benefit in large, randomised, placebo-controlled, multi-centre trials, low-dose steroids and recombinant activated protein C. Also included in this review are studies on antithrombin III, platelet-activating factor antagonists, complement modulators, nitric oxide synthase inhibitors and caspase inhibitors (apoptosis inhibitors).
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PMID:Experimental and emerging therapies for sepsis and septic shock. 1177 63

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

The endothelial protein C receptor (EPCR) facilitates protein C activation and plays a protective role in the response to Escherichia coli-mediated sepsis in primates. Previously, a soluble form of EPCR (sEPCR) in human plasma was characterized, and several studies indicated that generation of sEPCR is regulated by inflammatory mediators, including thrombin-mediated up-regulation of surface metalloproteolytic activity in vitro. This study addressed the question of whether plasma sEPCR levels reflect changes in thrombin generation in patients undergoing anticoagulant treatment. The sEPCR levels in patients treated with coumarin-type oral anticoagulants were significantly lower than those in healthy asymptomatic adult volunteers (105.3 +/- 70.8 ng/mL [n = 55] versus 165.8 +/- 115.8 ng/mL [n = 200]; P <.0001). A similar decline in plasma sEPCR levels was found in patients treated with unfractionated heparin. In healthy volunteers, sEPCR levels declined to about 100 ng/mL within 3 days after initiation of an 8-day period of warfarin administration and increased within 2 days after its cessation. Plasma sEPCR levels returned to pretreatment values within 1 week, and the changes in plasma sEPCR levels mirrored changes in values for international normalized ratios. A similar decline in sEPCR levels with time was observed in 7 patients beginning treatment with warfarin for a thrombotic disorder. Prothrombin fragment 1 + 2 levels also decreased in volunteers and patients given warfarin. These results show that plasma sEPCR levels decline in response to treatment with anticoagulants whose mechanism of action is known to decrease in vivo thrombin production.
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PMID:Plasma levels of endothelial protein C receptor respond to anticoagulant treatment. 1178 Dec 34

Despite the considerable advances made in understanding the pathophysiology of systemic inflammation during critical illness, clinical progress has been elusive as it remains a very deadly condition. Cortisol and thyroid hormone levels can be as predictive of outcome as the commonly used severity parameters (i.e. APACHE). Indeed, levels of endocrine humoral substances such as arachidonic acids, nitric oxide, endothelin, calcitonin precursors, leptin and adenosine correlate with the severity and outcome of critical illness. Furthermore, calcitonin precursors represent a potentially new hormokine paradigm, being transcriptionally activated in all cells in response to infection. The cytokines are immune markers that often correlate with severity and outcome, but their release is transient. In contrast, the so-called acute phase proteins, such as C-reactive protein and serum amyloid A, are highly sensitive to inflammatory activity and can be important markers of severity and outcome. Leukocyte esterase, adhesion molecules, platelet activating factor and activated protein C are additional humoral immune markers; the replacement of the latter has been shown to be a promising therapeutic option. Natriuretic peptides are neurocrine humoral markers that have important cardiovascular implications. The level of macrophage migrating inhibitory factor, released by the pituitary, is elevated in sepsis and counteracts glucocorticoid action. Cellular markers to severe stress include the enhanced expression of protective substances in the form of heat shock proteins. High mobility group-1 is a DNA-binding protein and a late mediator of the inflammatory response. Apoptotic markers such as the soluble fas ligand are also elevated in inflammation. In summary, during critical illness, the endocrine, immune and nervous systems elaborate a multitude of humoral markers, the roles of which merit further scrutiny in order to improve therapeutic outcome.
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PMID:Humoral markers of severity and prognosis of critical illness. 1180 May 23

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

Effective therapies for sepsis are being devised, after many failures. However, instead of a "one therapy for all" approach, management of sepsis will involve a menu of treatments, depending on the presence of inflammatory markers, the severity of disease, and other factors. This article looks at promising new therapies, including recombinant human activated protein C (rhAPC; drotrecogin alfa, Xigris), recently approved by the US Food and Drug Administration.
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PMID:Sepsis: menu of new approaches replaces one therapy for all. 1181 22

The incidence of sepsis and complications stemming from septicemia has remained constant in recent years despite improved levels of monitoring and care. Disseminated intravascular coagulation (DIC), a syndrome that occurs frequently in septic patients, is associated with increased mortality. Organ dysfunction is also a common sequela that is strongly correlated with DIC. Cytokines released early in the course of sepsis stimulate a procoagulant state that causes development of intravascular fibrin deposition. In a later stage of DIC, bleeding may occur in parallel because of consumption of clotting factors and inhibitors. Therapeutic strategies to attenuate or reverse these conditions have focused on multiple stages of the molecular cascade of events, including preventing cytokine induction, inhibiting coagulation processes, and promoting fibrinolysis. Recent clinical trials have supported the use of antithrombin and activated protein C supplementation in DIC associated with severe sepsis. Studies of other novel therapeutic avenues are still ongoing. Future efforts may be directed at combining 2 or more agents to achieve prompt and successful reversal of DIC.
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PMID:Pathogenesis and treatment of disseminated intravascular coagulation in the septic patient. 1181 2

Activated protein C (APC) is useful in the treatment of sepsis. Ischemia and acidosis, which often accompany sepsis, cause the release of copper from loosely bound sites. We investigated (i) whether physiological concentrations of copper inhibit APC anticoagulant activity and (ii) if any copper-induced APC inhibition is reversible by human serum albumin (HSA) or a high-affinity copper-binding analogue of the human albumin N-terminus, d-Asp-d-Ala-d-His-d-Lys (d-DAHK). APC activity after 30 min of incubation with CuCl2 (10 microM) was decreased 26% below baseline. HSA, both alone and when combined with various ratios of CuCl2, increased APC activity significantly above baseline. d-DAHK alone and 2:1 and 4:1 ratios of d-DAHK:CuCl2 also increased APC activity. APC contained 1.4 microM copper, which helps explain the increased APC activity with HSA and d-DAHK alone. These in vitro results indicate that copper inhibits APC activity and that albumin and d-DAHK reverse the copper-induced APC deactivation.
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PMID:Copper inhibits activated protein C: protective effect of human albumin and an analogue of its high-affinity copper-binding site, d-DAHK. 1182 Jul 75


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