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

Sepsis remains a major cause of death in hospitalized patients. Despite a massive research effort over the past 2 decades to identify innovative therapies for sepsis, current treatment strategies consist primarily of antiinfective agents and a variety of supportive measures. Activated protein C, an endogenous protein that inhibits thrombosis and inflammation while promoting fibrinolysis, plays an important role in the pathogenesis of sepsis. Recombinant human activated protein C, drotrecogin alfa (activated), when compared with placebo in a randomized, double-blind study of 1690 patients with severe sepsis (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS] trial), decreased the relative risk of death at 28 days by 19.4% (95% confidence interval 6.6-30.5%, p=0.005), although there was a trend for more serious bleeding (3.5% vs 2.0%, p=0.06) with its use. Drotrecogin alfa is the first antisepsis drug found to have a mortality benefit. It should be administered only to patients with severe sepsis who meet the PROWESS study inclusion criteria and should be avoided when risk factors for bleeding are present. Ongoing research will help determine the cost-effectiveness of drotrecogin alfa, as well as its role in critically ill populations not studied in the PROWESS trial.
 ...
PMID:Recombinant human activated protein C, drotrecogin alfa (activated): a novel therapy for severe sepsis. 1171 12

The role of activated protein C (APC) in coagulation, inflammation, and fibrinolysis and the pharmacology, pharmacokinetics, and trials of recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated), in sepsis are described. Protein C, a naturally occurring vitamin K-dependent serine protease in the blood, remains inactive until exposed to the thrombin-thrombomodulin complex. This change between the inactive and active forms occurs constantly in humans and serves to balance the coagulation cascade. APC functions in concert with protein S as an anticoagulant, a fibrinolytic agent, and an antiinflammatory agent. In response to serious infection, a procoagulant process is activated leading to thrombin and fibrin deposition in small vessels that results in decreased blood flow, decreased oxygen delivery, and organ failure. The body's natural defense during severe sepsis is to activate protein C through the thrombin-thrombomodulin complex in an attempt to restore the imbalance of the hemostatic systems. However, APC has a short half-life, and the pool of circulating protein C is rapidly depleted in severe sepsis. Low protein C levels have been correlated with poor outcome in patients with severe sepsis and in animal models. These observations led to a Phase III safety and efficacy trial of drotrecogin alfa (activated) that demonstrated a significant improvement in mortality compared with placebo (24.7% versus 30.8%). This 6.1% absolute difference in mortality translates to a 19.4% reduction in relative risk of death in the treated patients. The proper use of drotrecogin alfa (activated) will require careful consideration of appropriate patients to treat and further studies in patient populations that were excluded from the Phase III trial, as well as possible modification of dosing schemes on the basis of patient response.
 ...
PMID:Recombinant human activated protein C in severe sepsis. 1188 9

Protein C is a vitamin-K dependent zymogen of the anti-coagulant serine protease activated protein C (APC). In this paper, we report four lines of evidence that APC can activate protein C in pooled normal plasma, and purified protein C. First, the addition of APC to protein C-deficient plasma supplemented with protein C produces a prolongation of the clotting time of plasma that is proportional to the amount of protein C. This behavior was observed with APC from the Chromogenix APC resistance kit (Dia Pharm, Franklin, OH, USA) and from APC derived from the thrombin activation of human protein C (Enzyme Research Laboratories, South Bend, IN, USA). Secondly, using immunoblotting after gel electrophoresis, the disappearance of epitopes for monoclonal antibodies that recognize protein C but not APC indicates a time course for the activation by APC of protein C in pooled normal plasma and protein C purified from plasma. Thirdly, the same time course for the disappearance of protein C specific epitope can be followed using ELISA. Finally, protein C can be activated by APC as indicated by the increase in APC specific synthetic substrate Tryp-Arg-Arg-p nitroaniline hydrolysis. Kinetic data indicate a value of 4.7+/-0.4 mM(-1) s(-1) for the activation of protein C by APC under physiological conditions and in the presence of calcium. These observations document that APC must function not only in the inactivation of activated factors V and VIII, but also in the activation of protein C. This additional action of APC may be important to consider more broadly because of APC in the treatment of sepsis.
 ...
PMID:Proteolysis of protein C in pooled normal plasma and purified protein C by activated protein C (APC). 1189 50

Activated protein C (APC) reduced all-cause 28-day mortality by 19% in patients with severe sepsis (sepsis associated with acute organ dysfunction) in the Protein C Evaluation in Severe Sepsis (PROWESS) trial, leading to recent approval of recombinant APC for treatment of this condition in adults. This review summarizes current knowledge derived from studies of a variety of animal models in which infused human APC demonstrated beneficial activities. Based on in vivo and also in vitro data, APC manifests antithrombotic, profibrinolytic, anti-inflammatory, and antiapoptotic activities. APC is a normal circulating component of plasma, derived from the protein C zymogen, and is thus a natural endogenous protective homeostatic factor. Because of its multiple activities, APC has a potential role in the treatment of complex and challenging medical disorders, including thrombosis and stroke.
 ...
PMID:Activated protein C: potential therapy for severe sepsis, thrombosis, and stroke. 1212 82

The protein C pathway, which plays an important role in maintaining normal hemostasis and is a critical link between the inflammatory and procoagulant host responses to infection, is involved in modulating the coagulation and inflammation associated with severe sepsis. Recombinant human activated protein C (APC), or drotrecogin alfa (activated), shares the intrinsic pharmacologic activity of endogenous APC. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, drotrecogin alfa (activated) decreased absolute mortality by 6% and relative risk of mortality by 19% compared with placebo. Drotrecogin alfa (activated) is an important advancement in the treatment of adult patients with severe sepsis.
 ...
PMID:Pharmacology, clinical efficacy, and safety of drotrecogin alfa (activated). 1249 25

The key issues clinicians are facing regarding drotrecogin alfa (activated) include questions concerning the pathophysiology and appropriate patient selection for administration of this drug. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the efficacy of drotrecogin alfa (activated) was demonstrated in patients with severe sepsis. Because of this trial's strict inclusion and exclusion criteria, however, the applicability of the study criteria to different types of patients raises important issues. Coupling the data from the PROWESS trial with additional information being gained from expanding clinical experience, as well as additional studies, clinicians will be able to better understand and refine the use of activated protein C within their respective practices.
 ...
PMID:Current issues regarding the use of drotrecogin alfa (activated). 1249 27

Selecting patients for drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN) therapy outside of a clinical trial setting requires knowledge of the rationale that led the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) investigators to select the various entry criteria for the trial. Enrollment criteria for the study included a known or suspected infection, presence of at least 3 systemic inflammatory response syndrome (SIRS) criteria, and dysfunction of > or =1 organ or system. The infection criteria used in PROWESS were designed to be straightforward and were based on common clinical and radiological data. Although previous definitions of sepsis required only 2 SIRS criteria, the PROWESS trial investigators required the presence of > or =3 SIRS criteria to improve the sensitivity and specificity of these criteria for the diagnosis of sepsis. Acute organ dysfunction, the diagnostic criterion for severe sepsis, was used to define the study population because it identifies patients at significant risk of death. Characteristics of drotrecogin alfa (activated)-treated patients, including infection, modified SIRS criteria, and organ dysfunction, were similar to those of the placebo group and the general sepsis population. Proper clinical judgment and use of the these inclusion criteria as a guide will help clinicians select and treat sepsis patients with drotrecogin alfa (activated).
 ...
PMID:Selecting patients with severe sepsis for drotrecogin alfa (activated) therapy. 1252 13

Historically, clinical trials evaluating treatment of patients with severe sepsis have failed to show a reduction of mortality. However, retrospective analyses of some of these trials showed benefits in certain patient subgroups. Conversely, the recent Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, which evaluated the safety and efficacy of drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN), a recombinant form of human activated protein C, in adult patients with severe sepsis, is notable in that it is the first trial to show a reduction in 28-day all-cause mortality in the intent-to-treat population compared with the placebo group. When assessing a new intervention, patient exclusion criteria are important considerations in evaluating the evidence from a controlled clinical trial. Appropriate patient selection will be a key factor in the use of this newly approved therapeutic agent to treat severe sepsis. A review of the exclusion criteria used in the PROWESS trial should provide clinicians with a way of differentiating those patients in the critical care setting who will benefit most from treatment with drotrecogin alfa (activated) from those who should not be treated.
 ...
PMID:Identifying patients with severe sepsis who should not be treated with drotrecogin alfa (activated). 1252 14

In the United States, more than $16 billion annually is spent managing patients with severe sepsis and its sequelae. Insight into the inflammatory response, endothelial tissue, and the coagulation cascade suggest promising new treatment regimens that limit morbidity and mortality due to sepsis and multisystem organ failure. This article will discuss new information regarding the pathophysiology of the inflammatory response and sepsis. Current thoughts on clinical management and a promising new agent, Activated Protein C, will be presented.
 ...
PMID:New thoughts on sepsis: the unifier of critical care. 1254 98

The protein C anticoagulant pathway is critical for controlling microvascular thrombosis and is initiated when thrombin binds to thrombomodulin (TM) on the surface of the endothelium. Protein C activation is augmented by an endothelial cell protein C receptor (EPCR). EPCR is shed from the vasculature by inflammatory mediators and thrombin. EPCR binds to activated neutrophils in a process that involves proteinase 3 and Mac-1 and appears to inhibit leukocyte extravasation. EPCR can undergo translocation from the plasma membrane to the nucleus where it re-directs gene expression. During translocation, EPCR can carry activated protein C (APC) to the nucleus, possibly accounting for the ability of APC to modulate inflammatory mediator responses in the endothelium. TNF-alpha and other inflammatory mediators can down-regulate EPCR and TM. Inhibition of protein C pathway function increases cytokine elaboration, endothelial cell injury and leukocyte extravasation in response to endotoxin and infusion of APC reverses these processes. In vitro, APC has been reported to inhibit TNF-alpha elaboration from monocytes and to block leukocyte adhesion to selectins. Since thrombin can elicit many inflammatory responses in microvascular endothelium, loss of control of microvascular thrombin generation due to impaired protein C pathway function probably contributes to microvascular dysfunction in sepsis.
 ...
PMID:Coagulation and inflammation. 1283 62


<< Previous 1 2 3 4 5 6 7 8 9 Next >>