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)

Drotrecogin alfa (activated) or recombinant human activated protein C (rhAPC) has been registered for use as adjuvant treatment in severe sepsis since 2001 under the trade name Xigris essentially based on the results from one large clinical trial (the PROWESS trial). In a recently published second randomized clinical trial (the ADDRESS trial), enrolling patients with severe sepsis but with less risk of death, no effect of the treatment was shown, not even a trend to a positive effect in the subgroup of patients with a high risk of death that would match the present prescription label for Xigris. In addition, a large randomized, placebo-controlled trial with rhAPC in paediatric sepsis has recently been terminated prematurely because of lack of efficacy. Altogether, the robustness of the data supporting the use of rhAPC in treating patients with severe sepsis may indeed be questioned. A confirmatory clinical trial is required before rhAPC can be used with confidence. The side-effects and the cost of rhAPC are well documented but its efficacy is not.
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PMID:Activated protein C (Xigris) treatment in sepsis: a drug in trouble. 1726 Nov 52

The incidence of sepsis is expected to increase at a rate of 1.5% per year. Advances in our understanding of the sepsis syndrome have enabled researchers to identify new therapeutic targets and design therapies for existing mediators of sepsis. Drotrecogin alfa (activated) was the first biological treatment for serious sepsis approved by the Food and Drug Administration in 2001. There have also been promising research results involving ethyl pyruvate, glycogen synthase kinase-3 inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Here, we review these four compounds and compound classes as examples of emerging pharmacological treatments of severe sepsis and describe the current status of sepsis research.
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PMID:Promising therapeutic agents for sepsis. 1711 61

Drotrecogin alfa has been shown to reduce mortality in severe sepsis. However, it remains unlicensed for use in patients with previous liver transplantation. We report its use in such a case. Prior to administration a risk benefit analysis was performed in line with General Medical Council recommendations. This included being satisfied that no appropriately licensed alternative would better serve the patient's needs and that sufficient evidence existed to demonstrate the safety and efficacy of the drug. Responsibility was taken for prescription, monitoring and follow up. The process was carefully documented and the patient recovered fully with no adverse effects. To date the only published data on the use of drotrecogin alpha in transplant recipients is a case series of three patients. Further published data may encourage review of the licence.
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PMID:The use of drotrecogin alfa (activated) in a patient with recent orthotopic liver transplant. 1730 Mar 7

(1) The initial evaluation of drotrecogin alfa in the treatment of severe sepsis did not convincingly demonstrate the therapeutic potential of this recombinant form of activated protein C. It mainly included one study (PROWESS), a double-blind placebo-controlled trial, involving 1690 patients with sepsis of varying severities. In this trial, drotrecogin alfa seemed to reduce the overall mortality rate at 28 days from 31% to 25%. However, these results were undermined by methodological flaws, and retrospective subgroup analyses suggested that only the most seriously ill patients were likely to benefit from treatment with drotrecogin alfa. (2) The one-year results of the PROWESS trial showed a difference in the mortality rate in the subpopulation of patients with an APACHE II (Acute Physiology and Chronic Health Evaluation) score of at least 25 (48% versus 59%), but these results were undermined by the same methodological flaws. A more detailed retrospective subgroup analysis again suggested that patients with multiple organ failure would benefit from treatment with drotrecogin alfa. (3) Another retrospective subgroup analysis of the PROWESS trial suggests that adding drotrecogin alfa does not increase the efficacy of a heparin-containing regimen. There are no comparable data on the addition of drotrecogin alfa to steroid therapy. (4) Another placebo-controlled trial (the ADDRESS study) only included less severely ill patients; all 2640 participants had an APACHE II score of less than 25, or only one organ failure. There was no evidence of a reduction in mortality with drotrecogin alfa (overall mortality rate 18%). (5) A paediatric placebo-controlled trial was interrupted after 477 children had been enrolled, because drotrecogin alfa was ineffective and caused severe bleeding. (6) Data from ongoing comparative and non comparative studies confirm the increased risk of severe bleeding during drotrecogin alfa therapy, affecting about 7% of patients. (7) In practice, despite trials involving thousands of patients, there are still no firmly identified patient subgroups in which drotrecogin alfa is clearly beneficial. In contrast, the increased bleeding risk is well documented. Drotrecogin alfa should not be routinely used in the management of patients with severe sepsis.
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PMID:Drotrecogin alfa: a second look. More clinical trials in severe sepsis: mostly negative results. 1732 14

Thrombocytopenia is a common problem in critically ill patients, which is associated with increased mortality. Recently, Drotrecogin alfa (activated) (recombinant human activated protein C (APC)) was shown to reduce mortality in patients with severe sepsis. Only minimal effect of APC on coagulation markers was demonstrated. Nevertheless, low platelet count was identified as a risk factor for bleeding with use of this drug. We conducted this study to evaluate possible influence of APC on in vitro expression of platelet receptors at therapeutic and supra-therapeutic concentrations. Blood samples of volunteers and patients with severe sepsis were adjusted with APC to final concentrations of 0.045 microg mL(-1) APC (APC-45, therapeutic dose) and 0.225 microg mL(-1) APC (APC-225, five-fold therapeutic dose), respectively. The activation of platelets was mediated by two different agonists. APC had no significant influence on platelet activation, with or without stimulation at both concentrations. In group APC-225, CD62P showed a non-significant decrease. This in vitro study demonstrates that therapeutic plasma concentrations of Drotrecogin alfa (activated) have neither influence on expression of platelet activation markers nor on platelet-granulocyte complexes in blood of volunteers and patients with severe sepsis. Thus, a direct drug-platelet interaction seems unlikely.
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PMID:Effect of Drotrecogin alfa (activated) on platelet receptor expression in vitro. 1765 7

Severe sepsis is a common cause of death in critically ill patients. Several mechanisms have been implicated in the development of organ dysfunction in patients with severe sepsis. Among these, activation of inflammation and coagulation, together with endothelial dysfunction, seem to be major contributors. Several anti-inflammatory agents have been tried for the treatment of sepsis, with limited success. Anticoagulant drugs have been shown to be of potential interest for the therapy of severe sepsis. Among these agents, a natural anticoagulant named activated protein C, which is manufactured as a recombinant human protein under the name of drotrecogin alfa (activated), has been a topic of intense interest. Drotrecogin alfa (activated) is an antithrombotic and profibinolytic agent that also possesses anti-inflammatory and antiapoptotic properties. Small trials have shown that drotrecogin alfa (activated) reduces the sepsis-induced alterations in endothelial and microcirculatory function. In this review, the benefit-risk balance of drotrecogin alfa (activated) is assessed. The results of one phase II trial, two phase III trials (one including patients with high and low risk of death, the other restricted to patients with low risk of death) and several cohort studies have been published. The PROWESS (Recombinant human protein C Worldwide Evaluation in Severe Sepsis; phase III) trial showed that drotrecogin alfa (activated) is associated with a reduction in the risk of death in patients with severe sepsis, but this benefit seems to be greater in patients at high risk of death. Acute Physiology and Chronic Health Evaluation (APACHE) II scores and the number of failing organs have been proposed as means to identify patients with sepsis who are at a high risk of death, but these criteria may sometimes not make good indicators, especially as the APACHE II score has not been validated for this purpose. Bleeding is more common in drotrecogin alfa (activated)-treated patients than in placebo recipients; however, many of the additional episodes of bleeding in drotrecogin alfa (activated) recipients are procedure related. Importantly, bleeding did not outweigh the benefits of drotrecogin alfa (activated), as there was an overall survival benefit, provided only patients at high risk of death from sepsis were treated with drotrecogin alfa (activated). The bleeding rate associated with drotrecogin alfa (activated) was slightly higher in cohort studies than in clinical trials, but this may be related to the higher severity of illness in these patients. Thus, in clinical practice, great caution should be taken in the selection of patients to be treated, and unnecessary invasive procedures should be avoided in order to preserve the survival benefit conferred by drotrecogin alfa (activated).
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PMID:Benefit-risk assessment of drotrecogin alfa (activated) in the treatment of sepsis. 1797 39

The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome. Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial indicate that administration of drotrecogin alfa (activated; DrotAA) leads to an increase in endogenous protein C levels in severe sepsis patients. In a group as heterogeneous as sepsis patients, the currently approved dose and duration of administration (24 mug/kg per hour for 96 hours) might not be optimal in some individuals. The RESPOND (Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]) trial is a phase II study being conducted to explore the use of endogenous protein C level as both a biomarker and a steering parameter for administration of DrotAA. Eligible patients will receive DrotAA either at the normal, currently approved dose and duration of administration ('standard therapy') or at a higher dose with variable infusion duration or variable infusion duration only ('alternative therapy'). The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C. The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.
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PMID:The protein C pathway: implications for the design of the RESPOND study. 1826 91

Continued safety assessment is essential for any newly approved therapy. Drotrecogin alfa (activated; DrotAA), which is approved for use in severe sepsis, has undergone clinical trials with corresponding safety analyses since 1995. However, the only comprehensive review of all trials is that reported in 2003 by Bernard and coworkers. This is an important review that focuses on the safety profile of DrotAA in all published studies (six randomized clinical trials and five national registry studies) and in previously unpublished data. DrotAA treatment is associated with an increased risk for bleeding (which in general is manageable). Nevertheless, the available evidence shows that any adverse effects of DrotAA are outweighed by its benefits in patients with severe sepsis who are at high risk for death. So far, more than 9,000 patients have been enrolled in clinical trials involving DrotAA, providing a valuable safety database. It is of note that although DrotAA does increase the risk of bleeding, this has not been associated with an overall increase in the rate of all severe adverse events.
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PMID:The safety profile of drotrecogin alfa (activated). 1826 93

Severe infectious diseases after liver transplant are associated with high risk of multiorgan failure and mortality. Septic shock is difficult to manage in this setting since it is often unresponsive to conventional aggressive therapy. Adjuvant therapies have been proposed in association with full combination treatment to sustain the failing organs and improve outcomes in severe sepsis. Recombinant human activated protein C drotrecogin alfa, Xigris) has been occasionally administered to treat posttransplant sepsis to modulate and downregulate the complex network of inflammatory and coagulopathic processes. Herein we have reported on a patient who was given drotrecogin alfa 15 days following liver transplant for acute septic shock originating from a nosocomially acquired pneumonia. Recombinant activated drotrecogin alfa, associated with conventional aggressive treatment, was efficacious to revert the life-threatening "slippery slope" of vasoplegia and uncontrolled diffuse inflammation.
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PMID:Activated recombinant protein C in septic shock early after liver transplantation: a case report. 1867 33

Drotrecogin alfa (activated) (DrotAA) has been approved for therapy of severe sepsis and septic shock for 7 years, but controversy persists regarding efficacy and safety. Only a single randomized, controlled trial (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; PROWESS) has shown evidence of efficacy, and the risk of complications (especially hemorrhage) is recognized. Moreover, subsequent prospective studies (albeit in children and lower-risk adult patient populations) have been nonconfirmatory. Opinion is polarized whether DrotAA is effective and should be used. Safety data are not in dispute (DrotAA therapy increases risk of bleeding complications), but controversy exists regarding efficacy, the ethics of marketing the drug, and the design and conduct of current and future trials designed to resolve efficacy questions. DrotAA is approved therapy in the United States, the European Union, and many other countries, and clinicians should keep the drug in their armamentarium, balancing risk and benefit, for therapy of patients with severe sepsis or septic shock who are at high risk of death until the controversy is resolved by randomized, prospective trials now in progress.
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PMID:Current role of activated protein C therapy for severe sepsis and septic shock. 1868


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