scholarly journals Testing of anti-activated protein C antibodies in four drotrecogin alfa (activated) severe sepsis studies

Critical Care ◽  
2008 ◽  
Vol 12 (Suppl 2) ◽  
pp. P203 ◽  
Author(s):  
S Yan ◽  
J Brandt ◽  
G Vail ◽  
S Um ◽  
J Bourdage ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Drotrecogin Alfa Activated

Role of Activated Protein C in the Pathophysiology of Severe Sepsis

2003 ◽  
Vol 12 (6) ◽  
pp. 518-524 ◽  
Author(s):  
Patricia Dettenmeier ◽  
Bridget Swindell ◽  
Mary Stroud ◽  
Nancy Arkins ◽  
April Howard
Keyword(s):  
Severe Sepsis ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Therapeutic Agents ◽  
Multiple Organ ◽  
Phase 3 ◽  
The Past ◽  
Drotrecogin Alfa Activated

Sepsis is a complex syndrome that can lead to multiple organ failure and death. Severe sepsis has been associated with mortality rates ranging from 28% to 50% and is the most common cause of death in the noncardiac intensive care unit. Despite advances in both antibiotic therapy and supportive care, the mortality rate due to severe sepsis has remained fundamentally unchanged in the past several decades. With increased understanding of the pathophysiology of sepsis, particularly the intricate interplay between activation of coagulation and inflammation, novel therapeutic agents that may improve clinical outcomes are being researched and developed. The epidemiology, pathophysiology, and treatment of severe sepsis are reviewed. Also discussed are the recently published results from a multicenter, randomized, placebo-controlled phase 3 clinical trial of drotrecogin alfa (activated), a recombinant form of human activated protein C, in patients with severe sepsis. The nursing implications of this new approved therapy are discussed.

New and Emerging Therapies for Sepsis

2002 ◽  
Vol 36 (4) ◽  
pp. 648-654 ◽  
Author(s):  
Daniel P Healy
Keyword(s):  
Severe Sepsis ◽  
Inflammatory Response ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Antibody Fragment ◽  
Phase Iii ◽  
Human Form ◽  
Risk Of Death ◽  
Phase Iii Trials

OBJECTIVE: To review the recent advances related to the pathophysiology of sepsis and the rationale for recombinant human-activated protein C (drotrecogin alfa) and other antisepsis agents currently in Phase III trials. DATA SOURCES: A MEDLINE (1990–December 2001) search was performed to identify pertinent literature on the pathophysiology of sepsis and treatment strategies. The search was supplemented with AdisInsight (Adis International) using the search terms sepsis, severe sepsis, or septic shock combined with agents in Phase II or higher clinical development. Abstracts presented at infectious diseases and critical care meetings were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Clinical efficacy studies were selected for drotrecogin alfa and other Phase III investigational agents. DATA SYNTHESIS: Our current understanding of the pathophysiology of sepsis underscores the contribution of increased coagulation and diminished fibrinolytic activity working in conjunction with an excessive and dysregulated inflammatory response. The loss of homeostatic balance among these systems results in a systemic inflammatory response with generalized coagulopathy, microvascular thrombosis, and, ultimately, acute organ failure and death. As a result of these advances, several compounds are now in various phases of development. A recombinant human form of endogenous activated protein C (drotrecogin alfa) was recently approved by the Food and Drug Administration for severe sepsis in adults who have a high risk of death. It possesses anticoagulant, profibrinolytic, and antiinflammatory properties. Other compounds currently in Phase III trials include tissue-factor pathway inhibitor, tumor-necrosis factor antibody fragment, platelet-activating factor acetylhydrolase, antithrombin III, and pyridoxylated hemoglobin polyoxyethylene. CONCLUSIONS: With the recent approval of drotrecogin alfa, there is renewed optimism that we can effectively reduce sepsis-associated mortality.

Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis

2003 ◽  
Vol 90 (10) ◽  
pp. 642-653 ◽  
Author(s):  
S. Yan ◽  
Benjamin Margolis ◽  
José Lorente ◽  
James Russell ◽  
Ross Freebairn ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Statistical Methods ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Imputation Method ◽  
Double Blind Study ◽  
Strong Basis ◽  
Percent Change ◽  
Drotrecogin Alfa Activated ◽  
Anti Inflammatory

SummaryDrotrecogin alfa (activated) improved survival in patients with severe sepsis in PROWESS, a double-blind, study of 1690 adult patients randomized to drotrecogin alfa (activated) at 24 μg/kg/h (N=850) or placebo (N=840) infused for 96 hours. Pharmacodynamic effects of drotrecogin alfa (activated) were assessed with 15 prospectively defined systemic biomarkers of hemostasis, inflammation and endothelial injury. The last-observation-carried-forward (LOCF) method of imputation for missing observations was the prospectively defined statistical method. The results were also analyzed with only the observed values without imputation for missing data (repeated measures analysis). With both statistical methods, drotrecogin alfa (activated)-treated patients demonstrated antithrombotic (reduced markers of thrombin generation and accelerated normalization of anticoagulant factor, protein C and fibrinolytic factors) and anticoagulant (prolonged PT and APTT) effects compared with placebo. A profibrinolytic (reduction in plasminogen activator inhibitor-1) effect was significant only with the LOCF imputation method in observed case and percent change from baseline analyses. An anti-inflammatory (reduction in interleukin-6) effect was significant only with the LOCF imputation method in change from baseline and percent change from baseline analyses. Drotrecogin alfa (activated) is a new and promising agent for treatment of patients with severe sepsis. The extensive analysis of systemic biomarkers confirms the previously published antithrombotic effects. However, the present results using different statistical methods do not provide a strong basis for systemic anti-inflammatory or pro-fibrinolytic effects. These latter two effects may occur at the local or cellular level. The systemic biomarkers reported here might not be the most appropriate approach to demonstrate these potential effects of drotrecogin alfa (activated).

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