Daniel P Healy1. 1. College of Pharmacy, University of Cincinnati, and Shriners Hospitals for Children, PO Box 670004, Cincinnati, OH 45267-0004, USA. daniel.healy@uc.edu
Abstract
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.
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.