Author: Joyce, David E.

Source: Current Drug Targets, Volume 8, Number 4, April 2007 , pp. 491-191(-299)

Publisher: Bentham Science Publishers

Abstract:

A comprehensive understanding of severe sepsis, enough to develop a unified approach to treatment remains the “Holy Grail” for the critical care medical community. In simple terms sepsis is a bloodstream infection with progressive severity to produce vascular inflammatory perturbations leading to vascular collapse, organ dysfunction, and death. Sepsis consumes the host blood leukocyte response, endothelial responses and related cytokine responses. A formal clinical definition of “Severe Sepsis” was developed in 1992 by the joint American College of Chest Physicians/Society of Critical Care Medicine. This definition relies on criteria of clinical signs of a systemic inflammatory response (SIRS criteria) and the presence of at least one organ failure. As a disease state, severe sepsis afflicts 750,000 patients in the U.S annually and causes 250,000 deaths. Previous anti-cytokine approaches (e.g. antibody to TNF, anti-IL-1, etc...) in clinical trials were too specific and unsuccessful in achieving meaningful severe sepsis survival. Subsequently, agents addressing the inflammation-coagulation axis have been moderately successful in providing a survival advantage for severe sepsis patients. However, practical physiologic approaches of cardiovascular volume support, intensive insulin strategies, and other intensive organ support in the critical care unit have made a difference for some severe sepsis patients. This is a battle that is far from over.

In this issue of Current Drug Targets seven reviews address various aspects of sepsis. The first five manuscripts evaluate specific drug targets in sepsis: 1.) apoptosis, 2.) endothelium, 3.) vascular permeability, 4.) cancer and sepsis and a specific target of intermediary metabolism 5.) phosphoenol pyruvate/ethyl pyruvate. Two other reviews take a more clinical approach to cover important subpopulations of sepsis, 6.) bioterrorism agents and 7.) the solid organ transplant population.

In sepsis the host innate immune response calls in monocytes whose cytokine responses direct neutrophil and other leukocyte traffic. T-cells provide secondary responses and antiviral help. The stress response including steroids can reduce T-cell number leading to a degree of immune incompetence. Wesche-Soldato et al. review the leukocyte contribution to the host immune response with emphasis on T-cell apoptosis mechanisms and new promising drug targets aimed at this leukocyte subpopulation.

Bill Aird reviews the role of the endothelium in sepsis, a complex regulatory organ essential for maintaining vascular-organ homeostasis and interfacing both coagulation and the progressive inflammation encountered in this condition. Natural anticoagulants and anti-inflammatory drug targets highlight a portion of the potential treatment targets within the endothelium.

Vascular permeability occurs early in sepsis and intravascular volume loss accounts for concerning lung acute respiratory distress and the hypotension of distributive shock. Endotoxin, Tumor necrosis factor alpha and Thrombin (FIIa) incite this early endothelial permeability. Jacobsen et al. review subcellular mechanisms and potential drug targets aimed at reducing permeability.

Cancer and sepsis is a smaller subgroup. With an aging population and evolving therapies for cancer, this population may achieve some relevance. Since some tumors express Tissue Factor, Cancer Procoagulant, and secrete other procoagulant proteins, the thrombotic tendency in sepsis may play to worse outcomes for the cancer patient. The question posed suggests that anticoagulants may be worth considering in this compromised population.

Intermediary metabolism has received more notoriety with the finding that intensive insulin therapy can improve severe sepsis survival. Mitch Fink presents Ethyl Pyruvate (EP) as promising fit. From biochemical to cellular, to metabolism considerations through the relevant animal models EP should be near human dosing. Although presented as a single drug, the manuscript provides an excellent example of the process from molecule to mammal......

Document Type: Research article

DOI: http://dx.doi.org/10.2174/138945007780362755

Publication date: 2007-04-01

More about this publication?

• Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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