Current pharmaceutical design
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Over the past decade, trends in antimicrobial resistance, epidemiology, and drug development have occurred that affect both the empiric and definite selection of antimicrobials in the septic patient. The rapid spread of highly pathogenic community-associated methicillin resistant Staph aureus (MRSA) requires clinicians to consider the inclusion of empiric coverage for MRSA even in community-acquired sepsis. Moreover, vancomycin appears to be losing its effectiveness, and while a number of new agents with broad gram positive activity have been licensed, none have emerged as clearly superior. ⋯ Based on a desire to limit overall antimicrobial use, a re-evaluation of older data in both the neutropenic and non-neutropenic host has called into question the common practice of using combination therapy for some gram negative infections. An emerging consensus advocates emphasizing local unit specific antimicrobial sensitivity data in selecting empiric therapy and determining if combination therapy is required. New antifungal drugs and a better understanding of the risk factors for infection with Candida spp. has altered the approach to empiric and definitive treatment of Candida infections in the septic patient.
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Myocardial infarction necessitates new therapeutic interventions, since it still results in high morbidity and mortality worldwide. Reperfusion therapy itself results in (acceleration of) apoptosis, called myocardial ischemia/reperfusion (I/R) injury. For several decades it is known that the inflammatory response during reperfusion is the major cause of myocardial I/R injury. ⋯ Which TLRs are involved in the 'good' and which in the 'bad' effects of the inflammatory response remains to be addressed. This review will discuss both experimental and clinical research on inflammatory reactions that occur after myocardial ischemia/reperfusion (I/R). Data and conclusions concerning potential therapeutic targets in both experimental as clinical research settings will be reviewed.
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Intravascular and extravascular fibrin formation are characteristic findings in patients with sepsis, suggesting that the activation of coagulation and the inhibiton of fibrinolysis are important in the pathogenesis of sepsis. Activation of coagulation during sepsis is primarily driven by the tissue factor (TF) pathway, while inhibition of fibrinolysis is primarily due to increases in plasminogen activator inhibitor -1(PAI-1). ⋯ Recombinant human activated protein C (rhAPC) is currently the only pharmacologic therapy that has been shown to reduce mortality in adults with severe sepsis, highlighting the importance of coagulation and fibrinolysis as a therapeutic target in sepsis. This review summarizes recent basic and clinical findings with regard to the role of the coagulation cascade in sepsis and explores potential therapeutic targets in the coagulation and fibrinolytic pathways in the management of sepsis.
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The inability of present therapies to mitigate the devastating effects of sepsis and multiple organ failure in the critically ill patient indicates that more knowledge of the pathophysiology of sepsis is needed if we are to develop better, more effective interventions. This review will examine the concept that a portion of the immune and organ dysfunctions encountered in the septic rodent/ patient is a reflection of not only the types of cells stimulating/ mediating the apoptotic response, but also the varying capacity of the target cell in a given tissue/ organ to perceive these death receptor stimuli as either an apoptotic, inflammatory and/or necrotic signal. We hope the discussion of such studies provides not only new insight into the pathobiology of sepsis, but also suggests possible therapeutic targets for the management of this devastating condition.
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Non-enzymatic modification of proteins by reducing sugars, a process that is also known as Maillard reaction, leads to the formation of advanced glycation end products (AGEs) in vivo. There is a growing body of evidence that formation and accumulation of AGEs progress during normal aging, and at an extremely accelerated rate under diabetes, thus being involved in the pathogenesis of diabetic vascular complications. ⋯ Since oxidative stress generation and inflammation are closely associated with insulin resistance as well, it is conceivable that the AGEs-RAGE system could play a role in the pathogenesis of insulin resistance and subsequently the development of diabetes. In this paper, we review the role of the AGEs-RAGE system in insulin resistance, especially focusing on its effects on the insulin-signaling pathways in skeletal muscles and adipocytes.