Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the past 15 years, several anti-inflammatory treatments have failed to reduce mortality in patients with severe sepsis. However, recent evidence indicates that coagulation abnormalities in sepsis may play a major role in the pathogenesis of multiple organ failure and the high mortality rate in patients with severe sepsis. Interestingly, blockade of the coagulant pathway can inhibit both procoagulant and proinflammatory pathways in sepsis. Protein C, a natural anticoagulant, interrupts several of the pathophysiologic pathways in sepsis. Acquired protein C deficiency is present in the majority of septic patients and is associated with unfavorable outcomes. Protein C replacement therapy was effective in preclinical animal models of sepsis in reducing end-organ damage and mortality. Recent clinical trials of protein C replacement in human meningococcemia resulted in a markedly decreased morbidity and mortality. And, most importantly, in a recently completed large, randomized trial of activated protein C treatment in severe sepsis, mortality was reduced from 30.8% in the placebo group to 24.7% in the treatment group at 28 days. Thus, there is new evidence that mortality can be reduced among patients with severe sepsis through the use of a new therapy that inhibits the procoagulant and the inflammatory cascades.
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PMID:The Role of Protein C in Sepsis. 1155 61

Adjuvant therapy for severe sepsis and shock can be divided into 4 groups. The first group comprises those compounds with proven efficacy in human studies (activated protein C and recombinant bacterial permeability-increasing protein). The second group includes compounds with potential efficacy (heparin), while the third group represents those with no demonstrated efficacy in randomised clinical trials (tumour necrosis factor and interleukin-1 antibodies and receptor antagonists). The fourth group includes those drugs which have been found to be potentially effective in animal studies, but which have not yet been evaluated in humans (i.e., tyrosine kinase inhibitors, selective inducible nitric oxide synthase inhibitors, polyadenosine-diphosphate-ribose-polymerase and caspase III (apoptosis) inhibitors). Formal clinical comparisons between the various treatment options are necessary to assist the clinician in selecting the appropriate form of therapy.
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PMID:[Adjuvant therapies for sepsis and shock: which are more effective?]. 1157 77

Idiopathic purpura fulminans produces rapidly progressive hemorrhagic necrosis of the skin with disseminated intravascular coagulation in individuals without known abnormalities of the protein C pathway or acute infections. The disease mainly affects children and in 90 % of cases is preceded by a benign infection. Its pathogenesis involves a temporary autoimmune protein S deficiency that provokes a state of hypercoagulability. We present the case of a previously healthy 2-year-old boy with hemorrhagic skin lesions characteristic of purpura fulminans and disseminated intravascular coagulation without sepsis. Severe, temporary protein S deficiency was confirmed. The patient received daily replacement therapy with fresh frozen plasma for 12 days and anticoagulation with heparin for 3 months. Evolution was favorable. Although the other parameters returned to normal, protein S remained low for 50 days despite treatment. The patient has made a complete recovery.
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PMID:[Idiopathic purpura fulminans with transient protein S deficiency]. 1157 47

Many sequelae associated with endotoxaemic-induced shock result from excessive production of the cytokine mediators, tumour necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1) and IL-6 from lipopolysaccharide (LPS)-activated monocytes. Protein C (PC)/activated protein C (APC) has potent cytokine-modifying properties and is protective in animal models and human clinical trials of sepsis. The precise mechanism by which this anti-inflammatory response is achieved remains unknown; however, the recently described endothelial protein C receptor (EPCR) appears to be essential for this function. The pivotal role that monocytes play in the pathophysiology of septic shock led us to investigate the possible expression of a protein C receptor on the monocyte membrane. We used similarity algorithms to screen human sequence databases for paralogues of the EPCR but found none. However, using reverse transcription-polymerase chain reaction (RT-PCR), we detected an mRNA transcribed in primary human monocytes and THP1 cells that was identical to human EPCR mRNA. We also used immunocytochemical analysis to demonstrate the expression of a protein C receptor on the surface of monocytes encoded by the same gene as EPCR. These results confirm a new member of the protein C pathway involving primary monocytes. Further characterization will be necessary to compare and contrast its biological properties with those of EPCR.
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PMID:Characterization of protein C receptor expression in monocytes. 1170 43

Sepsis remains a major cause of death in hospitalized patients. Despite a massive research effort over the past 2 decades to identify innovative therapies for sepsis, current treatment strategies consist primarily of antiinfective agents and a variety of supportive measures. Activated protein C, an endogenous protein that inhibits thrombosis and inflammation while promoting fibrinolysis, plays an important role in the pathogenesis of sepsis. Recombinant human activated protein C, drotrecogin alfa (activated), when compared with placebo in a randomized, double-blind study of 1690 patients with severe sepsis (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS] trial), decreased the relative risk of death at 28 days by 19.4% (95% confidence interval 6.6-30.5%, p=0.005), although there was a trend for more serious bleeding (3.5% vs 2.0%, p=0.06) with its use. Drotrecogin alfa is the first antisepsis drug found to have a mortality benefit. It should be administered only to patients with severe sepsis who meet the PROWESS study inclusion criteria and should be avoided when risk factors for bleeding are present. Ongoing research will help determine the cost-effectiveness of drotrecogin alfa, as well as its role in critically ill populations not studied in the PROWESS trial.
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PMID:Recombinant human activated protein C, drotrecogin alfa (activated): a novel therapy for severe sepsis. 1171 12

At the 2001 Toronto Critical Care Medicine Symposium, exciting new research results were presented, including a randomized trial of peri-operative pulmonary-artery catheter use and evidence-based guidelines for the prevention of ventilator-acquired pneumonia. Presenters reviewed other important recent critical care developments such as (1) activated protein C and low-dose steroids in sepsis, (2) prone positioning and long-term outcomes in patients with adult respiratory distress syndrome, and (3) medical errors in the critical care unit. Along with these new findings, another theme emerged during the symposium. This theme emphasized that research breakthroughs are not sufficient in themselves: outcome studies are needed to learn how new research is applied on a large-scale basis within actual clinical practice. Furthermore, additional study is needed for an understanding of how physicians implement new research findings. Successful methods of enhancing the widespread adoption of new research require further study.
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PMID:Toronto Critical Care Medicine Symposium, 18-20 October 2001, Canada: research breakthroughs are not enough. 1173 21

Natural inhibitors of coagulation, in other words, antithrombin (AT), the protein C system, and tissue factor pathway inhibitor (TFPI), play an important role in controlling the activation of coagulation during disseminated intravascular coagulation (DIC). Furthermore, they may not only influence coagulation but also attenuate inflammatory responses during sepsis. Low circulating levels of AT and protein C have been associated with poor outcome. Replacement therapy with AT, activated protein C (APC), and TFPI has been shown to attenuate thrombin generation and to reduce mortality in experimental sepsis models. Experience with AT and APC in patients is promising. Data from large phase III trials of AT and APC as treatment of patients with severe sepsis will soon be available. Recombinant TFPI is currently in phase II clinical trials for severe sepsis.
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PMID:Anticoagulant factor concentrates in disseminated intravascular coagulation: rationale for use and clinical experience. 1174 Jun 90

Multiple organ failure (MOV) still represents the leading medical and economical problem in the care of the critically ill surgical patient. Although the incidence of MOF has tended to decrease over the last several years reflecting improved surgical and supportive therapy in the ICU, prognosis still remains serious when MOF develops. MOF seems to reflect a dysregulation of host-defence systems, such as innate immune, coagulation and complement systems, which are likely to reflect a more general dysregulation of cellular and subcellular functions, such as signal transduction and stress gene expression. Besides complexity and redundancy of the mediator systems involved, their beneficial local reparative as opposed to detrimental systemic effects may have contributed to the disappointing results of anti-mediator strategies in the treatment of MOF and sepsis. Although treatment of the underlying disease remains the cornerstone of the care of the critically ill patient to prevent MOF, recent results indicating a decreased mortality in severely septic patients receiving activated protein C as a supportive treatment suggest that modulation of the mediator cascades of sepsis and MOF remains a generally promising therapeutic strategy.
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PMID:[Multiple organ failure. Mechanisms, clinical manifestations and treatment strategies]. 1176 Apr 77

The underlying principles of sepsis therapy have remained unchanged for decades. These include: prompt institution of antimicrobial agents aimed at the inciting pathogen, source control directed at removal of the infection nidus whenever possible, and support of organ dysfunction. Despite advances in antibiotics, surgical techniques and organ support technology, the morbidity and mortality from sepsis-related diseases have remained substantially unchanged (30 - 50%). Immunomodulation of the inflammatory cascade has been suggested as a crucial but inadequately addressed element in the treatment of sepsis. The list of potential therapeutic targets has been growing as more and more mediators are identified in the pathogenesis of sepsis. To date, numerous anti-inflammatory agents, found to have favourable effects in animal models of septic shock, have been tested in a number of clinical trials on thousands of patients. In this first of a three part series, we go through some of the background and current strategies in sepsis therapy. In this review, we include the two novel therapies that have shown clear survival benefit in large, randomised, placebo-controlled, multi-centre trials, low-dose steroids and recombinant activated protein C. Also included in this review are studies on antithrombin III, platelet-activating factor antagonists, complement modulators, nitric oxide synthase inhibitors and caspase inhibitors (apoptosis inhibitors).
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PMID:Experimental and emerging therapies for sepsis and septic shock. 1177 63

Despite advances in supportive care, sepsis and septic shock continue to be major causes of morbidity and mortality in critically ill patients. The lack of efficacy of anti-inflammatory drugs in patients with sepsis has shifted interest toward developing alternative treatments. The observation that clotting system activation may in part underlie the physiological derangements of sepsis has resulted in efforts to target the clotting cascade as a therapeutic strategy. Anticoagulants have been shown to ameliorate physiological derangements and improve survival in animal sepsis models. Three agents have undergone extensive study in humans: recombinant human activated protein C (rhAPC, drotrecogin-alpha), antithrombin III (ATIII) and tissue factor pathway inhibitor (TFPI). While a recent Phase III study of rhAPC suggests a survival benefit in patients with sepsis, major concerns about this trial include the manner in which the study was conducted, the potential toxicity of rhAPC and the questionable efficacy of this agent in patients with low mortality risk. Further clinical testing of rhAPC appears to be necessary to better define the target population most appropriate for its use. In contrast, a large Phase III study of high dose ATIII in patients with sepsis failed to show a treatment benefit with this agent. Finally, while TFPI has undergone extensive preclinical and Phase II testing, the results of Phase III studies have not been published. In summary, while coagulation inhibitors may ultimately have a therapeutic role in selected subgroups of patients with sepsis, the efficacy and safety of this class of agents remain to be proven.
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PMID:Coagulation inhibitors in the treatment of sepsis. 1177 22


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