Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients
ABSTRACT Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been introduced to reduce the high risk of death associated with severe sepsis or septic shock. This systematic review is an update of a Cochrane review originally published in 2007.
We assessed the benefits and harms of APC for patients with severe sepsis or septic shock.
We searched CENTRAL (The Cochrane Library 2012, Issue 6); MEDLINE (2010 to June 2012); EMBASE (2010 to June 2012); BIOSIS (1965 to June 2012); CINAHL (1982 to June 2012) and LILACS (1982 to June 2012). There was no language restriction.
We included randomized clinical trials assessing the effects of APC for severe sepsis or septic shock in adults and children. We excluded studies on neonates. We considered all-cause mortality at day 28 and at the end of study follow up, and hospital mortality as the primary outcomes.
We independently performed trial selection, risk of bias assessment, and data extraction in duplicate. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model.
We identified one new randomized clinical trial in this update which includes six randomized clinical trials involving 6781 participants in total, five randomized clinical trials in adult (N = 6307) and one randomized clinical trial in paediatric (N = 474) participants. All trials had high risk of bias and were sponsored by the pharmaceutical industry. APC compared with placebo did not significantly affect all-cause mortality at day 28 compared with placebo (780/3435 (22.7%) versus 767/3346 (22.9%); RR 1.00, 95% confidence interval (CI) 0.86 to 1.16; I(2) = 56%). APC did not significantly affect in-hospital mortality (393/1767 (22.2%) versus 379/1710 (22.1%); RR 1.01, 95% CI 0.87 to 1.16; I(2) = 20%). APC was associated with an increased risk of serious bleeding (113/3424 (3.3%) versus 74/3343 (2.2%); RR 1.45, 95% CI 1.08 to 1.94; I(2) = 0%). APC did not significantly affect serious adverse events (463/3334 (13.9%) versus 439/3302 (13.2%); RR 1.04, 95% CI 0.92 to 1.18; I(2) = 0%). Trial sequential analyses showed that more trials do not seem to be needed for reliable conclusions regarding these outcomes.
This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. APC seems to be associated with a higher risk of bleeding. The drug company behind APC, Eli Lilly, has announced the discontinuation of all ongoing clinical trials using this drug for treating patients with severe sepsis or septic shock. APC should not be used for sepsis or septic shock outside randomized clinical trials.
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ABSTRACT: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that form a family of 24 members in mammals. Evidence of the pathological roles of MMPs in various diseases, combined with their druggability, has made them attractive therapeutic targets. Initial drug discovery efforts focused on the roles of MMPs in cancer progression, and more than 50 MMP inhibitors have been investigated in clinical trials in various cancers. However, all of these trials failed. Reasons for failure include the lack of inhibitor specificity and insufficient knowledge about the complexity of the disease biology. MMPs are also known to be involved in several inflammatory processes, and there are new therapeutic opportunities for MMP inhibitors to treat such diseases. In this Review, we discuss the recent advances made in understanding the role of MMPs in inflammatory diseases and the therapeutic potential of MMP inhibition in those conditions.dressNature Reviews Drug Discovery 11/2014; DOI:10.1038/nrd4390 · 37.23 Impact Factor
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ABSTRACT: The rapid increase in the incidence of multi-drug-resistant infections today has led to enormous interest in antimicrobial peptides (AMPs) as suitable compounds for developing unusual antibiotics. In this study clavanin A, an antimicrobial peptide, previously isolated from the marine tunicate Styela clava, was selected as a purposeful molecule that could be used in controlling infection and further synthesized. Clavanin A was in vitro evaluated against Staphylococcus aureus and Escherichia coli as well as toward L929 mice fibroblasts and SPCs cells. Moreover, this peptide was here challenged in an in vivo wound and sepsis model, and immune response was also analysed. Despite displaying clear in vitro antimicrobial activity toward Gram-positive and negative bacteria, clavanin A showed no cytotoxic activities against mammalian cells, and in acute toxicity tests no adverse reaction was observed at any of the concentrations. Moreover, clavanin A significantly reduced the S. aureus colony forming units in an experimental wound model. This same peptide also reduced the mortality of mice with E. coli and S. aureus by 80 % when compared with control animals (PBS-treated), these data suggest that clavanin A prevents the start of sepsis and thereby reduces mortality. These data suggest that clavanin A is an AMP that could improve the development of novel peptide-based strategies for the treatment of wound and sepsis infections. Copyright © 2014, American Society for Microbiology. All Rights Reserved.Antimicrobial Agents and Chemotherapy 12/2014; 59(3). DOI:10.1128/AAC.03732-14 · 4.45 Impact Factor
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ABSTRACT: The present study aimed to combine observational evidence with randomised controlled trials (RCTs) by using the Bayesian approach. Electronic databases, including PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ISI Web of Science, EMBASE and EBSCO were searched from inception to January 2014. RCTs and observational studies (OS) investigating the effectiveness of activated protein C (aPC) on mortality reduction were included for analysis. Patients with sepsis. aPC. Observational evidence was incorporated into the analysis by using power transformed priors in a Bayesian. Trial sequential analysis was performed to examine changes over time and whether further studies need to be conducted. a total of 7 RCTs and 12 OS were included for the analysis. There was moderate heterogeneity among included RCTs (I(2)=48.6%, p=0.07). The pooled OR for mortality from RCTs was 1.00 (95% CI 0.84 to 1.19). In OS, there was potential publication bias as indicated by the funnel plot and the pooled OR for mortality with the use of aPC was 0.67 (95% CI 0.62 to 0.72). The pooled effect sizes of RCTs were changed by using different power transform priors derived from observational evidence. When observational evidence was used at its 'face value', the treatment effect of aPC was statistically significant in reducing mortality. while RCT evidence showed no beneficial effect of aPC on sepsis, observational evidence showed a significant treatment effect of aPC. By using power transform priors in Bayesian model, we explicitly demonstrated how RCT evidence could be changed by observational evidence. The protocol for the current study was registered in PROSPERO (registration number: CRD42014009562). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.BMJ Open 01/2015; 5(1):e006524. DOI:10.1136/bmjopen-2014-006524 · 2.06 Impact Factor