Safety, Pharmacokinetics, and Pharmacodynamics of Drotrecogin Alfa (Activated) in Children With Severe Sepsis

Barton, Phil; Kalil, André C.; Nadel, Simon; Goldstein, Brahm; Okhuysen-Cawley, Regina; Brilli, Richard J.; Takano, Jeanne S.; Martin, Lynn D.; Quint, P.; Yeh, Timothy S.; Dalton, Heidi J.; Gessouron, Morris R.; Brown, Kellie E.; Betts, Helen; Levin, Michael; Macias, William L.; Small, David S.; Wyss, V; Bates, Becky; Utterback, Barbara G.; Giroir, Brett P.

doi:10.1542/peds.113.1.7

Cited by 102 publications

(59 citation statements)

References 30 publications

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“…[5][6][7][8][9]21,39 The systemic anticoagulant and antihemostatic side effects of exogenous APC at about 10-fold above baseline levels have been documented in the clinic. [39][40][41] Accordingly, when endogenous APC exceeds a critical plasma concentration, it is also reasonably expected to impair hemostasis. The lowest-dose PCA increased endogenous APC only 5-fold, which might explain its apparent safety.…”

Section: Discussionmentioning

confidence: 99%

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

Gruber

Marzec

Bush

et al. 2007

Blood

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The anticoagulant and anti-inflammatory enzyme, activated protein C (APC), naturally controls thrombosis without affecting hemostasis. We therefore evaluated whether the integrity of primary hemostasis was preserved during limited pharmacological antithrombotic protein C activator (PCA) treatment in baboons. The double-mutant thrombin (Trp215Ala/ Glu217Ala) with less than 1% procoagulant activity was used as a relatively selective PCA and compared with systemic anticoagulation by APC and low-molecular-weight heparin (LMWH) at doses that inhibited fibrin deposition on thrombogenic segments of arteriovenous shunts. As expected, both systemic anticoagulants, APC (0.028 or 0.222 mg/kg for 70 minutes) and LMWH (0.325 to 2.6 mg/kg for 70 minutes), were antithrombotic and prolonged the template bleeding time. In contrast, PCA at doses (0.0021 to 0.0083 mg/kg for 70 minutes) that had antithrombotic effects comparable with LMWH did not demonstrably impair primary hemostasis. PCA bound to platelets and leukocytes, and accumulated in thrombi. APC infusion at higher circulating APC levels was less antithrombotic than PCA infusion at lower circulating APC levels. The observed dissociation of antithrombotic and antihemostatic effects during PCA infusion thus appeared to emulate the physiological regulation of intravascular blood coagulation (thrombosis) by the endogenous protein C system. Our data suggest that limited pharmacological protein C activation might exhibit considerable thrombosis specificity. IntroductionSystemic anticoagulants can completely interrupt thrombus formation, but their usefulness is limited because their antithrombotic and antihemostatic activities are mechanistically tied. Highly effective plasma concentrations of systemic anticoagulants, such as those used for temporary thrombo-prophylaxis in interventional cardiology, prevent thrombin generation in both the blood vessel and the wound and can paralyze hemostasis with potentially fatal consequences. Due to safety considerations, the vast majority of patients who receive antithrombotic treatment are not anticoagulated to full efficacy. Thrombotic blood vessel occlusions causing myocardial infarction and ischemic stroke thus continue to contribute to mortality statistics. 1 Until more thrombosis-specific intravascular anticoagulants become available, balancing the potential benefits and risks of systemic anticoagulation remains a critical hurdle for the clinician.Occlusive thrombus formation is naturally down-regulated without bleeding complications most of the time following thrombogenic stimuli, such as blood vessel injuries or infections. It thus seems possible that selective pharmacological enhancement of the natural antithrombotic systems could achieve thrombosis specificity. Enhancement of the endogenous protein C pathway in the vicinity of thrombus formation might offer this wider therapeutic window. Thrombin is the natural protein C activator enzyme that activates protein C on such anatomic surfaces as the endothelial lining of blood vessels. ...

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Section: Discussionmentioning

confidence: 99%

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

Gruber

Marzec

Bush

et al. 2007

Blood

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“…15 Neonatal sepsis mortality is higher than in children and adults, 16,17 peaking in premature infants, where rates can approach 50%. 18 Neonates have welldescribed deficits in adaptive and innate immune function that place them at risk for the development of a serious bacterial infection.…”

Section: Introductionmentioning

confidence: 99%

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Wynn

Scumpia²,

Winfield³

et al. 2008

Blood

159

167

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Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell-directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b ؉ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality. IntroductionSepsis causes profound defects in innate and acquired immunity. In septic adults, circulating leukocytes fail to mount an attenuated inflammatory response, monocytes have defective antigen presentation in part due to reduced MHC class II expression, and dendritic cells and lymphocytes exhibit increased apoptosis. [1][2][3][4] These deficiencies contribute to a failure to clear primary pathogens, an increased propensity to develop superinfections, and an inability to mount adaptive immune responses. Considerable progress has been made in understanding the pathogenesis of and identifying potential immunomodulatory therapies for treating sepsis in adult animals. For example, MyD88 and type I interferon signaling pathways 5,6 are important requisites for innate and inflammatory host defense responses to pathogens. 7,8 Stimulating the innate immune system with Toll-like receptor (TLR) agonists improves survival in adult animal models of sepsis. 9,10 Similarly, absence of the adaptive immune system 11 or an inability of B cells to produce antibodies 12 predisposes adult mice to a poor outcome in sepsis. Correction of adaptive immune dysfunction by prevention of lymphocyte apoptosis or treatment with agonistic glucocorticoid-induced tumor necrosis factor (TNF) receptor antibody (anti-GITR) to stimulate effector T-cell function, improves survival in animal models of adult sepsis. 11,13 These studies highlight the importance of both the innate and adaptive immune systems in eliminating invading pathogens in adult mammals. However, the mechanisms of protective immunity in neonates that do not possess a fully intact immune system, and who develop sepsis at increased rates, 14 are less clear.More than 1 million babies die each year worldwide within the first 4 weeks of life from sepsis. 15 Neonatal sepsis mortality is higher than in children and adults, 16,17 peaking in premature infants, where r...

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“…A incidência de sangramento grave foi de 2,4% e 4,8% entre os pacientes envolvidos na 1ª e 2ª etapas do estudo. A taxa de mortalidade observada (9,6%) não foi significativamente diferente da mortalidade atribuída à sepse grave na população pediátrica (10,8%) estimada pelo PIM 15 . Mais recentemente, o ENHANCE pediátrico envolveu 187 pacientes com idades de zero (RNT > 38 semanas) a 18 anos, tendo como objetivo a avaliação das taxas de mortalidade no 4º e 28º dias entre pacientes com sepse grave que receberam PCA.…”

Section: Discussionunclassified

“…Neste momento, ainda não existe autorização do FDA para a utilização da medicação em crianças. Entretanto, alguns estudos têm demonstrado possíveis benefí-cios do seu uso nestes pacientes 15,16 . O objetivo deste estudo foi descrever o caso de um recém-nascido que se beneficiou do uso da PCA no tratamento de sepse, que evoluiu para choque e disfunção de múltiplos órgãos e sistemas (DMOS).…”

Section: Introductionunclassified

Proteína C ativada no tratamento de recém-nascido com sepse, choque e disfunção de múltiplos órgãos e sistemas: relato de caso e revisão de literatura

Georgetti¹,

Eugénio²

2006

Rev. bras. ter. intensiva

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Safety, Pharmacokinetics, and Pharmacodynamics of Drotrecogin Alfa (Activated) in Children With Severe Sepsis

Cited by 102 publications

References 30 publications

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Proteína C ativada no tratamento de recém-nascido com sepse, choque e disfunção de múltiplos órgãos e sistemas: relato de caso e revisão de literatura

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