Asunto(s)
Anticoagulantes/uso terapéutico , Antitrombina III/uso terapéutico , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Coagulación Sanguínea/efectos de los fármacos , Proteína C/uso terapéutico , Sepsis/tratamiento farmacológico , Trombomodulina/uso terapéutico , Anticoagulantes/efectos adversos , Antitrombina III/efectos adversos , Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/diagnóstico , Trastornos de la Coagulación Sanguínea/mortalidad , Ensayos Clínicos como Asunto , Medicina Basada en la Evidencia , Humanos , Proteína C/efectos adversos , Sepsis/sangre , Sepsis/diagnóstico , Sepsis/mortalidad , Resultado del TratamientoRESUMEN
OBJECTIVES: Preeclampsia is characterized by maternal systemic inflammation and coagulation activation, akin to the sepsis syndrome. Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) may modify disease progression to safely prolong pregnancies and improve perinatal outcomes. Both maternal and perinatal risks are highest remote from term. STUDY DESIGN: Open-label, single arm safety and efficacy trial of rhAPC in consenting pregnant women with severe early-onset preeclampsia. Disease severity-matched rhAPC-naïve controls were identified from an existing database. An additional six women were recruited as biomarker controls. MAIN OUTCOME MEASURES: Primary safety outcome: incidence of peripartum bleeding; primary efficacy outcome: duration of pregnancy after enrolment. RESULTS: Twelve (31.6%) of 38 eligible women consented; 3 did not receive the infusion due to staffing. Therefore, 9 women received rhAPC (24⯵g/kg/hr for ≤96â¯h antenatally). No safety issues were identified. There was a marginal prolongation in eligibility-to-delivery intervals for women receiving rhAPC (Mantel-Cox pâ¯=â¯0.052; Gehan-Breslow-Wilcoxon pâ¯=â¯0.049). Compared with both the pre-infusion phase in the rhAPC-treated women themselves and with fullPIERS rhAPC-naïve women, rhAPC was associated with increased urine output during the infusion (6/9 vs 1/9 had urine output >100â¯mL/h during the infusion, Fisher's exact pâ¯=â¯0.003). CONCLUSIONS: These data support further investigation of APC in women with severe early-onset preeclampsia; recombinant and purified human APC is available. In addition, these data will inform the design and implementation of randomized controlled trials aiming to modify and/or moderate the proinflammatory and proacoagulant state of preeclampsia.
Asunto(s)
Fibrinolíticos/administración & dosificación , Preeclampsia/tratamiento farmacológico , Atención Prenatal/métodos , Proteína C/administración & dosificación , Adulto , Biomarcadores/sangre , Colombia Británica , Femenino , Fibrinolíticos/efectos adversos , Humanos , Infusiones Parenterales , Periodo Periparto , Hemorragia Posparto/inducido químicamente , Preeclampsia/sangre , Preeclampsia/diagnóstico , Preeclampsia/fisiopatología , Embarazo , Proteína C/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Tissue factor pathway inhibitor (TFPI) antibodies, which have been reported in patients with antiphospholipid syndrome (APS), may impair TFPI activity and contribute to hypercoagulability, but their role in APS and in thrombosis remains undefined. OBJECTIVE/METHODS: We assessed the presence and avidity of TFPI IgG antibodies, associations with protein C IgG antibodies and associations with clinical disease severity, in 50 patients with thrombotic APS and 50 thrombotic control patients, on long term anticoagulation with warfarin. RESULTS: Thrombotic APS patients had a significantly higher prevalence of TFPI IgG antibodies (40%; 20/50) compared to thrombotic controls (18%; 9/50). TFPI antibodies were predominantly high avidity in APS (50%, 10/20 of positive patients) and strongly associated with a severe thrombotic phenotype (venous and arterial thromboembolism or recurrent thromboembolic episodes despite therapeutic anticoagulation) (odds ratio (OR): 12.0, 95%CI: 2.2-66.1, pâ¯=â¯0.004), while thrombotic control patients mainly showed low avidity antibodies (78%, 7/9 of positive patients). Coexistence of TFPI and protein C IgG antibodies, regardless of their avidity, was strongly associated with a more severe thrombotic phenotype in APS patients (OR: 20.2, 95%CI: 2.0-47.0, pâ¯<â¯0.0001) and also in thrombotic controls (OR: 75.0, 95%CI 1.2-195, pâ¯=â¯0.02). CONCLUSIONS: Coexistent TFPI and protein C IgG antibodies, irrespective of their avidity, may be a useful marker for a severe thrombotic phenotype in thrombotic patients. This suggests a possibly pathophysiological relationship between the two antibodies, predisposing to thrombosis with a possibly more general role in the development of thrombotic complications.
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Síndrome Antifosfolípido/inmunología , Pruebas de Coagulación Sanguínea/métodos , Lipoproteínas/efectos adversos , Proteína C/efectos adversos , Estudios Transversales , Femenino , Humanos , Lipoproteínas/metabolismo , Masculino , Persona de Mediana Edad , Fenotipo , Proteína C/metabolismoRESUMEN
Bronchopulmonary dysplasia (BPD) is a severe lung disease of preterm infants, which is characterized by fewer, enlarged alveoli and increased inflammation. BPD has grave consequences for affected infants, but no effective and safe therapy exists. We previously showed that prophylactic treatment with interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD induced by perinatal inflammation and hyperoxia. Here, we used the same BPD model to assess whether an alternative anti-inflammatory agent, protein C (PC), is as effective as IL-1Ra against BPD. We also tested whether delayed administration or a higher dose of IL-1Ra affects its ability to ameliorate BPD and investigated aspects of drug safety. Pups were reared in room air (21% O2 ) or hyperoxia (65% or 85% O2 ) and received daily injections with vehicle, 1200 IU/kg PC, 10 mg/kg IL-1Ra (early or late onset) or 100 mg/kg IL-1Ra. After 3 or 28 days, lung and brain histology were assessed and pulmonary cytokines were analysed using ELISA and cytokine arrays. We found that PC only moderately reduced the severe impact of BPD on lung structure (e.g. 18% increased alveolar number by PC versus 34% by IL-1Ra); however, PC significantly reduced IL-1ß, IL-1Ra, IL-6 and macrophage inflammatory protein (MIP)-2 by up to 89%. IL-1Ra at 10 mg/kg prevented BPD more effectively than 100 mg/kg IL-1Ra, but only if treatment commenced at day 1 of life. We conclude that prophylactic low-dose IL-1Ra and PC ameliorate BPD and have potential as the first remedy for one of the most devastating diseases preterm babies face.
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Displasia Broncopulmonar/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Proteína C/administración & dosificación , Animales , Animales Recién Nacidos , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Displasia Broncopulmonar/complicaciones , Displasia Broncopulmonar/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Inflamación/complicaciones , Inflamación/patología , Proteína Antagonista del Receptor de Interleucina 1/efectos adversos , Pulmón/efectos de los fármacos , Pulmón/patología , Ratones , Embarazo , Proteína C/efectos adversos , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/patologíaRESUMEN
During an episode of sepsis, systemic inflammatory response phenomenon triggers a series of procoagulant mechanisms. It has been suggested that the use of activated protein C could play a role in the management of this pathology, but there is no consensus. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified seven systematic reviews covering 35 primary studies addressing the question of this article, including six randomized trials. We extracted data, combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded activated protein C in sepsis probably does not decrease the mortality rate and increases the rate of hemorrhagic events.
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Antiinfecciosos/uso terapéutico , Proteína C/uso terapéutico , Sepsis/tratamiento farmacológico , Antiinfecciosos/efectos adversos , Hemorragia/epidemiología , Humanos , Proteína C/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Sepsis/mortalidad , Sepsis/fisiopatologíaRESUMEN
BACKGROUND AND PURPOSE: The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial. METHODS: The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria. RESULTS: Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment. CONCLUSIONS: It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714.
Asunto(s)
Isquemia Encefálica/terapia , Protocolos Clínicos , Ensayos Clínicos como Asunto/normas , Fármacos Neuroprotectores/farmacología , Selección de Paciente , Proteína C/farmacología , Proteínas Recombinantes/farmacología , Accidente Cerebrovascular/terapia , Isquemia Encefálica/tratamiento farmacológico , Método Doble Ciego , Humanos , Trombolisis Mecánica , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/efectos adversos , Proteína C/administración & dosificación , Proteína C/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Accidente Cerebrovascular/tratamiento farmacológico , Terapia TrombolíticaRESUMEN
APC (activated protein C), derived from the plasma protease zymogen, is antithrombotic and anti-inflammatory. In preclinical injury models, recombinant APC provides neuroprotection for multiple injuries, including ischemic stroke. APC acts directly on brain endothelial cells and neurons by initiating cell signaling that requires multiple receptors. Two or more major APC receptors mediate APC's neuroprotective cell signaling. When bound to endothelial cell protein C receptor, APC can cleave protease-activated receptor 1, causing biased cytoprotective signaling that reduces ischemia-induced injury. Pharmacological APC alleviates bleeding induced by tissue-type plasminogen activator in murine ischemic stroke studies. Remarkably, APC's signaling promotes neurogenesis. The signaling-selective recombinant variant of APC, 3K3A-APC, was engineered to lack most of the APC's anticoagulant activity but retain APC's cell signaling actions. Recombinant 3K3A-APC is in ongoing National Institutes of Health (NIH)-funded clinical trials for ischemic stroke.
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Isquemia Encefálica/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Trombosis Intracraneal/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Proteína C/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Daño por Reperfusión/prevención & control , Accidente Cerebrovascular/tratamiento farmacológico , Terapia Trombolítica/efectos adversos , Animales , Antígenos CD/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Receptor de Proteína C Endotelial , Hemostasis/efectos de los fármacos , Humanos , Trombosis Intracraneal/metabolismo , Trombosis Intracraneal/patología , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/efectos adversos , Proteína C/efectos adversos , Receptor Cross-Talk/efectos de los fármacos , Receptor PAR-1/metabolismo , Receptores de Superficie Celular/agonistas , Receptores de Superficie Celular/metabolismo , Proteínas Recombinantes/efectos adversos , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patologíaRESUMEN
It is imperative to maintain normal blood flow to provide adequate oxygen supply to specific organs and cells, as well as for the removal of metabolic byproducts. Therefore, any situation that results in blood clotting can injure or kill living tissues. In this paper, we describe a case where a protein C deficient subject who would, by all medical indicators, be at 100 % risk of experiencing thrombophlebitis, deep vein thrombosis, and or lung emboli, is able to escape all pathologies by using perioperative zymogen protein C (ZPC). This protein C deficient patient has a long history of blood clotting, particularly from surgical procedures. The patient is 81 years old and first experienced clotting due to hernia surgery in 1964, when he was hospitalized for 16 days post-surgery with life threatening complications. It was later determined in 1980, after many episodes, that the patient had hereditary protein C deficiency at the 38 % level. In his hernia surgery, perioperative ZPC was used along with accepted anticoagulation procedures with no blood clots or other related side effects occurring. This procedure can greatly benefit protein C deficient patients, and could potentially find use for non-PC deficient patients in surgeries and a variety of other medical treatments. This particular case helps to validate the importance of ZPC in effecting safer surgery in high-risk patients. It also supports the mechanism of ZPC acting as an anticoagulant without causing bleeding. Most importantly, each clinical case study represents a unique combination of surgeon, hematologist, medical staff, and patient functioning as a coordinated team. In this case, smaller amounts of very expensive ZPC achieved safe and efficacious results, which is hugely important for future clinical applications when considering the production cost of ZPC. More studies must be done to establish minimum dosing while achieving safe and efficacious outcomes.
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Anticoagulantes/administración & dosificación , Coagulación Sanguínea/efectos de los fármacos , Precursores Enzimáticos/administración & dosificación , Hernia Inguinal/cirugía , Herniorrafia , Deficiencia de Proteína C/tratamiento farmacológico , Proteína C/administración & dosificación , Trombosis de la Vena/prevención & control , Warfarina/administración & dosificación , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Anticoagulantes/economía , Pruebas de Coagulación Sanguínea , Análisis Costo-Beneficio , Costos de los Medicamentos , Sustitución de Medicamentos , Precursores Enzimáticos/efectos adversos , Precursores Enzimáticos/economía , Herniorrafia/efectos adversos , Humanos , Masculino , Seguridad del Paciente , Proteína C/efectos adversos , Proteína C/economía , Deficiencia de Proteína C/sangre , Deficiencia de Proteína C/diagnóstico , Deficiencia de Proteína C/economía , Recurrencia , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Trombosis de la Vena/sangre , Trombosis de la Vena/economía , Trombosis de la Vena/etiología , Warfarina/efectos adversosRESUMEN
PURPOSE: To determine whether protein C zymogen (protein C concentrates or human protein C) improves clinically relevant outcomes in adult patients with severe sepsis and septic shock. METHODS: This is a randomized, double-blind, placebo-controlled, parallel-group trial that from September 2012 to June 2014 enrolled adult patients with severe sepsis or septic shock and high risk of death and of bleeding (e.g., APACHE II greater than 25, extracorporeal membrane oxygenation or disseminated intravascular coagulopathy). All patients completed their follow-up 90 days after randomization and data were analyzed according to the intention-to-treat principle. Follow-up was performed at 30 and 90 days after randomization. The primary endpoint was a composite outcome of prolonged intensive care unit (ICU) stay and/or 30-day mortality. Secondary endpoints included mortality. RESULTS: The study was stopped early in a situation of futility for the composite outcome of prolonged ICU stay and/or 30-day mortality that was 79 % (15 patients) in the protein C zymogen group and 67 % (12 patients) in the placebo group (p = 0.40) and for a concomitant safety issue: ICU mortality was 79 % (15 patients) in the protein C zymogen group vs 39 % (7 patients) in the placebo group (p = 0.020), and 30-day mortality was 68 vs 39 % (p = 0.072). CONCLUSION: Protein C zymogen did not improve clinically relevant outcomes in severe sepsis and septic shock adult patients. Given its high cost and the potential increase in mortality, the use of this drug in adult patients should be discouraged.
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Fibrinolíticos/administración & dosificación , Unidades de Cuidados Intensivos , Tiempo de Internación , Proteína C/administración & dosificación , Sepsis/tratamiento farmacológico , Anciano , Distribución de Chi-Cuadrado , Método Doble Ciego , Terminación Anticipada de los Ensayos Clínicos , Femenino , Fibrinolíticos/efectos adversos , Fibrinolíticos/metabolismo , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Proteína C/efectos adversos , Proteína C/metabolismo , Vesículas Secretoras/metabolismo , Sepsis/mortalidad , Choque Séptico/tratamiento farmacológico , Choque Séptico/mortalidad , Resultado del TratamientoRESUMEN
Severe congenital protein C (PC) deficiency (SCPCD) is associated with disseminated intravascular coagulation (DIC), purpura fulminans (PF), and vascular thromboembolic events (TE), often leading to organ failure and death. PC replacement therapy offers a safe, effective treatment for thromboembolic complications of SCPCD and secondary prophylaxis for recurrent DIC, PF, and TEs. A prospective, multi-centre, open-label, phase 2/3 study was conducted to demonstrate the safety and efficacy of protein C concentrate for treatment of PF and acute TEs. Fifteen enrolled patients with SCPCD received protein C concentrate; 11 received treatment for acute TEs (PF, 18 events; PF and other coumarin-related vascular thromboembolic events [coumarin-induced skin necrosis; CISN], 1 event; venous thrombosis, 5 events). Pre-defined efficacy criteria for treatment of acute TEs were compared with a historical control arm (i. e. patients receiving conventional therapy without protein C replacement). PF/CISN was demonstrated by pre-defined primary and secondary efficacy ratings. Primary ratings of protein C concentrate-treated episodes were significantly higher (p=0.0032) than in the historical control. For 19 PF/CISN episodes in 11 patients, 94.7 % of treatments were rated effective and 5.3 % effective with complications (not related to protein C concentrate). In a secondary efficacy rating, all treatments were rated effective (68.4 % excellent; 21.1 % good; 10.5 % fair). For 5/24 vascular thrombosis episodes, 80 % of treatments were rated excellent and 20 % were rated good. No treatment-related adverse events or serious adverse events occurred. In conclusion, protein C concentrate provides an efficacious, safe treatment for PF, CISN, and other TEs in SCPCD patients.
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Deficiencia de Proteína C/tratamiento farmacológico , Proteína C/uso terapéutico , Púrpura Fulminante/tratamiento farmacológico , Tromboembolia/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Coagulación Intravascular Diseminada/tratamiento farmacológico , Coagulación Intravascular Diseminada/etiología , Coagulación Intravascular Diseminada/prevención & control , Femenino , Humanos , Recién Nacido , Masculino , Estudios Prospectivos , Proteína C/efectos adversos , Proteína C/farmacocinética , Deficiencia de Proteína C/complicaciones , Deficiencia de Proteína C/congénito , Púrpura Fulminante/etiología , Púrpura Fulminante/prevención & control , Prevención Secundaria , Tromboembolia/etiología , Tromboembolia/prevención & control , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: Activated protein C (APC), an endogenous anticoagulant, has antithrombotic, fibrinolytic and anti-inflammatory properties. We recently conducted a controlled study (APCAP, activated protein C in severe acute pancreatitis) of APC treatment of patients with severe acute pancreatitis (SAP). Here we studied the effect of APC on the pivotal coagulation parameters of the surviving patients in the APCAP study. METHODS: The study consisted of 20 patients of whom 10 patients had received APC and 10 patients had received placebo. Coagulation parameters, physiological anticoagulants, thrombograms and circulating levels of IL-6 and CRP were determined on admission and at days 1, 3-4 and 6-7. RESULTS: During follow-up, the temporal levels of prothrombin time (PT) decreased and the temporal levels of thromboplastin time (TT) increased in placebo group (p< 0.001 for both), but not in APC group. The temporal levels of antithrombin (AT) increased less in APC group than in placebo group (p = 0.011). The shapes of the SAP patients' thrombograms were strongly deranged and were marginally affected by APC treatment. CONCLUSIONS: Coagulopathy in SAP, a complex phenomenon, is not alleviated by APC treatment. Rather, the patients receiving APC are heading toward normal homeostasis of coagulation slower than patients receiving placebo.
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Anticoagulantes/uso terapéutico , Pancreatitis/sangre , Pancreatitis/tratamiento farmacológico , Proteína C/uso terapéutico , Enfermedad Aguda , Adulto , Anticoagulantes/efectos adversos , Proteínas Antitrombina/análisis , Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/etiología , Femenino , Humanos , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Pancreatitis/complicaciones , Tiempo de Tromboplastina Parcial , Proteína C/efectos adversos , Tiempo de ProtrombinaRESUMEN
OBJECTIVE: An increased risk of bleeding is observed in patients receiving activated protein C (APC), which may be a limiting factor for the application of novel APC therapies. Since APC's therapeutic effects often require its cytoprotective activities on cells but not APC's anticoagulant activities, an agent that specifically antagonizes APC's anticoagulant effects but not its cytoprotective effects could provide an effective means to control concerns for risk of bleeding. We hypothesized that superFVa, an engineered activated FVa-variant that restores hemostasis in hemophilia could reduce APC-induced bleeding. APPROACH AND RESULTS: SuperFVa was engineered with mutations of the APC cleavage sites (Arg506/306/679Gln) and a disulfide bond (Cys609-Cys1691) between the A2 and A3 domains, which augment its biological activity and cause high resistance to APC. SuperFVa normalized APC-prolonged clotting times and restored APC-suppressed thrombin generation in human and murine plasma at concentrations where wild-type (wt) FVa did not show effects. Following intravenous injection of APC into BALB/c mice, addition to whole blood ex vivo of superFVa but not wt-FVa significantly normalized whole blood clotting. Blood loss following tail clip or liver laceration was significantly reduced when superFVa was administered intravenously to BALB/c mice prior to intravenous APC-treatment. Furthermore, superFVa abolished mortality (â¼50%) associated with excessive bleeding following liver laceration in mice treated with APC. CONCLUSIONS: Our results provide proof of concept that superFVa is effective in preventing APC-induced bleeding and may provide therapeutic benefits as a prohemostatic agent in various situations where bleeding is a serious risk.
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Anticoagulantes/efectos adversos , Factor Va/farmacología , Hemorragia/etiología , Hemorragia/prevención & control , Proteína C/efectos adversos , Proteínas Recombinantes/farmacología , Animales , Coagulación Sanguínea/efectos de los fármacos , Factor Va/administración & dosificación , Femenino , Hemorragia/mortalidad , Hemostasis/efectos de los fármacos , Ratones , Modelos Animales , Tiempo de Protrombina , Proteínas Recombinantes/administración & dosificación , Trombina/metabolismoRESUMEN
BACKGROUND/AIMS: End-stage renal disease (ESRD) patients treated with hemodialysis (HD) experience a high risk of death. ESRD patients with elevated levels of pro-inflammatory cytokines are at increased risk of death from cardiovascular events and infection. HD is often facilitated by the use of an anticoagulant. We hypothesized that the use of an anticoagulant that also possessed anti-inflammatory qualities without significant immunosuppressive effects may reduce the risk of death. In this pilot study, we sought to determine the optimal dose of activated protein C (APC) to achieve adequate regional anticoagulation for HD and determine if the drug can be safely used in ESRD patients treated with HD. METHODS: Twelve stable HD patients were enrolled into this safety and dose-finding study. Varying doses of APC were administered in place of usual heparin at varying doses to determine the range of APC that can be used for extracorporeal circuit anticoagulation. Partial thromboplastin time was assessed at fixed intervals during the HD treatment. RESULTS: The average age of study patients was 49 ± 12 years. 75% of patients were African-American and 66.7% were male. The optimal dose of APC to induce adequate anticoagulation was 24-30 µg/kg/h. No patients experienced any serious adverse events. One patient had their infusion stopped early due to refractory intradialytic hypertension. CONCLUSIONS: For ESRD patients undergoing HD, an initial starting dose of 24-30 µg/kg/h achieves a target partial thromboplastin time that should be adequate for circuit anticoagulation. This dose appears safe and was well tolerated.
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Antiinfecciosos/administración & dosificación , Fallo Renal Crónico/terapia , Proteína C/administración & dosificación , Diálisis Renal , Antiinfecciosos/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Fallo Renal Crónico/sangre , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina Parcial , Proteína C/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversosRESUMEN
Since the first description of subcutaneous protein C concentrate as treatment for severe protein C deficiency in 1996, further cases have been reported but there is no uniform approach to this form of treatment. In order to assess the safety and effectiveness of subcutaneous protein C concentrate and suggest recommendations for future use, patients who had received subcutaneous protein C concentrate were identified from the literature, by contacting the manufacturers and by personal communication. Treatment details were available from 14 cases. Apart from one case where the infusion interval was inadvertently increased, no thrombotic events occurred even when doses were subsequently reduced. Initially, a trough protein C level of >0·25 iu/ml should be aimed for. Subsequently, a smaller dose of subcutaneous protein C concentrate, especially if taken with an oral anticoagulant, may be protective maintenance treatment. The treatment was well tolerated with few side effects. Subcutaneous protein C concentrate on its own or combined with an oral anticoagulant appears to be safe and effective as maintenance treatment of severe protein C deficiency. A major advantage is the avoidance of central venous access devices. The incidence of neurodevelopmental handicap was high with blindness affecting the majority of patients.
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Deficiencia de Proteína C/tratamiento farmacológico , Proteína C/administración & dosificación , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Infusiones Subcutáneas , Masculino , Persona de Mediana Edad , Proteína C/efectos adversos , Proteína C/metabolismo , Deficiencia de Proteína C/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Activated Protein C (APC) stimulates multiple cytoprotective pathways via the protease activated receptor-1 (PAR-1) and promotes anticoagulation. 3K3A-APC was designed for preserved activity at PAR-1 with reduced anticoagulation. This Phase 1 trial characterized pharmacokinetics and anticoagulation effects of 3K3A-APC. METHODS: Subjects (n=64) were randomly assigned to receive 3K3A-APC (n=4) at 6, 30, 90, 180, 360, 540 or 720 µg/kg or placebo (n=6) and were observed for 24 hr. After safety review additional subjects received drug every 12 hr for 5 doses (n=6 per group) at 90, 180, 360, or 540 µg/kg or placebo (n=8) and were observed for 24 hr. RESULTS: All subjects returned for safety assessments at 72 hours and 15 days. We found few adverse events in all groups. Systolic blood pressure increased in both active and placebo groups. Moderately severe headache, nausea and vomiting were reported in one of two subjects treated with 720 µg/kg so 540 µg/kg was considered the highest tolerated dose. Mean plasma concentrations increased in proportion to dose. Clearance ranged from 11,693 ± 807 to 18,701 ± 4,797 mL/hr, volume of distribution ranged from 4,873±828 to 6,971 ± 1,169 mL, and elimination half-life ranged from 0.211 ± 0.097 to 0.294 ± 0.054 hours. Elevations in aPTT were minimal. CONCLUSIONS: 3K3A-APC was well tolerated at multiple doses as high as 540 µg/kg. These results should be confirmed in stroke patients with relevant co-morbidities. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01660230.
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Anticoagulantes/administración & dosificación , Voluntarios Sanos , Proteína C/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Adulto , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Estudios de Cohortes , Humanos , Placebos , Proteína C/efectos adversos , Proteína C/farmacocinética , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinéticaRESUMEN
CONTEXT: Microvascular thrombosis is a critical event in severe acute pancreatitis. Human recombinant activated protein C (Xigris®, Eli Lilly, Indianapolis, IN, USA) modulates the interplay between pro-inflammatory and pro-coagulant pathways and maintains microvascular patency. However, the anticoagulant properties of Xigris® may precipitate bleeding from the inflamed pancreas. OBJECTIVE: This study tests the hypothesis that Xigris® can ameliorate experimental acute pancreatitis without causing pancreatic haemorrhage. METHODS: Sprague Dawley rats were allocated as follows: Group 1: control (n=7); Group 2: acute pancreatitis (n=6); Group 3: administration of Xigris® 500 µg/kg body weight before induction of acute pancreatitis (n=6); and Group 4: Administration of Xigris® 500 µg/kg body weight 30 minutes after induction of acute pancreatitis (n=6). Acute pancreatitis was induced by intraperitoneal administration of L-arginine 300 mg/100 g body weight. Animals were sacrificed at 48 hours and biochemical, haematological, and histological markers of pancreatic haemorrhage and inflammation assessed. RESULTS: Median lipase in animals with acute pancreatitis was 10 U/mL (range: 7-16 U/mL) compared to 5.5 (range: 3-8 U/mL) in controls (P=0.028). Lipase was also elevated in animals given Xigris® both before (12 U/mL, range: 8-22 U/mL; P=0.031 vs. control group) and after (46 U/mL, range: 9-71 U/mL; P=0.015 vs. control group) induction of acute pancreatitis). Haemoglobin levels were similar among all groups (P=0.323). There was no histological evidence of pancreatic haemorrhage in animals treated with Xigris®. Pre-treatment with Xigris® was associated with a significant reduction in pancreatic injury. This effect was absent when Xigris® was administered after induction of acute pancreatitis. CONCLUSION: Xigris® did not lead to pancreatic haemorrhage in experimental acute pancreatitis. Administration of Xigris® prior to induction of acute pancreatitis was associated with amelioration of injury. This effect was not seen with administration of Xigris® after induction of acute pancreatitis.