Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.584
Filtrar
1.
Clin Appl Thromb Hemost ; 30: 10760296241238013, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38494906

RESUMO

Direct oral factor Xa inhibitors are replacing vitamin K-dependent antagonists as anticoagulation treatment in many clinical scenarios. Trauma centers are noting an increase in patients presenting on these medications. The 2018 Food and Drug Administration approval of andexanet alfa provides an alternative anticoagulation reversal. Barriers may limit utilization of new medications including a lack of grade 1A evidence supporting the use of prothrombin complex concentrate (PCC) versus andexanet alfa and cost. To evaluate barriers of andexanet alfa utilization by trauma surgeons, a 15-question survey was conducted. There was a 9% completion rate (n = 89). The results revealed 23.5% would choose andexanet alfa as first-line treatment in children, and 25.8% as first-line treatment in adults. The majority of respondents, 64.7% and 67.4%, would use PCC preferentially in children and adults, respectively. Respondents indicated that cost burden was an overriding factor (76.3%); 42.4% cited lack of high-level efficacy data of andexanet alfa for reversal of factor Xa inhibitors. Additional double-blinded multi-institutional randomized controlled trials comparing 4F-PCC and andexanet alfa for factor Xa inhibitor reversal are needed to support efficacy especially with the increased cost associated.


Assuntos
Inibidores do Fator Xa , Fator Xa , Adulto , Criança , Humanos , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Fator Xa/farmacologia , Fator Xa/uso terapêutico , Anticoagulantes/uso terapêutico , Antitrombina III , Fibrinolíticos/uso terapêutico , Fator IX , Proteínas Recombinantes/uso terapêutico
2.
CNS Drugs ; 38(3): 163-168, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38396232

RESUMO

Andexanet alfa is a specific reversal agent for factor Xa inhibitors with immediate reversal of their anticoagulant effect. Andexanet alfa is currently approved for use in patients treated with rivaroxaban and apixaban who have life-threatening or uncontrolled bleeding. New data from both controlled clinical trials and real-world experience are continuously being published, providing greater insight into the clinical characteristics of the drug, such as efficacy and safety. It is worth considering that andexanet alfa could be of benefit in a variety of different clinical scenarios where patients receiving treatment with apixaban and rivaroxaban (and endoxaban) have life-threatening conditions. These different clinical scenarios, which range from pre-treatment of urgent surgery, especially neurosurgical interventions, and concomitant use of andexanet alfa and prothrombin complex concentrate to onset of bleeding more than 6 h prior to admission, should be clarified as well as the issue of "low/high" dose of andexanet alfa and the need for baseline anti-Xa inhibitor levels measured by point-of-care testing. Finally, management of patients at high risk of thrombosis or recent arterial/venous thrombotic events needs to be further explored. In this current opinion, we address these urgent questions in the light of recent literature and clinical trial data.


Assuntos
Hemorragia , Rivaroxabana , Humanos , Rivaroxabana/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Fator Xa/uso terapêutico , Fator Xa/farmacologia , Inibidores do Fator Xa/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Anticoagulantes/uso terapêutico
3.
Emerg Med J ; 41(3): 162-167, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38267194

RESUMO

BACKGROUND: Andexanet alfa was approved in 2018 for reversal of direct oral anticoagulants but due to issues of cost and access, four-factor prothrombin complex concentrate (4F-PCC) continues to be used for this indication. The objective of this study is to evaluate outcomes of reversal with these agents in patients with isolated traumatic brain injuries (TBI). METHODS: This is a retrospective review of 35 trauma centres from 2014 to 2021. Patients were included with an Abbreviated Injury Scale (AIS)>2 for head and having received andexanet alfa or 4F-PCC within 24 hours of admission. Patients were excluded if P2Y12 inhibitor use or AIS>2 outside of head. Primary outcome includes rate of mortality/hospice at hospital discharge. Secondary outcomes include a composite of serious hospital complications. A subgroup analysis of severe TBI patients (AIS head 4 or 5) was completed. Multivariable logistic regression was used to account for differences in comorbidities and TBI severity. RESULTS: 4F-PCC was given to 265 patients with another 59 receiving andexanet alfa. Patients in the andexanet alfa group were more likely to have an AIS head score of 5 (47.5% vs 26.1%; p<0.005). After adjusting for severity of TBI and comorbidities with regard to tomortality/hospice, there were 15 (25.4%) patients in the andexanet alfa group and 49 (18.5%) in the 4F-PCC group (OR 1.34; 95% CI 0.67 to 2.71). This remained consistent when looking at severe patients with TBI with 12 (28.6%) andexanet alfa patients and 37 (28.7%) 4F-PCC patients (OR 0.93 (95% CI 0.40 to 2.16)). Severe hospital complications were also similar between groups with 5 (8.5%) andexanet alfa patients as compared with 21 (7.9%) 4F-PCC patients (OR 1.01; 95% CI 0.36 to 2.88). CONCLUSION: There was no firm conclusion on the treatment effect in mortality/hospice or serious complications among isolated TBI patients reversed with 4F-PCC as compared with andexanet alfa.


Assuntos
Fatores de Coagulação Sanguínea , Lesões Encefálicas Traumáticas , Humanos , Fatores de Coagulação Sanguínea/efeitos adversos , Fator Xa/farmacologia , Fator Xa/uso terapêutico , Estudos Retrospectivos , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/induzido quimicamente , Anticoagulantes/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Proteínas Recombinantes/uso terapêutico
4.
Kardiol Pol ; 82(1): 123-139, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38230495

RESUMO

Andexanet alfa (AA) is a recombinant inactive analog of human activated factor X (FXa), effectively reversing the effects of its inhibitors - rivaroxaban and apixaban, which are available in Poland. The drug was approved for clinical use registration after the publication of the results of the ANNEXA-4 trial (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors 4), in which its efficacy in restoring hemostasis in life-threatening hemorrhages in patients receiving using the aforementioned anticoagulants was demonstrated. Hence, AA is now recommended for patients on apixaban or rivaroxaban therapy with massive and uncontrollable hemorrhages, including hemorrhagic strokes (HS) and gastrointestinal bleeding. Drug-specific chromogenic anti-Xa assays are generally best suited for estimating rivaroxaban and apixaban plasma levels, aside from direct assessment of their concentrations. The absence of anti-Xa activity, determined using these assays, allows us to rule out the presence of clinically relevant plasma concentrations of any FXa inhibitor. On the other hand, the dose of AA should not be modified based on the results of coagulation tests, as it depends solely on the time that elapsed since the last dose of FXa inhibitor and oon the dose and type of FXa inhibitor. AA is administered as an intravenous (i.v.) bolus, followed by an i.v. infusion of the drug. The maximum reversal of anti-Xa activity occurs within two minutes of the end of the bolus treatment, with the continuation of the continuous i.v. infusion allowing the effect to be maintained for up to two hours afterwards. Because anticoagulant activity can reappear after the infusion is completed, it is currently unclear at what point after AA administration FXa inhibitors or heparin should be re-administered. In Poland AA is starting to become available and its urgent need to administer it to patients with severe bleeding on apixaban or rivaroxaban.


Assuntos
Fator Xa , Rivaroxabana , Humanos , Rivaroxabana/uso terapêutico , Fator Xa/uso terapêutico , Polônia , Inibidores do Fator Xa/uso terapêutico , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Anticoagulantes/uso terapêutico
5.
Biochem Biophys Res Commun ; 696: 149473, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38241814

RESUMO

The saliva of the medicinal leech contains various anticoagulants. Some of them, such as hirudin, are well known. However, it is reasonable to believe that not all anticoagulant proteins from medicinal leech saliva have been identified. We previously performed a comprehensive study of the transcriptome, genome, and proteome of leech salivary gland cells, which led to the discovery of several previously unknown hypothetical proteins that may have anticoagulant properties. Subsequently, we obtained a series of recombinant proteins and investigated their impact on coagulation in in vitro assays. We identified a previously undescribed protein that exhibited a high ability to suppress coagulation. The His-tagged recombinant protein was expressed in Escherichia coli and purified using metal chelate chromatography. To determine its activity, commonly used coagulation methods were used: activated partial thromboplastin time, prothrombin time, and thrombin inhibition clotting assay. Clotting and chromogenic assays for factor Xa inhibition were performed to evaluate anti-Xa activity. We used recombinant hirudin as a control anticoagulant protein in all experiments. The new protein showed significantly greater inhibition of coagulation than hirudin at the same molar concentrations in the activated partial thrombin time assay. However, hirudin demonstrated better results in the direct thrombin inhibition test, although the tested protein also exhibited the ability to inhibit thrombin. The chromogenic analysis of factor Xa inhibition revealed no activity, whereas the clotting test for factor Xa showed the opposite result. Thus, a new powerful anticoagulant protein has been discovered in the medicinal leech. This protein is homologous to antistatin, with 28 % identical amino acid residues. The recombinant protein was expressed in E. coli. This protein is capable of directly inhibiting thrombin, and based on indirect evidence, other proteases of the blood coagulation cascade have been identified.


Assuntos
Anticoagulantes , Hirudinas , Anticoagulantes/farmacologia , Hirudinas/farmacologia , Hirudinas/genética , Hirudinas/metabolismo , Trombina/metabolismo , Fator Xa , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas Recombinantes/metabolismo
6.
Molecules ; 29(2)2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38257286

RESUMO

Cardiovascular diseases caused by blood coagulation system disorders are one of the leading causes of morbidity and mortality in the world. Research shows that blood clotting factors are involved in these thrombotic processes. Among them, factor Xa occupies a key position in the blood coagulation cascade. Another coagulation factor, XIa, is also a promising target because its inhibition can suppress thrombosis with a limited contribution to normal hemostasis. In this regard, the development of dual inhibitors as new generation anticoagulants is an urgent problem. Here we report the synthesis and evaluation of novel potential dual inhibitors of coagulation factors Xa and XIa. Based on the principles of molecular design, we selected a series of compounds that combine in their structure fragments of pyrrolo[3,2,1-ij]quinolin-2-one and thiazole, connected through a hydrazine linker. The production of new hybrid molecules was carried out using a two-stage method. The reaction of 5,6-dihydropyrrolo[3,2,1-ij]quinoline-1,2-diones with thiosemicarbazide gave the corresponding hydrazinocarbothioamides. The reaction of the latter with DMAD led to the target methyl 2-(4-oxo-2-(2-(2-oxo-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1(2H)-ylidene)hydrazineyl)thiazol-5(4H)-ylidene)acetates in high yields. In vitro testing of the synthesized molecules revealed that ten of them showed high inhibition values for both the coagulation factors Xa and XIa, and the IC50 value for some compounds was also assessed. The resulting structures were also tested for their ability to inhibit thrombin.


Assuntos
Doenças Cardiovasculares , Fator Xa , Humanos , Trombina , Anticoagulantes/farmacologia , Coagulação Sanguínea
7.
Br J Anaesth ; 132(2): 251-259, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38030550

RESUMO

BACKGROUND: The comparative effectiveness of the specific antidote andexanet alfa vs the nonspecific therapy four-factor prothrombin complex concentrates (4F-PCCs) as reversal agents for direct factor Xa (FXa) inhibitors in severely bleeding patients is unclear. We hypothesised that specific reversal using andexanet alfa would be more effective than a high dose of PCC (50 IU kg-1) for reversing the FXa inhibitor rivaroxaban. METHODS: The reversal potential of andexanet alfa, various 4F-PCCs, and activated PCC was investigated ex vivo in human blood anticoagulated with rivaroxaban (37.5, 75, 150, and 300 ng ml-1) using a panel of coagulation parameters, including conventional coagulation assays, thrombin generation, and a newly developed viscoelastometric device. We simulated in vivo conditions of coagulation activation and fibrin formation using flow chamber experiments of thrombogenicity potential under arterial flow conditions. RESULTS: The 4F-PCCs normalised clotting profiles only at low rivaroxaban concentrations, whereas andexanet alfa and activated PCC significantly shortened clotting time at all rivaroxaban concentrations. Only andexanet alfa restored thrombin generation to baseline. Flow chamber results showed that various 4F-PCCs concentration-dependently restored clot formation. CONCLUSIONS: In contrast to thrombin generation measurements, haemostatic reversal of rivaroxaban using high-dose 4F-PCCs exhibited similar efficacy as andexanet alfa in flow chamber experiments. The haemostatic effects of 4F-PCCs and andexanet alfa in the context of bleeding patients taking FXa inhibitors requires further study.


Assuntos
Hemostáticos , Rivaroxabana , Humanos , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Fatores de Coagulação Sanguínea/farmacologia , Fatores de Coagulação Sanguínea/uso terapêutico , Fator IX , Fator Xa/farmacologia , Fator Xa/uso terapêutico , Inibidores do Fator Xa/farmacologia , Hemorragia/tratamento farmacológico , Hemostáticos/uso terapêutico , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Rivaroxabana/farmacologia , Trombina
9.
J Thromb Thrombolysis ; 57(2): 285-292, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37932587

RESUMO

Following FDA approval in 2018, consensus guidelines recommend andexanet alfa as first-line therapy for the management of life-threatening or uncontrollable bleeding in patients taking oral factor Xa (FXa) inhibitors. Dosing is based on the specific FXa inhibitor and dose, and the time elapsed since the patient's last administration of the medication. Additionally, at our institution, anti-FXa screens and drug-specific assays are obtained to guide subsequent dosing based on institution protocol. The objective of this study was to evaluate andexanet alfa utilization based on anti-Xa and FXa-inhibitor-specific assays and assess associated outcomes. This was a retrospective, single-center study aimed to describe the use of anti-FXa and specific direct oral anticoagulant assays to guide the utilization and administration of andexanet alfa. Secondary endpoints evaluated included thrombotic events during index hospitalization, hospital length of stay, hospital mortality, and discharge disposition. Overall, most patients were prescribed apixaban for atrial fibrillation and received andexanet alfa for reversal of intracranial hemorrhage in the emergency department. In general, DOAC-specific assays were concordant with last known times; however, there appears to be minimal correlation with DOAC-specific assay levels and survival. There were 9 thrombotic events (8.7%) in 8 patients. In this cohort, collection of an anti-FXa assay screen was a practical strategy to guide reversal with andexanet alfa; however, the addition of DOAC-specific assay levels may not enhance clinical utility.


Assuntos
Fator Xa , Trombose , Humanos , Fator Xa/uso terapêutico , Fator Xa/farmacologia , Preparações Farmacêuticas , Estudos Retrospectivos , Inibidores do Fator Xa/efeitos adversos , Trombose/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Anticoagulantes/farmacologia , Rivaroxabana/efeitos adversos
10.
J Atheroscler Thromb ; 31(3): 201-213, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37635060

RESUMO

AIMS: Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan. METHODS: This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment. RESULTS: A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events. CONCLUSION: Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.


Assuntos
Hemostáticos , Piridinas , Tiazóis , Trombose , Humanos , Inibidores do Fator Xa/efeitos adversos , Rivaroxabana/efeitos adversos , Fator Xa/uso terapêutico , Fator Xa/farmacologia , Japão , Estudos Prospectivos , Hemorragia/tratamento farmacológico , Hemorragia/prevenção & controle , Hemorragia/induzido quimicamente , Antitrombina III/uso terapêutico , Hemostáticos/uso terapêutico , Trombose/tratamento farmacológico , Fibrinolíticos , Proteínas Recombinantes/efeitos adversos , Anticoagulantes/efeitos adversos
12.
Thromb Haemost ; 124(1): 20-31, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37604188

RESUMO

BACKGROUND: Andexanet alfa (andexanet) is a reversal agent for use in patients with life-threatening or uncontrolled bleeding treated with oral factor Xa (FXa) inhibitors. There are limited data on the dose-response relationship of andexanet and FXa inhibitor-related bleeding. OBJECTIVE: The aim of this study was to assess the dose-related effectiveness of andexanet in reducing blood loss, improving survival, and reversing apixaban anticoagulation in a porcine polytrauma model. METHODS: Apixaban was given orally to 40 male pigs for 3 days at a dose of 20 mg/d. On day 3, following bilateral femur fractures and blunt liver injury, animals (n = 8/group) received andexanet (250-mg bolus, 250-mg bolus + 300-mg 2-hour infusion, 500-mg bolus, or 500-mg bolus + 600-mg 2-hour infusion) or vehicle (control). Total blood loss was the primary endpoint. Coagulation parameters were assessed for 300 minutes or until death. Data were analyzed with a mixed-model analysis of variance. RESULTS: Administration of 250-mg bolus + 300-mg infusion, andexanet 500-mg bolus, and 500-mg bolus + 600-mg infusion significantly decreased total blood loss by 37, 58, and 61%, respectively (all p < 0.0001), with 100% survival. Andexanet 250-mg bolus was ineffective in reducing total blood loss (6%) and mortality (63% survival) versus controls. Andexanet 500-mg bolus ± infusion neutralized anti-FXa activity to less than 50 ng/mL. Andexanet neutralization of thrombin generation and thromboelastometry parameters was dose and infusion time dependent. CONCLUSION: In a porcine polytrauma model with major bleeding on apixaban, andexanet dose dependently decreased anti-FXa activity. Lower anti-FXa levels (<50 ng/mL) with andexanet 500-mg bolus ± infusion were correlated with 60% less blood loss and 100% survival versus controls.


Assuntos
Fator Xa , Traumatismo Múltiplo , Pirazóis , Piridonas , Humanos , Masculino , Animais , Suínos , Fator Xa/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Traumatismo Múltiplo/complicações , Traumatismo Múltiplo/tratamento farmacológico , Traumatismo Múltiplo/induzido quimicamente , Proteínas Recombinantes/uso terapêutico , Anticoagulantes/uso terapêutico
13.
Br J Anaesth ; 132(2): 215-217, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38071150

RESUMO

This study in vitro comprehensively assessed reversal of the anticoagulant effects of rivaroxaban, an oral factor Xa inhibitor, using andexanet alfa and various prothrombin complex concentrate (PCC) products in a battery of tests. In static coagulation assays, andexanet alpha outperformed PCCs except for activated PCC being more effective in standard coagulation times. However, in a flow chamber model mimicking arterial shear, both andexanet alpha and high-concentration PCC restored fibrin formation, but not platelet adhesion. In the Russell's viper venom test and anti-Xa assay, only andexanet alpha could be tested for efficacy. The antidote effects of andexanet alpha and PCCs in restoring coagulation can be qualitatively or selectively demonstrated using in vitro coagulation tests.


Assuntos
Antídotos , Inibidores do Fator Xa , Fator Xa , Humanos , Inibidores do Fator Xa/farmacologia , Antídotos/farmacologia , Antídotos/uso terapêutico , Fatores de Coagulação Sanguínea/farmacologia , Fatores de Coagulação Sanguínea/uso terapêutico , Rivaroxabana/farmacologia , Fator IX , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Anticoagulantes/efeitos adversos
15.
Cells ; 12(24)2023 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-38132169

RESUMO

Atrial fibrillation (AF), characterised by irregular high-frequency contractions of the atria of the heart, is of increasing clinical importance. The reasons are the increasing prevalence and thromboembolic complications caused by AF. So-called atrial remodelling is characterised, among other things, by atrial dilatation and fibrotic remodelling. As a result, AF is self-sustaining and forms a procoagulant state. But hypercoagulation not only appears to be the consequence of AF. Coagulation factors can exert influence on cells via protease-activated receptors (PAR) and thereby the procoagulation state could contribute to the development and maintenance of AF. In this work, the influence of FXa on Heart Like-1 (HL-1) cells, which are murine adult atrial cardiomyocytes (immortalized), was investigated. PAR1, PAR2, and PAR4 expression was detected. After incubations with FXa (5-50 nM; 4-24 h) or PAR1- and PAR2-agonists (20 µM; 4-24 h), no changes occurred in PAR expression or in the inflammatory signalling cascade. There were no time- or concentration-dependent changes in the phosphorylation of the MAP kinases ERK1/2 or the p65 subunit of NF-κB. In addition, there was no change in the mRNA expression of the cell adhesion molecules (ICAM-1, VCAM-1, fibronectin). Thus, FXa has no direct PAR-dependent effects on HL-1 cells. Future studies should investigate the influence of FXa on human cardiomyocytes or on other cardiac cell types like fibroblasts.


Assuntos
Fibrilação Atrial , Fator Xa , Animais , Camundongos , Fator Xa/metabolismo , NF-kappa B/metabolismo , Receptor PAR-1/metabolismo , Receptor PAR-2/metabolismo , Transdução de Sinais
16.
Expert Opin Investig Drugs ; 32(11): 1085-1094, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37955047

RESUMO

BACKGROUND: SAR107375E is a direct dual inhibitor of both Factor Xa and Factor IIa and has shown potent anticoagulation activity in vitro and animals. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of SAR107375E in healthy Chinese adult subjects. METHODS: In this randomized, double-blind, placebo-controlled trial, 60 healthy Chinese adult subjects were administered intravenously single ascending doses (0.5, 1.5, 3.0, 5.0, 7.5, 10.0, 15.0, or 20.0 mg) of SAR107375E (N = 44) or placebo (N = 16). Plasma and urine concentrations of SAR107375E were measured and used to calculate pharmacokinetic parameters. Coagulation functions were measured and compared with baseline values. Treatment-emergent adverse events were recorded to evaluate safety. RESULTS: In plasma, from the 0.5 to 20.0 mg dose group, t1/2 is 1.51-4.00 h, Cmax is 59.05-1360 ug/L, and AUC0-t is 25.01-528.45 h*ug/L. And it shows dose proportionality in the 5.0-20.0 mg range. Activated partial thromboplastin time and Ecarin clotting time correlated linearly with drug plasma concentration. No serious adverse events were reported during the study. CONCLUSION: SAR107375E exhibits good safety and tolerability, predictable pharmacokinetics and pharmacodynamics. CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn, identifier is CTR20211082.


Assuntos
Anticoagulantes , Fator Xa , Adulto , Humanos , Anticoagulantes/efeitos adversos , Protrombina , Testes de Coagulação Sanguínea , Método Duplo-Cego , Relação Dose-Resposta a Droga , Área Sob a Curva
17.
Clin Neurol Neurosurg ; 235: 108040, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37944307

RESUMO

INTRODUCTION: There is substantial debate on the best method to reverse factor Xa-inhibitors in patients following traumatic brain injury (TBI). Prothrombin complex concentrates (PCC) have been used for this indication but their role has been questioned. This study reported failure rates with PCC in patients following TBI and as a secondary objective, compared 4-factor (4 F-PCC) and activated PCC (APCC). MATERIAL AND METHODS: Consecutive patients with TBI on factor Xa-inhibitors admitted to one of two trauma centers were retrospectively identified. Patients with penetrating TBI, delays in PCC administration (>6 h), receipt of tranexamic acid, factor VIIa or no follow up CT-scan were excluded. The primary outcome was treatment failure defined as hematoma expansion > 20% from baseline for SDH, EDH or IPH, a new hematoma not present on the initial CT scan or any expansion of a SAH or IVH. Hematoma expansion was further categorized as symptomatic or asymptomatic, designated by a change in the motor GCS score, neurologic exam or change ≥ 3 in NIH Stroke Scale. Multi-variate analysis was performed. RESULTS: There were 43 patients with a mean age of 77 ± 13 years with primarily mild TBI (95%) after a ground level fall (79%). The mean dose was 41 ± 12 units/kg. Sixty percent received 4 F-PCC and 40% APCC. The incidence of treatment failure was 28% (12/43). Of the 12 patients with hematoma expansion, only 3 were symptomatic (9.3%). Hematoma expansion with 4 F-PCC and APCC were similar (27% vs. 29%,p = .859). Only sex was associated with hematoma expansion on multivariate analysis [OR (95% CI) = 6.7 (1.1 - 40.9)]. CONCLUSION: PCC was an effective option for factor Xa inhibitor reversal following TBI. The relationship between radiographic expansion and clinical expansion was poor.


Assuntos
Lesões Encefálicas Traumáticas , Inibidores do Fator Xa , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Fator Xa , Estudos Retrospectivos , Fatores de Coagulação Sanguínea/uso terapêutico , Fatores de Coagulação Sanguínea/farmacologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/complicações , Hematoma/complicações , Anticoagulantes
18.
Acta Biochim Pol ; 70(4): 991-995, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-38011253

RESUMO

Previously, the direct interactions of Bß26-42 fibrin residues with prothrombin were demonstrated. It was also shown that forming prothrombin complexes with E- or DDE-fragments causes non-enzymatic prothrombin activation. The direct measuring of the prothrombin level in the blood plasma of patients with acute myocardial infarction (AMI) allowed us to find a situation where such an activation can occur in vivo. Blood coagulation parameters in the blood plasma of patients with AMI were measured at 2 hours, three days, and seven days after the thrombolysis by streptokinase accompanied with intravenous administration of anticoagulants: unfractionated high molecular weight heparin (HMWH) and low-molecular-weight heparin (LMWH). The prothrombin level in the blood plasma of patients with AMI was normal before thrombolytic therapy and substantially decreased after streptokinase administration. This effect was prominent in the case of concomitant anticoagulant therapy with LMWH and was not observed when HMWH was applied. It can be explained by the fact that LMWH preferentially inhibits factor Xa, while the HMWH is an effective inhibitor of both factor Xa and thrombin. This observation suggested that the prothrombin level decrease was caused by the thrombin-like activity and possible autolysis of prothrombin by thrombin. Also, thrombolytic therapy with streptokinase caused the accumulation of fibrin degradation products (FDPs), some of which were able to bind prothrombin. The dramatic decrease of prothrombin level in the blood plasma of patients with AMI during thrombolysis allowed us to conclude the non-enzymatic prothrombin activation with the following autolysis of prothrombin that contributes to the pathology.


Assuntos
Infarto do Miocárdio , Protrombina , Humanos , Protrombina/metabolismo , Protrombina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Trombina , Fator Xa/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Heparina/farmacologia , Heparina/uso terapêutico , Estreptoquinase/uso terapêutico , Estreptoquinase/farmacologia , Terapia Trombolítica , Anticoagulantes/uso terapêutico
19.
Sci Rep ; 13(1): 16488, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37779119

RESUMO

Platelet-stored activated blood coagulation factor X (FXa) has great potential in the gene therapy of hemophilia B (HB). However, we still need to understand more about the properties of FXa-storing platelets and how dietary factors affect them. We created transgenic mice called 2bFXa-HB, which had stable expression and storage of FXa in their platelets, resulting in the alleviation of the bleeding disorder in these mice. Even after inducing anti-factor IX (FIX) inhibitors in 2bFXa-HB mice, the hemorrhage phenotype could still be rescued by the expression of FXa. The activation capacity of 2bFXa-HB platelets remained unchanged, and there were no signs of elevated thrombotic risk in these mice. In an acute alcohol exposure mouse model, a single administration of alcohol reduced both the number of platelets and their activation capacity, as well as impaired coagulation function. However, it did not increase the markers of thrombotic risk in either 2bFXa-HB or HB mice. These results suggest that FXa storage in platelets is safe and effective for treatment of HB, but alcohol could impair the therapeutic effect of FXa-containing platelets.


Assuntos
Hemofilia B , Trombose , Camundongos , Animais , Hemofilia B/metabolismo , Plaquetas/metabolismo , Coagulação Sanguínea , Camundongos Transgênicos , Fator Xa/metabolismo , Trombose/metabolismo , Etanol/farmacologia , Etanol/metabolismo
20.
PeerJ ; 11: e16097, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37786576

RESUMO

Background: Factor Xa (FXa) not only plays an active role in the coagulation cascade but also exerts non-hemostatic signaling through the protease-activated receptors (PARs). This study aimed to investigate whether the FXa inhibitor, Rivaroxaban (RIV), attenuates adverse cardiac remodeling in rats with myocardial infarction (MI) and to identify the underlying molecular mechanisms it uses. Methods: An MI model was induced in eight-week-old, male Wistar rats, by permanent ligation of the left anterior descending coronary artery. MI rats were randomly assigned to receive RIV or protease-activated receptors 2-antagonist (PAR-2 antagonist, FSLLRY) treatment for four weeks. Histological staining, echocardiography and hemodynamics were used to assess the cardioprotective effects of RIV. Meanwhile, pharmacological approaches of agonist and inhibitor were used to observe the potential pathways in which RIV exerts antifibrotic effects in neonatal rat cardiac fibroblasts (CFs). In addition, real-time PCR and western blot analysis were performed to examine the associated signaling pathways. Results: RIV presented favorable protection of left ventricular (LV) cardiac function in MI rats by significantly reducing myocardial infarct size, ameliorating myocardial pathological damage and improving left ventricular (LV) remodeling. Similar improvements in the PAR-2 antagonist FSLLRY and RIV groups suggested that RIV protects against cardiac dysfunction in MI rats by ameliorating PAR-2 activation. Furthermore, an in vitro model of fibrosis was then generated by applying angiotensin II (Ang II) to neonatal rat cardiac fibroblasts (CFs). Consistent with the findings of the animal experiments, RIV and FSLLRY inhibited the expression of fibrosis markers and suppressed the intracellular upregulation of transforming growth factor ß1 (TGFß1), as well as its downstream Smad2/3 phosphorylation effectors in Ang II-induced fibrosis, and PAR-2 agonist peptide (PAR-2 AP) reversed the inhibition effect of RIV. Conclusions: Our findings demonstrate that RIV attenuates MI-induced cardiac remodeling and improves heart function, partly by inhibiting the activation of the PAR-2 and TGF-ß1 signaling pathways.


Assuntos
Infarto do Miocárdio , Rivaroxabana , Ratos , Animais , Masculino , Rivaroxabana/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Fator Xa/metabolismo , Remodelação Ventricular , Ratos Wistar , Transdução de Sinais , Infarto do Miocárdio/tratamento farmacológico , Fibrose , Receptores Ativados por Proteinase
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...