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1.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232517

RESUMO

Current guidelines recommend monitoring the anticoagulant effect of unfractionated heparin (UFH) by measuring anti-Xa activity rather than activated partial thromboplastin time (aPTT) in intensive care unit (ICU) patients. The primary objective of this study was to evaluate the correlation of aPTT, anti-Xa activity, and thrombin generation in UFH-treated ICU patients. A prospective observational pilot study was conducted in adult surgical ICU patients treated with UFH. aPTT and anti-Xa activity were monitored daily. The therapeutic target was aPTT between 50 s and 84 s, and/or anti-Xa between 0.3 and 0.7 U/mL. Correlation among aPTT, anti-Xa activity, and thrombin generation was determined by measuring endogenous thrombin potential (ETP), with the inflammatory response evaluated. C-reactive protein (CRP) was used as a marker of inflammatory response. The plasma of 107 samples from 30 ICU patients was analyzed. The correlation between aPTT and anti-Xa activity was 0.66, CI95% [0.54;0.76] (p < 0.0001). Although thrombin generation, aPTT, and anti-Xa were correlated with inflammatory responses, the correlation was higher with thrombin generation and anti-Xa activity compared to aPTT. When aPTT was in a therapeutic range, a low thrombin generation was observed but was 50% inhibited when anti-Xa was in a therapeutic range. Coagulation testing with aPTT, anti-Xa correlated with thrombin generation. A 50% decrease in thrombin generation was observed when anti-Xa was within a therapeutic range. Further work is needed to evaluate coagulation biomarker responses and clinical outcomes in specific ICU populations.


Assuntos
Heparina , Trombina , Adulto , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Biomarcadores , Proteína C-Reativa , Monitoramento de Medicamentos , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Heparina/farmacologia , Heparina de Baixo Peso Molecular , Humanos , Unidades de Terapia Intensiva , Tempo de Tromboplastina Parcial , Estudos Prospectivos
2.
Biopharm Drug Dispos ; 43(5): 192-200, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36195699

RESUMO

It was reported that high-dose cyclosporine at 500 mg daily increases edoxaban exposure. We investigated whether cyclosporine <500 mg daily leads to edoxaban-induced bleeding in the clinical setting. This case series study included patients receiving edoxaban and cyclosporine at Mie University Hospital. The outcomes were bleeding and anticoagulant markers, including activated partial thromboplastin time (APTT), prothrombin time (PT), and the international normalized ratio of prothrombin time (PT-INR). We examined the genotypes of cytochrome P450 3A5 (CYP3A5), multidrug resistance 1 (ABCB1), and solute carrier organic anion transporter 1B1 (SLCO1B1). Trends in anticoagulant markers were analyzed. Thirteen patients received edoxaban (standard dose; n = 3 and reduced dose; n = 10) and cyclosporine (1.94 ± 1.42 mg/kg). A bleeding event occurred in one patient receiving a standard dose of edoxaban plus cyclosporine of 25 mg daily (HAS-BLED score of 2 and genotypes; CYP3A5*3/*3, ABCB1 3435CT, and SLCO1B1*1a/*1b). After edoxaban treatment, anticoagulant markers were prolonged (APTT; 27.95 ± 3.64 s vs. 31.11 ± 3.90 s, p < 0.001, PT; 11.53 ± 1.01 s vs. 13.03 ± 0.98 s, p = 0.002, PT-INR; 0.98 ± 0.09 vs. 1.11 ± 0.11, p = 0.007). In summary, the genotypes of CYP3A5, ABCB1, and SLCO1B1 and the dosage of edoxaban may affect the risk of bleeding by edoxaban when co-administered with cyclosporine, even at low doses.


Assuntos
Citocromo P-450 CYP3A , Inibidores do Fator Xa , Humanos , Citocromo P-450 CYP3A/genética , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Ciclosporina/efeitos adversos , Anticoagulantes/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado
3.
Semin Thromb Hemost ; 48(7): 808-813, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36174600

RESUMO

There are situations where monitoring direct oral anticoagulants (DOACs) would be useful, including bleedings and trauma. The thromboelastographic technique has proven useful in bleeding situations in trauma and heart surgery. The aim of this study was to examine the effect of DOACs on all currently commercially available conventional TEG®5000 assays as well as novel modified assay using Ecarin and human factor Xa (HFXa). Healthy male volunteers were given single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg. Kaolin, RapidTEG, functional fibrinogen, PlateletMapping assay, and novel modified assays using Ecarin and HFXa were prepared. All TEG parameters were recorded. DOAC concentrations were correlated to the parameters with highest response to the DOAC effect. Sensitivity and negative predictive value of the parameter with highest response to DOAC concentration of 50 ng/mL was calculated. None of the conventional TEG assays demonstrated significant response to the effect on apixaban. Using Ecarin, reaction time R was strongly correlated with dabigatran concentrations. Using HFXa assay, R was strongly correlated with rivaroxaban and apixaban concentrations: r = 0.96, 0.84, and 0.86, respectively; p < 0.0001 for all. The R times obtained with the modified assays demonstrated strong sensitivity and negative predictive values for DOAC levels of ≥50 ng/mL. We have demonstrated that TEG®5000 can monitor the DOAC effect on hemostasis when the appropriate activator is used with significant correlation with DOAC concentrations. Larger clinical studies are warranted for correlation of TEG profile and clinical outcomes.


Assuntos
Dabigatrana , Rivaroxabana , Masculino , Humanos , Rivaroxabana/farmacologia , Rivaroxabana/uso terapêutico , Tromboelastografia/métodos , Fator Xa , Antitrombinas/uso terapêutico , Caulim , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Hemorragia/tratamento farmacológico , Fibrinogênio , Administração Oral , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico
4.
Biomater Adv ; 139: 213012, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35882156

RESUMO

Blood purification therapy is widely used in the treatment of critically ill patients. However, most dialysis membranes are prone to thrombosis. Activated coagulation factor X (FXa) functions at the intersection of intrinsic, extrinsic, and common coagulation pathways and plays a central role in thrombogenesis. To date, few dialysis membranes that directly inhibit FXa have been reported. We modified a polyethersulfone(PES) membrane using apixaban as an FXa inhibitor and investigated the performance of this membrane (AMPES). The contact angle of the modified membrane was reduced. PWF and retention rates of BSA were increased, demonstrating good hydrophilicity and dialysis performance. Albumin adsorption was reduced from 141.8 ± 15.5 to 114.1 ± 6.9 µg cm-2. Reduced protein adsorption, especially targeted anti-FXa effect, inhibited the activation of intrinsic, extrinsic, and common coagulation pathways, as evidenced by significant prolongations of activated partial thromboplastin time, prothrombin time, and thrombin time by 145.04, 46.84 and 11.46 s, respectively. Furthermore, we determined the FXa concentration of each group, and found that the modified membrane had better anticoagulant performance through the inhibition of FXa. Favorable antiplatelet activity was also demonstrated. Thromboelastogram was used to comprehensively evaluate the anticoagulant and antithrombotic activities of the modified membrane. The R value was increased by 43.1 min, while the reduction in α angle was 42.5°. The coagulation comprehensive index reduction was 34.3. In addition, C3a and C5a were decreased by 15.3 % and 30.4 %, respectively. Furthermore, in vitro cytotoxicity and erythrocyte stability testing as well as in vivo murine experiments demonstrated the biosafety of the modified membrane. These results indicate that the AMPES dialysis membrane has an excellent potential for clinical applications.


Assuntos
Inibidores do Fator Xa , Membranas Artificiais , Polímeros , Diálise Renal , Sulfonas , Trombose , Animais , Anticoagulantes/farmacologia , Antitrombina III , Fator Xa/metabolismo , Inibidores do Fator Xa/farmacologia , Fibrinolíticos/farmacologia , Humanos , Camundongos , Pirazóis , Piridonas , Diálise Renal/instrumentação , Trombose/tratamento farmacológico
5.
Pharmacol Res Perspect ; 10(3): e00963, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35680619

RESUMO

Apixaban is a factor Xa (FXa) inhibitor and standard-of-care anticoagulant with FXa Ki and plasma protein binding (free fraction) averages 0.08 nM and 0.13 in humans and 0.16 nM and 0.37 in rabbits, respectively. Apixaban at the approved dose of 5 mg BID achieved maximum and minimum plasma concentration of 373 nM (95% CI: 198 - 699 nM) and 224 nM (95% CI 89-501 nM), respectively, in patients with nonvalvular atrial fibrillation (AF). We calibrated the rabbit model of electrolytic-mediated arterial thrombosis (ECAT) against apixaban and correlated the potencies derived from the rabbit ECAT to in vivo efficacious exposure levels in AF patients. Vehicle and apixaban at multiple doses were infused IV in ECAT rabbits and their effects on thrombus weight were measured. Apixaban exhibited dose-related efficacy in preventing thrombosis in ECAT rabbits with EC20 , EC50 , EC60 , EC70 and EC80 of 18, 101, 169, 296, and 585 nM, respectively. After correcting for the human-to-rabbit potency based on FXa Ki and plasma protein binding, we estimated a rabbit-equally-effective plasma concentration of 157 and 259 nM to the trough and peak plasma concentration in AF patients treated with 5 mg BID of apixaban. These rabbit-equally-effective plasma concentrations matched well with the rabbit ECAT EC60 and EC70 . This study supports the potential of the rabbit ECAT to predict in vivo therapeutic drug exposure of FXa inhibitors. Achieving human-equally-effective plasma concentrations to the rabbit ECAT EC60 and EC70  may produce clinical efficacy in patient populations like AF.


Assuntos
Anticoagulantes , Trombose , Animais , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Calibragem , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Humanos , Pirazóis , Piridonas , Coelhos , Trombose/tratamento farmacológico , Trombose/prevenção & controle
7.
Eur J Med Chem ; 238: 114437, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35635944

RESUMO

A rational structure-based approach was employed to develop novel 3-amidinophenylalanine-derived matriptase inhibitors with improved selectivity against thrombin and factor Xa. Of all 23 new derivatives, several monobasic inhibitors exhibit high matriptase affinities and strong selectivity against thrombin. Some inhibitors also possess selectivity against factor Xa, although less pronounced as found for thrombin. A crystal structure of a selective monobasic matriptase inhibitor in complex with matriptase and three crystal structures of related compounds in trypsin and thrombin have been determined. The structures offer an explanation for the different selectivity profiles of these inhibitors and contribute to a more detailed understanding of the observed structure-activity relationship. Selected compounds were tested in vitro against a matriptase-dependent H9N2 influenza virus strain and demonstrated a concentration-dependent inhibition of virus replication in MDCK(II) cells.


Assuntos
Fator Xa , Vírus da Influenza A Subtipo H9N2 , Fenilalanina/química , Fator Xa/metabolismo , Inibidores do Fator Xa/farmacologia , Vírus da Influenza A Subtipo H9N2/metabolismo , Serina Endopeptidases , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacologia , Relação Estrutura-Atividade , Trombina
8.
Pest Manag Sci ; 78(8): 3433-3441, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35545958

RESUMO

BACKGROUND: Mosquito control is still the main prevention and control measure for numerous mosquito-borne diseases causing millions of deaths each year. New strategies for mosquito control are in demand. Proteases play an important role in mosquito physiology, therefore this study explored the inhibition of a serpin (serine protease inhibitor) in mosquitoes and its effect on reproductive capacity. RESULTS: A factor Xa inhibitor homolog (named Pipiserpin) was amplified and identified in Culex pipiens pallens mosquitoes. We expressed a recombinant Pipiserpin protein in vitro against which a mouse antiserum was generated. We found that female mosquitoes expressed more Pipiserpin protein than male mosquitoes. After mating, female mosquitoes were fed with blood mixed with different amounts of antisera and results showed that consumption of Pipiserpin impeded ovary development and decreased eggs hatching rates compared to that of the pre-immune serum group. CONCLUSION: We identified a Culex mosquito factor Xa inhibitor, Pipiserpin, which affects female reproductive potential. Our results suggest that Pipiserpin may be a novel target for mosquito population control. The conclusions from our study on Cx. pipiens pallens might serve as a reference for the development of control measures for other mosquitoes as well. © 2022 Society of Chemical Industry.


Assuntos
Culex , Animais , Inibidores do Fator Xa/farmacologia , Feminino , Masculino , Camundongos , Controle de Mosquitos
9.
J Clin Pharm Ther ; 47(8): 1284-1292, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35504629

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Although predictable pharmacokinetic and pharmacodynamic of rivaroxaban allow fixed dosing regimens without routine coagulation monitoring, there is still the necessity to monitor and predict the effects of rivaroxaban in specific conditions and different populations. The current study was designed and conducted to analyze the rivaroxaban population pharmacokinetics in Iranian patients and establish a pharmacokinetic/pharmacodynamic model to predict the relationship between rivaroxaban concentration and its anticoagulant activity. METHODS: A sequential nonlinear mixed effect pharmacokinetic/pharmacodynamic modeling method was used to establish the relation between rivaroxaban concentration and anti-factor Xa activity, prothrombin time, and activated partial thromboplastin time (aPTT) as pharmacodynamic biomarkers in a population of sixty-nine Iranian patients under treatment with oral rivaroxaban. Rivaroxaban plasma concentration was quantified by a validated high-performance liquid chromatography-tandem mass spectrometry. RESULTS AND DISCUSSION: The typical population values (inter-individual variability%) of the oral volume of distribution and clearance for a one-compartment model were 61.2 L (21%) and 3.68 L·h-1 (61%), respectively. Creatinine clearance and Child-Turcotte-Pugh score were found to affect the clearance. A direct link linear structural model best fitted the data for both prothrombin time and aPTT. The baseline estimates of aPTT and prothrombin time in the population were 35.0 (15%) and 12.6 (2%) seconds, respectively. The slope of the relationship between apTT, prothrombin time, and rivaroxaban concentration was 0.033 (28%) and 0.018 (54%) s·ml·ng-1 , respectively. The selected model for anti-factor Xa activity consisted of a direct link inhibitory Emax model with Hill coefficient. The maximum level of inhibition (Emax ) was 4 IU·ml-1 . The concentration of rivaroxaban producing 50% of the maximum inhibitory effect (EC50 ) was 180 (24%) ng·ml-1 , and Hill coefficient (γ) was 1.44 (108%). No covariates showed a statistically significant effect on PT and activated partial thromboplastin time prolonging properties and anti-factor Xa activity. WHAT IS NEW AND CONCLUSION: Our results confirmed that pharmacokinetic/pharmacodynamic models similar to those of the other studies describe the relationship between the rivaroxaban concentration and its anticoagulant effect in Iranian patients. However, considerable differences were observed in the parameters of the pharmacodynamics-pharmacokinetic models with the results of other reports that can explain the unpredictable effects of rivaroxaban in some patients.


Assuntos
Inibidores do Fator Xa , Rivaroxabana , Anticoagulantes/farmacologia , Inibidores do Fator Xa/farmacologia , Humanos , Irã (Geográfico) , Morfolinas/farmacocinética , Tempo de Tromboplastina Parcial , Rivaroxabana/farmacologia , Tiofenos/farmacocinética
10.
Int J Lab Hematol ; 44(4): 785-795, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35438827

RESUMO

INTRODUCTION: Global coagulation assays may be of added value to the anti-Xa assay for monitoring heparin therapy. Unlike most testing methods, the thrombin generation assay (TGA) has the ability to assess the overall function of the hemostatic system, which provides information on the anticoagulation status of patients. We compared the TGA, measured with ST Genesia® STG-DrugScreen® reagent, with the anti-Xa assay for monitoring heparin therapy in inflammatory and non-inflammatory patients. We also determined reference values for STG-DrugScreen® thrombin generation (TG) parameters. METHODS: Reference values were determined on 120 healthy donors. Furthermore, a spiking experiment with unfractionated heparin (UFH) and low molecular weight heparin (LMWH) was performed, and samples of patients receiving UFH or LMWH were analyzed with ST Genesia® and the anti-Xa assay. RESULTS: High discrepancy between TG parameters and anti-Xa activity was observed for low LMWH anti-Xa levels. TG parameters were affected in 36/46 (time to peak) to 42/46 (peak height) patients during UFH therapy with sub-target anti-Xa activity levels. CONCLUSION: TGA seems insufficiently sensitive for low concentrations of LMWH. There may be an added value of the TGA for monitoring UFH in so-called heparin-resistant patients. Therefore, the TGA has the potential to be introduced as an additional tool for monitoring heparin therapy.


Assuntos
Heparina de Baixo Peso Molecular , Heparina , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Testes de Coagulação Sanguínea , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Heparina/efeitos adversos , Heparina de Baixo Peso Molecular/farmacologia , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Trombina
12.
Biochem Biophys Res Commun ; 603: 138-143, 2022 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-35287055

RESUMO

Schistosoma japonicum is a parasitic worm that lives in the mesenteric vein of its host and feeds on blood, suggesting that it might be a natural resource of novel anticoagulants. Here, by comprehensive analyses of the genomic sequences of Schistosoma japonicum, a new Kunitz-type gene precursor was identified. The Kunitz-type gene precursor codes for an 18-residue signal peptide and a 60-residue mature peptide. The Kunitz peptide was functionally expressed, and it had apparent inhibitory activity towards the intrinsic coagulation pathway but no effect on the extrinsic coagulation pathway even at the high concentration of 3 µM. Enzyme and inhibitor experiments further showed that the Kunitz domain peptide was a potent and selective FXa inhibitor, so it was named Schixator (Schistosoma FXa inhibitor). Schixator inhibits coagulation factor FXa with a Ki of 2.66 nM, but had weak inhibitory activity towards chymotrypsin, FXIa, plasma kallikrein, and plasmin, and no inhibitory activity towards trypsin, elastase, FIIa or FXIIa. In vivo, the intravenous administration of Schixator into mice dramatically decreased the number of thrombi in the carotid artery in an FeCl3-induced thrombus formation model without producing bleeding complications. To the best of our knowledge, Schixator is the first potent and selective FXa inhibitor from parasitic worms with antithrombotic effects and a low bleeding risk that provides a new clue for lead drug discovery against thrombosis-associated human diseases.


Assuntos
Schistosoma japonicum , Trombose , Animais , Anticoagulantes/farmacologia , Coagulação Sanguínea , Inibidores do Fator Xa/farmacologia , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Hemorragia , Camundongos , Trombose/tratamento farmacológico
13.
Physiol Rep ; 10(5): e15218, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35262272

RESUMO

Chronic kidney disease (CKD) is an increasing and life-threatening disease worldwide. Recent evidence indicates that blood coagulation factors promote renal dysfunction in CKD patients. Activated factor X (FXa) inhibitors are safe and first-line drugs for the prevention of thrombosis in patients with atrial fibrillation. Here, we investigated the therapeutic effects of edoxaban on CKD using the mouse 5/6 nephrectomy model. Eight-week-old wild-type mice were subjected to 5/6 nephrectomy surgery and randomly assigned to two groups, edoxaban or vehicle admixture diet. Edoxaban treatment led to reduction of urinary albumin excretion and plasma UN levels compared with vehicle group, which was accompanied with reduced glomerular cross-sectional area and cell number. Edoxaban treatment also attenuated fibrinogen positive area in the remnant kidneys after subtotal nephrectomy. Moreover, edoxaban treatment resulted in attenuated tubulointerstitial fibrosis after 5/6 nephrectomy, which was accompanied by reduced expression levels of epithelial-mesenchymal transition (EMT) markers, inflammatory mediators, and oxidative stress markers in the remnant kidneys. Treatment of cultured proximal tubular cells, HK-2 cells, with FXa protein led to increased expression levels of EMT markers, inflammatory mediators, and oxidative stress markers, which were abolished by pretreatment with edoxaban. Treatment of HK-2 cells with edoxaban attenuated FXa-stimulated phosphorylation levels of extracellular signal-regulated kinase (ERK) and NF-κB. Our findings indicate that edoxaban can improve renal injury after subtotal nephrectomy by reducing EMT and inflammatory response, suggesting that FXa inhibition could be a novel therapeutic target for CKD patients with atrial fibrillation.


Assuntos
Fibrilação Atrial , Insuficiência Renal Crônica , Animais , Fibrilação Atrial/patologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Fibrose , Humanos , Mediadores da Inflamação/farmacologia , Rim , Camundongos , Nefrectomia/efeitos adversos , Piridinas , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Tiazóis
14.
J Ethnopharmacol ; 287: 114964, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-34990765

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The cardiovascular and cerebrovascular diseases affect human health globally. Naoxintong capsules (NXTs), a famous Chinese Patent Medicine, has been especially applied to treat cerebral infarction and coronary heart disease in clinical practice. The anticoagulant activity of this prescription plays an important role in this course of treatment. AIM OF THE STUDY: Thrombin and factor Xa (FXa) are two key targets considering the anticoagulant activity. The purpose of this investigation is to screen the quanlity markers as key thrombin and FXa inhibitors for the anticoagulant activity oriented quality control of Chinese patent medicine. MATERIALS AND METHODS: Simple multi-polar solvent extraction processes using various proportions of solvents were conducted and their thrombin/FXa inhibitory activities were evaluated in vitro. Bivariate correlation analysis (BCA), grey correlation analysis (GCA), and orthogonal partial least squares discriminate analysis (OPLS-DA) were adopted for screening the potential active markers related to the anticoagulant activity. The chemical structures of these active compounds were identified by UHPLC-Q-TOF-MS/MS and their thrombin/FXa inhibitory activity was determined. The molecular docking technology was applied to explore the interaction between the compounds and targets. The contribution of these anticoagulant active ingredients in NXT was also investigated. Last but not the least, the contents of these markers in NXT were determined by liquid chromatography-electrospray ionization tandem triple quadrupole mass spectrometry (HPLC-ESI-MS/MS) method. RESULTS: The results showed that the NXT extract exhibited great activity against thrombin and FXa, especially extracted by 75% methanol (v/v). Six marker compounds with potential anticoagulant activity were screened out. Therein, four of the active compounds owing thrombin inhibitory activity (paeoniflorin, lithospermic acid, salvianolic acid B, Z-ligustilide) and five of the active compounds owing FXa inhibitory activity (3,5-dicaffeoylquinic acid, rosmarinic acid, lithospermic acid, salvianolic acid B and Z-ligustilide). In addition, these active compounds accounted for a large proportion of thrombin/FXa inhibitory activity of NXTs. The binding energy also showed the strong interaction formed by close connection of the compounds to the residues of targets. CONCLUSIONS: The proposed integrated stategy could be an efficient strategy to screen potential thrombin/FXa inhibitors for the bioactivity related quanlity control of Chinese patent medicine.


Assuntos
Anticoagulantes/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Inibidores do Fator Xa/farmacologia , Trombina/antagonistas & inibidores , Animais , Anticoagulantes/química , Bovinos , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Inibidores do Fator Xa/química , Simulação de Acoplamento Molecular , Controle de Qualidade , Espectrometria de Massas em Tandem
15.
Am J Cardiol ; 162: 80-85, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34756422

RESUMO

Direct oral anticoagulants (DOACs) can potentially interact with multiple prescription medications. We examined the prevalence of co-prescription of DOACs with interacting medications and its impact on outcomes in patients with atrial fibrillation (AF). Patients with AF treated with a DOAC from 2010 to 2017 at the Mayo Clinic and co-prescribed medications that are inhibitors or inducers of the P-glycoprotein and/or Cytochrome P450 3A4 pathways were identified. The outcomes of stroke, transient ischemic attack, or systemic embolism, major bleeding, and minor bleeds were compared between patients with and without an enzyme inducer. Cox proportional hazards model was used to assess the association between interacting medications and outcomes. Of 8,576 patients with AF (mean age 70 ± 12 years, 35% female) prescribed a DOAC (38.6% apixaban, 35.8% rivaroxaban, 25.6% dabigatran), 2,610 (30.4%) were on at least 1 interacting agent: the majority were on an enzyme inhibitor (n = 2,592). Prescribed medications included non-dihydropyridine calcium channel blocker (n = 1,412; 16.5%), antiarrhythmic medication (n = 790; 9.2%), antidepressant (n = 659; 7.7%), antibiotic/antifungal (n = 77; 0.90%), antiepileptics (n = 17; 0.2%) and immunosuppressant medications (n = 19; 0.2%). Patients on an interacting medication were more likely to receive a lower dose of DOAC than indicated by the manufacturer's labeling (15.0% vs 11.4%, p <0.0001). In multivariable analysis, co-prescription of an enzyme inhibitor was not associated with risk of any bleeding (hazard ratio 0.87 [0.71 to 1.05], p = 0.15) or stroke, transient ischemic attack, or systemic embolism (hazard ratio 0.82 [0.51 to 1.31], p = 0.39). In conclusion, DOACs are co-prescribed with medications with potential interactions in 30.4% of patients with AF. Co-prescription of DOACs and these drugs are not associated with increased risk of adverse embolic or bleeding outcomes in our cohort.


Assuntos
Fibrilação Atrial/complicações , Embolia/epidemiologia , Inibidores do Fator Xa/uso terapêutico , Hemorragia/epidemiologia , Polimedicação , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Interações Medicamentosas , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica , Modelos de Riscos Proporcionais , Acidente Vascular Cerebral/etiologia
16.
Naunyn Schmiedebergs Arch Pharmacol ; 395(2): 159-166, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34851448

RESUMO

Apixaban is used to treat venous thromboembolism (VTE) at 10 mg twice daily (BID) for 7 days, followed by 5 mg BID without dose adjustment, and non-valvular atrial fibrillation (NVAF) at 5 mg BID or 2.5 mg BID with dose adjustment criteria (DAC) including age, body weight, and renal function. The anti-factor Xa activity (AXA), prothrombin time (PT), and activated partial thromboplastin time (APTT) in patients with VTE receiving 10 mg BID of apixaban remains unclear. Twenty-six patients (70.8±15.4 years, 10 males) with VTE receiving 10 mg BID of apixaban were enrolled. The patients were divided into two groups based on whether they met the DAC of NVAF: DAC group (n=8) and non-DAC group (n=18). Trough and peak AXA values, PT, and APTT were measured at 10 mg BID dosage and then at 5 mg BID dosage. Coagulation markers in recipients of 10 mg BID therapy were significantly higher than those of 5 mg BID recipients. A significant and strong positive correlation was observed between AXA and PT at trough and peak times. The AXA values and PT in the DAC group were significantly higher than those in the non-DAC group. No significant inter-group differences were seen in APTT. This study provides the first report of AXA distribution in VTE patients receiving 10 mg BID of apixaban. Our findings indicate that coagulation markers may differ in patients with VTE-prescribed higher doses of apixaban and a DAC may be warranted in such patients.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Tromboembolia Venosa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Coagulação Sanguínea/efeitos dos fármacos , Fator Xa/metabolismo , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Pirazóis/farmacologia , Piridonas/farmacologia
17.
J Atheroscler Thromb ; 29(7): 1059-1068, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34334529

RESUMO

AIMS: Measurement of protein S (PS) activity in patients taking direct oral anticoagulants (DOACs) using reagents based on a clotting assay results in falsely high PS activity, thus masking inherited PS deficiency, which is most frequently seen in the Japanese population. In this study, we investigated the effect of factor Xa (FXa) inhibitors on PS activity using the reagent on the basis of the chromogenic assay, which was recently developed in Japan. METHODS: The study enrolled 152 patients (82 males and 70 females; the average age: 68.5±14.0 years) receiving three FXa inhibitors (rivaroxaban, edoxaban, and apixaban). PS activity was measured using the reagents on the basis of the clotting and chromogenic assays. RESULTS: PS activity measured by the clotting assay reagents exhibited falsely high values depending on the plasma concentrations of FXa inhibitors in patients taking either rivaroxaban or edoxaban. However, none of the three FXa inhibitors affected PS activity when measured using the chromogenic assay. CONCLUSION: In patients taking rivaroxaban or edoxaban, inherited PS deficiency is likely missed because the levels of PS activity measured using the reagents based on the clotting assay are falsely high. However, we report that three FXa inhibitors do not affect PS activity measured by the chromogenic assay. When measuring the levels of PS activity in patients undergoing DOACs, the principles of each reagent should be understood. Furthermore, plasma samples must be collected at the time when plasma concentrations of DOACs are lowest or the DOAC-Stop reagent should be used.


Assuntos
Inibidores do Fator Xa , Proteína S/análise , Rivaroxabana , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/farmacologia , Coagulação Sanguínea , Fator Xa/farmacologia , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rivaroxabana/farmacologia , Rivaroxabana/uso terapêutico , Trombofilia
18.
Eur J Clin Pharmacol ; 78(1): 89-98, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34414464

RESUMO

PURPOSE: Data on the anti-Xa efficacy of fondaparinux in dialysis-dependent chronic kidney disease (DD-CKD) patients are scarce. This study characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of fondaparinux in DD-CKD patients undergoing renal replacement therapy (RRT), to assess dosing strategies. METHODS: A retrospective, observational study was conducted using data on anti-Xa activity (112 samples) from 12 (3 male and 9 female) DD-CKD patients (median (IQR) age 71 years (63-88), weight 73 kg (59-98.5)). Eleven patients underwent high-flux or low-flux hemodialysis (HD) and one patient underwent peritoneal dialysis. Three patients were also treated with therapeutic plasma exchange (TPE). A non-linear mixed effects analysis was performed using NONMEM 7.3.0. RESULTS: The lab-specific slope of the relationship between fondaparinux concentration and anti-Xa levels was 1.18 IU/µg. In a one-compartment model, clearance (CL) and volume of distribution (Vd) were 0.05289 L/h and 5.55 L, respectively. High-flux HD was found to increase the CL of fondaparinux 2.26 times. TPE also considerably increased CL, but the fold-change could not be accurately estimated. Low-flux HD and peritoneal dialysis did not impact PK parameters. CONCLUSIONS: Model-based simulations showed that standard dosing (2.5 mg three times weekly before HD) results in a median anti-Xa activity of 0.55 IU/mL and 0.98 IU/mL, pre- and post-low-flux HD, respectively. In patients undergoing high-flux HD, these values are approximately 27% lower. Additional caution is warranted with TPE, as this treatment can reduce anti-Xa activity even further.


Assuntos
Inibidores do Fator Xa/farmacocinética , Fondaparinux/farmacocinética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia , Terapia de Substituição Renal , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Peso Corporal , Inibidores do Fator Xa/farmacologia , Feminino , Fondaparinux/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
20.
Clin Appl Thromb Hemost ; 28: 10760296221083667, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35275493

RESUMO

DOAC Dipstick determines specifically the presence and absence of direct oral anticoagulants (DOACs) from patients' urine samples and handmade test strips performed as well as the commercial version. To compare plasma activity (chromogenic substrate assays) from plasma samples with results from urine samples (DOAC test strips) of patients treated with heparin, low-molecular weight heparin (LMWH) and without anticoagulation. Plasma anti-factor Xa (aXa) activity was determined by Coamatic chromogenic substrate assay and compared to the presence of anticoagulants in urine by DOAC test strips. Patients were treated for least 5 days and samples were taken 4 hrs after administration in comparison to no treatment with an anticoagulant (n = 42). A total of 100 patients were included treated with heparin (n = 29), LMWH nadroparin (n = 29) or no anticoagulants (n = 42). Plasma aXa levels of patients treated with heparin (2 × 7.500 IU daily subcutaneously, 12 male, age 67.4 ± 11.5 years) were 0,18 IU/ml ± 0,15 IU/ml (mean, standard deviation), with LMWH (1 × 3000 IU daily subcutaneously, 15 male, age 64.2 ± 14.1 years) 0,17 IU/ml ± 0,16 IU/l, and with no anticoagulants (28 male, age 64.2 ± 15.6 years) 0,02 IU/ml ± 0.01 IU/ml. All factor Xa and thrombin inhibitor pad results of test strips were negative. We conclude that DOAC Dipstick has a high probability of not detecting heparin and LMWH in patients on treatment as well as in urine samples of patients not treated with an anticoagulant.


Assuntos
Heparina de Baixo Peso Molecular , Heparina , Administração Oral , Idoso , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Heparina/farmacologia , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/farmacologia , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade
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