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1.
J Thromb Thrombolysis ; 49(3): 395-403, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31925664

RESUMO

Although DOACs do not require regular measurements of their blood concentrations, clinical situations may require an assessment of their concentration. Among the factor Xa inhibitors, edoxaban is the only compound for which some metabolites (e.g. edoxaban-M4) are reported to be pharmacologically active. Therefore, their contribution could interfere with assays used for the estimation of edoxaban concentration. In addition, drug interactions may alter the metabolite/parent compound ratio making the sole estimation of edoxaban concentration, a poor assessment of the overall anticoagulation. To develop a validated UHPLC-MS/MS method to quantify simultaneously edoxaban and its more relevant M4-metabolite in human plasma. Electrospray ionization and chromatographic separation were optimized for the simultaneous dosage of edoxaban and edoxaban-M4. The method was validated according to regulatory guidelines for bioanalytical method validation. The total run time was 6 min. The method was validated for calibration curves, precision, accuracy, carry-over, selectivity, matrix effect and short-time stability. This method permits quantification of edoxaban and edoxaban-M4 providing complementary information about the inhibitory effect of this active metabolite in chronometric or chromogenic assays. Although patients treated with edoxaban exhibits usually low concentrations of active metabolites, the measurement of edoxaban-M4 is interesting; especially in case of drug interactions. Indeed, concomitant prescriptions of edoxaban and carbamazepine or rifampicin is frequent and may lead to disturbance of the estimations of edoxaban concentration by chromogenic anti-Xa assays. Therefore, patients are at risk of having inadequate control of anticoagulation supporting the need of measuring the most representative edoxaban metabolite concomitantly to the parent compound.


Assuntos
Inibidores do Fator Xa/farmacocinética , Piridinas/farmacocinética , Espectrometria de Massas em Tandem , Tiazóis/farmacocinética , Cromatografia Líquida de Alta Pressão , Inibidores do Fator Xa/administração & dosagem , Humanos , Piridinas/administração & dosagem , Tiazóis/administração & dosagem
2.
Medicine (Baltimore) ; 98(27): e16164, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277120

RESUMO

Thrombosis are severe complications of paroxysmal nocturnal hemoglobinuria (PNH), effectively reduced by eculizumab. Extracellular vesicles (EVs) may play a central role. The objective of this study was to assess the procoagulant activity of plasma isolated from PNH patients (treated or not by eculizumab) and to quantify their circulating EVs.We iteratively collected the platelet-free-plasma of 17 PNH patients and 16 matched healthy volunteers, quantified their circulating EVs by flow cytometry and evaluated their procoagulant activity by thrombin generation and STA-Procoag-procoagulant phospholipid (PPL) assays.A significant decrease of EVs from platelets (P = .024) and an increase of the STA-Procoag-PPL clotting time (P = .049) was observed after initiation of eculizumab and up to 11 weeks after. This reduction of prothrombotic biomarkers was not observed with the thrombin generation test due to a lack of sensitivity of this assay. Active hemolysis was observed in 90% of patients and elevated D-dimers in 41% of them. However, no significant difference was observed between patients and control subjects regarding the procoagulant activity, the EVs quantity, or the cellular origin. Lactate dehydrogenase (LDH) levels were lower in eculizumab-treated patients compared to nontreated patients (441 vs 2448 IU/L). D-dimers and LDH decreased after administration of eculizumab (mean decrease of 1307 ng/mL and 4159 IU/L, respectively).These observations suggest a decrease of the phospholipid-dependent procoagulant potential of EVs after eculizumab therapy in PNH patients. TRIAL REGISTRATION:: NUB: B039201214365.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Hemoglobinúria Paroxística/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Estudos de Casos e Controles , Citometria de Fluxo , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/complicações , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Trombose/etiologia
3.
Nano Converg ; 5(1): 31, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30467733

RESUMO

Inorganic transition metal dichalcogenide nanostructures are interesting for several biomedical applications such as coating for medical devices (e.g. endodontic files, catheter stents) and reinforcement of scaffolds for tissue engineering. However, their impact on human blood is unknown. A unique nanomaterial surface-engineering chemical methodology was used to fabricate functional polyacidic polyCOOH inorganic nanotubes of tungsten disulfide towards covalent binding of any desired molecule/organic species via chemical activation/reactivity of this former polyCOOH shell. The impact of these nanotubes on hemolysis, platelet aggregation and blood coagulation has been assessed using spectrophotometric measurement, light transmission aggregometry and thrombin generation assays. The functionalized nanotubes do not induce hemolysis but decrease platelet aggregation and induce coagulation through intrinsic pathway activation. The functional nanotubes were found to be more thrombogenic than the non-functional ones, suggesting lower hemocompatibility and increased thrombotic risk with functionalized tungsten disulfide nanotubes. These functionalized nanotubes should be used with caution in blood-contacting devices.

4.
Nanomedicine (Lond) ; 13(2): 145-155, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29173016

RESUMO

AIM: To study the biopersistence of a silicon carbide (SiC) nanoaerosol in rat lungs, as time-dependent clearance and spatial distribution. MATERIALS & METHODS: Sprague-Dawley rats were exposed 6 h/day during 5 days to a SiC nanoaerosol at 4.91 mg SiC/l. SiC biopersistence in rat lungs sections was assessed over 28 days by micro-particle-induced x-ray emission (µPIXE) as 2D maps and by particle-induced x-ray emission (PIXE) for whole-lung quantification. 2D maps were analyzed for SiC spatial distribution as skewness and kurtosis. RESULTS: Half-time clearance was 10.9 ± 0.9 days, agreeing with PIXE measurements. Spatial-temporal analysis of SiC indicated decreased symmetry and homogeneity. CONCLUSION: Fast SiC clearance points that current nanoaerosol exposure may not be enough to trigger lung overload. Spatial distribution shows an asymmetric and nonhomogeneous SiC clearance.


Assuntos
Aerossóis/química , Compostos Inorgânicos de Carbono/química , Compostos Inorgânicos de Carbono/metabolismo , Nanoestruturas/química , Compostos de Silício/química , Compostos de Silício/metabolismo , Animais , Feminino , Pulmão/diagnóstico por imagem , Taxa de Depuração Metabólica , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Espectrometria por Raios X , Propriedades de Superfície , Distribuição Tecidual
5.
Blood Transfus ; 16(2): 163-172, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28287378

RESUMO

BACKGROUND: Thrombotic effects are possible complications of red blood cell transfusion. The generation and accumulation of procoagulant red blood cell extracellular vesicles during storage may play an important role in these thrombotic effects. The objective of this study was to assess the value of a simple phospholipid-dependent clot-based assay (STA®-Procoag-PPL) to estimate the procoagulant activity of stored red blood cells and changes in this activity during storage of the blood component. MATERIALS AND METHODS: Extracellular vesicles from 12 red blood cell concentrates were isolated at 13 storage time-points and characterised by quantitative and functional methods: the degree of haemolysis (direct spectrophotometry), the quantification and determination of cellular origin (flow cytometry) and the procoagulant activity (thrombin generation and STA®-Procoag-PPL assays) were assessed. RESULTS: The mean clotting time of extracellular vesicles isolated from red blood cell concentrates decreased from 117.2±3.6 sec on the day of collection to 33.8±1.3 sec at the end of the storage period. This illustrates the phospholipid-dependent procoagulant activity of these extracellular vesicles, as confirmed by thrombin generation. Results of the peak of thrombin and the STA®-Procoag-PPL were well correlated (partial r=-0.41. p<0.001). In parallel, an exponential increase of the number of red blood cell-derived extracellular vesicles from 1,779/µL to 218,451/µL was observed. DISCUSSION: The STA®-Procoag-PPL is a potentially useful technique for assessing the procoagulant activity of a red blood cell concentrate.


Assuntos
Coagulação Sanguínea , Preservação de Sangue , Eritrócitos/citologia , Eritrócitos/metabolismo , Vesículas Extracelulares/metabolismo , Adulto , Testes de Coagulação Sanguínea , Transfusão de Eritrócitos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/sangue , Trombose/etiologia , Fatores de Tempo , Reação Transfusional/sangue
6.
Nanotoxicology ; 8(2): 220-32, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23521718

RESUMO

The study of the haemocompatibility of nanomaterials that could be in contact with blood (e.g. nanoparticle (NP)-based drug-delivery system) is of major importance. The primary objective of this study was to compare the ability of six platelet functional tests to assess the impact of NPs on platelet function. The secondary objective was to determine an accurate and reliable screening test to measure the potential impact of NPs on primary haemostasis whatever their physicochemical properties. Four types of carbon NPs (carbon black, fullerenes, single-walled carbon nanotubes and multi-walled carbon nanotubes) were investigated on six platelet function tests: light transmission aggregometry, whole-blood impedance aggregometry, platelet function analyser-100 (PFA-100®) and Cone-and-Plate(let) analyser (Impact-R®), transmission- and field emission gun scanning electron microscopy (FEG-SEM). We considered that Impact-R® supported by FEG-SEM is the reference method to investigate the potential impact of NPs on platelet function.


Assuntos
Plaquetas/efeitos dos fármacos , Carbono/toxicidade , Nanoestruturas/toxicidade , Testes de Função Plaquetária/métodos , Testes de Toxicidade/métodos , Plaquetas/citologia , Plaquetas/metabolismo , Humanos
7.
Toxicol Rep ; 1: 172-187, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-28962237

RESUMO

BACKGROUND: Titanium carbide (TiC) is used for ceramic metal composites in several industries and is regarded as a nanomaterial for catalyst and battery applications. However, there are very few studies in regard to the toxicological potential of TiC nanoparticles (NPs). OBJECTIVE: To study the toxicodynamics and toxicokinetics of TiC NPs in Sprague Dawley rats in acute (24 h) and subacute (28 days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 1000 mg kg-1; the subacute doses were 0.5 and 50 mg kg-1. RESULTS: Organ histopathological examination (esophagus, stomach, intestines, spleen, liver, and kidneys) indicates the absence of damage at all applied doses, in both assessments. In the acute administration, alkaline phosphatases increased (5, 300 and 1000 mg kg-1), ASAT increased (1000 mg kg-1) and bile salts decreased (0.5 mg kg-1). No alterations in urine parameters (sodium, potassium, osmolarity) were found. Acute administration of TiC caused mineral changes in organs (liver, spleen, kidneys). TiC was mostly cleared by feces excretion 24 h after administration, in subacute administration causing variations in mineral absorption (Mg, Al, P, S, Ca, Zn). TiC could pass the intestinal barrier as TiC traces were detected in urine. CONCLUSION: No sign of toxicity was found after oral administration. TiC was excreted mostly in feces producing mineral absorption alterations. Low traces were retrieved in urine, indicating that TiC can cross the intestinal barrier.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30023015

RESUMO

Silver nanoparticles (Ag NPs) are increasingly used in biomedical applications because of their large antimicrobial spectrum. Data in the literature on the ability of Ag NPs to perform their desired function without eliciting undesirable effects on blood elements are very limited and contradictory. We studied the impact of Ag NPs on erythrocyte integrity, platelet function and blood coagulation. Erythrocyte integrity was assessed by spectrophotometric measurement of haemoglobin release. Platelet adhesion and aggregation was determined by light transmission aggregometry and scanning electron microscopy. The calibrated thrombin generation test was used to study the impact on coagulation cascade. We demonstrated that Ag NPs induced haemolysis. They also increase platelet adhesion without having any impact on platelet aggregation. Finally, they also had procoagulant potential. Bringing all data from these tests together, the no observed effect concentration is 5 µg/mL.

9.
Eur J Med Chem ; 65: 32-40, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23688698

RESUMO

New series of original 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas were synthesized and evaluated as thromboxane A2 receptor (TP receptor) antagonists. A functional pharmacological test was used, which consisted of measuring the inhibition of intracellular calcium mobilization in a model of mammalian cell line that specifically over-expressed the individual TPα or TPß isoforms. 2-Arylamino-5-cyanobenzenesulfonylureas exhibited virtually identical affinity and/or functional activity than 2-aryloxy-5-cyanobenzenesulfonylureas for both TPα and TPß, but some 2-aryloxy-substituted compounds showed increased selectivity for TPß relative to TPα. Several compounds were found to be as potent as the 2-arylamino-5-nitrobenzenesulfonylurea reference compound BM-573, supporting the view that the bioisosteric replacement of the nitro group by a cyano group was tolerated. TP receptor antagonist activity of the most promising molecules was confirmed in a platelet aggregation assay using the TP receptor agonist U-46619 as a proaggregant. Three compounds (7e, 7h and 8h) were identified as leads for further non-clinical pharmacological and toxicological studies.


Assuntos
Nitrilas/farmacologia , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/farmacologia , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Compostos de Sulfonilureia/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Relação Estrutura-Atividade , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/química
10.
Toxicol Appl Pharmacol ; 264(2): 232-45, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22981607

RESUMO

BACKGROUND: Silicon carbide (SiC) presents noteworthy properties as a material such as high hardness, thermal stability, and photoluminescent properties as a nanocrystal. However, there are very few studies in regard to the toxicological potential of SiC NPs. OBJECTIVES: To study the toxicity and biodistribution of silicon carbide (SiC) nanoparticles in an in vivo rat model after acute (24h) and subacute (28days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 600mg·kg(-1), while the subacute doses were 0.5 and 50mg·kg(-1). RESULTS: SiC biodistribution and elemental composition of feces and organs (liver, kidneys, and spleen) have been studied by Particle-Induced X-ray Emission (PIXE). SiC and other elements in feces excretion increased by the end of the subacute assessment. SiC did not accumulate in organs but some elemental composition modifications were observed after the acute assessment. Histopathological sections from organs (stomach, intestines, liver, and kidneys) indicate the absence of damage at all applied doses, in both assessments. A decrease in the concentration of urea in blood was found in the 50mg·kg(-1) group from the subacute assessment. No alterations in the urine parameters (sodium, potassium, osmolarity) were found. CONCLUSION: This is the first study that assesses the toxicity, biodistribution, and composition changes in feces and organs of SiC nanoparticles in an in vivo rat model. SiC was excreted mostly in feces and low traces were retrieved in urine, indicating that SiC can cross the intestinal barrier. No sign of toxicity was however found after oral administration.


Assuntos
Materiais Biocompatíveis/farmacocinética , Materiais Biocompatíveis/toxicidade , Compostos Inorgânicos de Carbono/farmacocinética , Compostos Inorgânicos de Carbono/toxicidade , Fezes/química , Nanopartículas/toxicidade , Compostos de Silício/farmacocinética , Compostos de Silício/toxicidade , Ração Animal/análise , Animais , Elementos Químicos , Feminino , Granuloma/induzido quimicamente , Granuloma/patologia , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Espectroscopia Fotoeletrônica , Ratos , Ratos Sprague-Dawley , Espectrometria por Raios X , Distribuição Tecidual
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