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1.
Chem Biol Interact ; 311: 108796, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421116

RESUMO

Lambda-cyhalothrin (LCT) is a broad-spectrum pesticide widely used in agriculture throughout the world. This pesticide is considered a potential contaminant of surface and underground water as well as food, posing a risk to ecosystems and humans. In this sense, we decided to evaluate the activity of enzymes belonging to the purinergic system, which is linked with regulation of extracellular nucleotides and nucleosides, such as adenosine triphosphate (ATP) and adenosine (Ado) molecules involved in the regulation of inflammatory response. However, there are no data concerning the effects of LCT exposure on the purinergic system, where extracellular nucleotides act as signaling molecules. The aim of this study was to evaluate nucleotide hydrolysis by E-NTPDase (ecto-nucleoside triphosphate diphosphohydrolase), Ecto-NPP (ecto-nucleotide pyrophosphatase/phosphodiesterase), ecto-5'-nucleotidase and ecto-adenosine deaminase (E-ADA) in platelets and liver of adult rats on days 7, 30, 45 and 60 after daily gavage with 6.2 and 31.1 mg/kg bw of LCT. Gene expression patterns of NTPDases1-3 and 5'-nucleotidase were also determined in those tissues. In parallel, lambda-cyhalothrin metabolites [3-(2-chloro-3,3,3- trifluoroprop-1-enyl)-2,2-dimethyl-cyclopropane carboxylic acid (CFMP), 4-hydroxyphenoxybenzoic acid (4-OH-3-PBA), and 3-phenoxybenzoic acid (3-PBA)] were measured in plasma. Results showed that exposure rats to LCT caused a significant increase in the assessed enzymes activities. Gene expression pattern of ectonucleotidases further revealed a significant increase in E-NTPDase1, E-NTPDase2, and E-NTPDase3 mRNA levels after LCT administration at all times. A dose-dependent increase in LCT metabolite levels was also observed but there no significant variations in levels from weeks to week, suggesting steady-steady equilibrium. Correlation analyses revealed that LCT metabolites in the liver and plasma were positively correlated with the adenine nucleotides hydrolyzing enzyme, E-ADA and E-NPP activities in platelets and liver of rats exposed to lambda-cyhalothin. Our results show that LCT and its metabolites may affect purinergic enzymatic cascade and cause alterations in energy metabolism.


Assuntos
Plaquetas/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nitrilos/farmacologia , Nucleotidases/genética , Nucleosídeos de Purina/metabolismo , Piretrinas/farmacologia , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Animais , Plaquetas/enzimologia , Plaquetas/metabolismo , Cromatografia Líquida de Alta Pressão , Hidrólise , Fígado/enzimologia , Fígado/metabolismo , Masculino , Espectrometria de Massas , Nitrilos/sangue , Nitrilos/metabolismo , Nucleotidases/metabolismo , Piretrinas/sangue , Piretrinas/metabolismo , Pirofosfatases/genética , Pirofosfatases/metabolismo , Ratos , Ratos Wistar
2.
Fitoterapia ; 137: 104282, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31381956

RESUMO

Four new polyketides, alternatains A-D (1-4), along with 17 known compounds (5-21) were obtained from the solid substrate fermentation cultures of Alternaria alternata MT-47, an endophytic fungus isolated from the medicinal plant of Huperzia serrata. Their structures were elucidated by extensive spectroscopic and spectrometric techniques (1D and 2D NMR, IR, and HRESIMS) and calculated electronic circular dichroism (ECD) method. Compounds 4, 6, 15, and 21 exhibited inhibitory activities on ATP release of thrombin-activated platelets with IC50 values in the range of 18.2-68.8 µM.


Assuntos
Alternaria/química , Anticoagulantes/farmacologia , Plaquetas/efeitos dos fármacos , Huperzia/microbiologia , Policetídeos/farmacologia , Acetilcolinesterase , Trifosfato de Adenosina , Anticoagulantes/isolamento & purificação , Butirilcolinesterase , China , Inibidores da Colinesterase , Endófitos/química , Humanos , Estrutura Molecular , Plantas Medicinais/microbiologia , Policetídeos/isolamento & purificação
3.
Cancer Treat Res ; 179: 37-54, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31317479

RESUMO

For over 100 years, a link has been recognized between thrombosis and cancer. However, whether this was a causal or correlational relationship was debated. It is now well established that cancer and thrombosis are mechanistically related in intricate ways and can directly fuel each other. Here, we present an historical perspective of platelets and how their physiological function in hemostasis can contribute to tumor development and metastasis. This emerging field has garnered great interest as aspirin therapy has been proposed as a prevention strategy for some malignancies. We highlight the advances that have been made, presenting platelets as a key component that supports many of the hallmarks of cancer that have been described and conclude with future directions and studies that are needed to clarify the role of platelets in cancer and solidify platelet modulating therapies within oncology.


Assuntos
Plaquetas/fisiologia , Hemostasia/fisiologia , Neoplasias/fisiopatologia , Trombose/fisiopatologia , Plaquetas/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Humanos , Neoplasias/complicações , Neoplasias/prevenção & controle , Trombose/etiologia , Trombose/prevenção & controle
4.
Int J Nanomedicine ; 14: 4817-4831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308660

RESUMO

Background: In vitro (1R,3S)-1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxyl-Lys(Pro-Ala-Lys)-Arg-Gly-Asp-Val (MTCA-KKV) adheres activated platelets, targets P-selectin and GPIIb/IIIa. This led to the development of MTCA-KKV as thrombus targeting nano-medicine. Methods: MTCA-KKV was characterized by nano-feature, anti-thrombotic activity, thrombolytic activity, thrombus target and targeting release. Results: In vivo 0.01 µmol/kg of MTCA-KKV formed nano-particles less than 100 nm in diameter, targeted thrombus, released anti-thrombotic and thrombolytic pharmacophores, prevented thrombosis and dissolved blood clots. Conclusion: Based on the profiles of targeting thrombus, targeting release, inhibiting thrombosis and dissolving blood clots MTCA-KKV is a promising nano-medicine.


Assuntos
Coagulação Sanguínea , Carbolinas/química , Carbolinas/uso terapêutico , Nanopartículas/química , Peptídeos/uso terapêutico , Trombose/sangue , Trombose/tratamento farmacológico , Administração Oral , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Carbolinas/administração & dosagem , Eritrócitos/efeitos dos fármacos , Humanos , Leucócitos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Nanopartículas/ultraestrutura , Selectina-P/metabolismo , Peptídeos/farmacologia , Adesividade Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier
5.
BMJ ; 365: l2211, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171523

RESUMO

OBJECTIVE: To test the hypothesis that ticagrelor plus aspirin is safe and superior to clopidogrel plus aspirin for reducing high platelet reactivity at 90 days and stroke recurrence in patients with minor stroke or transient ischaemic attack, particularly in carriers of the CYP2C19 loss-of-function allele and patients with large artery atherosclerosis. DESIGN: Open label, blinded endpoint, randomised controlled phase II trial. SETTING: Prospective studies conducted at 26 centres in China, August 2015 to March 2017. PARTICIPANTS: 675 patients with acute minor stroke or transient ischaemic attack. INTERVENTION: Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300 mg loading dose, 75 mg daily thereafter) on a background of aspirin (100 mg daily for the first 21 days) within 24 hours of symptom onset. MAIN OUTCOME MEASURES: Primary outcome was the proportion of patients with high platelet reactivity at 90 days. High platelet reactivity was defined as P2Y12 reaction units of more than 208. Secondary outcomes included high platelet reactivity at 90 days (7 days either way) in patients carrying genetic variants that would affect clopidogrel metabolism, and any stroke (ischaemic or haemorrhagic) recurrence at 90 days (7 days either way), six months, and one year. RESULTS: At 90 days, high platelet reactivity occurred in 35 (12.5%) of 280 patients in the ticagrelor/aspirin group and 86 (29.7%) of 290 patients in the clopidogrel/aspirin group (risk ratio 0.40; 95% confidence interval 0.28 to 0.56; P<0.001), and in 10.8% versus 35.4% (0.31; 0.18 to 0.49; P<0.001) of patients carrying CYP2C19 loss-of-function alleles. Stroke occurred in 21 (6.3%) of 336 patients in the ticagrelor/aspirin group and 30 (8.8%) of 339 patients in the clopidogrel/aspirin group (hazard ratio 0.70; 95% confidence interval 0.40 to 1.22; P=0.20). Patients with large artery atherosclerosis in the ticagrelor/aspirin group had a lower stroke recurrence at 90 days than those in the clopidogrel/aspirin group (6.0% v 13.1%; hazard ratio 0.45, 95% confidence interval 0.20 to 0.98; P=0.04). No difference was seen in the rates of major or minor haemorrhagic events between the ticagrelor/aspirin and clopidogrel/aspirin groups (4.8% v 3.5%; P=0.42). CONCLUSION: Patients with minor stroke or transient ischaemic attack who are treated with ticagrelor plus aspirin have a lower proportion of high platelet reactivity than those who are treated with clopidogrel plus aspirin, particularly for those who are carriers of the CYP2C19 loss-of-function allele. The results of this study should be evaluated further in large scale, phase III trials and in different populations. TRIAL REGISTRATION: Clinicaltrials.gov NCT02506140.


Assuntos
Aspirina/uso terapêutico , Clopidogrel/uso terapêutico , Ataque Isquêmico Transitório/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Ticagrelor/uso terapêutico , Adulto , Idoso , Plaquetas/efeitos dos fármacos , China , Quimioterapia Combinada , Feminino , Humanos , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/fisiologia , Estudos Prospectivos , Acidente Vascular Cerebral/fisiopatologia , Resultado do Tratamento
6.
Life Sci ; 231: 116522, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31158377

RESUMO

AIM: Liver fibrosis is a serious health problem which is a critical cause of morbidity and mortality worldwide. It is the main complication of untreated chronic inflammatory liver diseases which can progress to liver cirrhosis, hepatocellular carcinoma, and finally death. Coagulation cascade plays a mechanistic role in the pathogenesis of different chronic inflammatory disease including atherosclerosis, stroke, and tissue fibrosis. The current study was designed to investigate the effect of inhibition of coagulation cascade on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. MATERIAL AND METHODS: The study was conducted in rats. Rats were treated with CCl4 subcutaneously for 6 consecutive weeks to determine the onset of coagulation system activation in relation to development of fibrosis. To investigate the effects of coagulation system inhibition in CCl4-induced liver fibrosis, the anticoagulants drugs dabigatran and clopidogrel were administrated orally concurrently with CCl4 treatment. KEY FINDINGS: The results of our study revealed that during the first week, there were significant elevations of fibrin, tissue factor expressions, and prothrombin time (PT) coupled with neutropenia without significant changes in liver fibrosis markers such as TGF-ß, α-SMA and collagen deposition. Starting from the second week, tissue injury markers including the oxidative, inflammatory and fibrosis markers as well as histopathological changes became evident progressively. Intriguingly, dabigatran and clopidogrel significantly normalized the biochemical and pathological changes. SIGNIFICANCE: In conclusion, activation of coagulation cascade is a triggering stimulus in the initiation of CCl4-induced liver fibrosis and the anticoagulant drugs may exert promising anti-fibrotic effect.


Assuntos
Clopidogrel/farmacologia , Dabigatrana/farmacologia , Cirrose Hepática/tratamento farmacológico , Animais , Anticoagulantes/metabolismo , Anticoagulantes/farmacologia , Biomarcadores/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Tetracloreto de Carbono/farmacologia , Clopidogrel/metabolismo , Dabigatrana/metabolismo , Fígado/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Trombina/efeitos dos fármacos , Trombina/metabolismo
7.
Ann Hematol ; 98(8): 1933-1936, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201513

RESUMO

Ruxolitinib is the only commercially available JAK1/2 inhibitor approved for the treatment of myelofibrosis-related splenomegaly and symptoms. During treatment, as rare conditions, leukocytosis and/or thrombocytosis could develop and the management of these situations is not well established. We report here 53 myelofibrosis patients that received a combination of hydroxyurea and ruxolitinib because of uncontrolled myeloproliferation. Both drugs were administered outside clinical trials. At 48 weeks, a significant reduction in leucocyte and platelet counts was observed (p = 0.02 and p = 0.04, respectively). Additionally, the spleen volume decreased from a median value of 10 cm below the left costal margin (range, 0-10) to 6 cm (range, 0-15). The rate of spleen response increased from 14% at the start of the combination to 45% after 48 weeks. The safety profile of the combination was consistent with that observed with ruxolitinib single agent. These data require further confirmation in large cohorts of patients prospectively assessed.


Assuntos
Plaquetas/efeitos dos fármacos , Hidroxiureia/uso terapêutico , Leucócitos/efeitos dos fármacos , Mielofibrose Primária/tratamento farmacológico , Pirazóis/uso terapêutico , Esplenomegalia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Plaquetas/patologia , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Mielofibrose Primária/complicações , Mielofibrose Primária/mortalidade , Mielofibrose Primária/patologia , Estudos Retrospectivos , Esplenomegalia/complicações , Esplenomegalia/mortalidade , Esplenomegalia/patologia , Análise de Sobrevida , Resultado do Tratamento
8.
J Stroke Cerebrovasc Dis ; 28(8): 2302-2310, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31174954

RESUMO

BACKGROUND: Aggregation of platelets is a trigger for additional development of larger thrombi. This study aimed to identify factors that may affect platelet aggregability and their role in clinical outcomes in acute ischemic stroke. METHODS: Consecutive acute ischemic stroke patients (n = 352) who were transferred within 24 hours after its onset were enrolled. Peripheral venous blood was sampled to measure platelet aggregability and other parameters. RESULTS: Mean values of spontaneous small-sized platelet aggregates and collagen- or adenosine diphosphate (ADP)-induced large-sized aggregates were elevated in acute ischemic stroke. In atherothrombotic stroke (n = 178), collagen and ADP-induced large-sized aggregates were positively correlated with HbA1c, respectively. High incidence of the modified Rankin Scales (mRS) 5-6 at discharge was associated with diabetes complication (odds ratio [OR] 8.77, 95% confidence interval [CI] 1.32-57.56). The proportion of patients who were functionally independent (the mRS 0-2) at discharge was lower in the middle tertile of collagen and ADP-induced large-sized aggregates than their low tertile (OR 2.46, 95% CI 1.09-5.58; OR 2.43, 95% CI 1.05-5.59, respectively). Prestroke administration of aspirin recovered the proportion of independence at discharge (OR 0.25, 95% CI 0.06-0.99), and ameliorated incidence of the mRS 5-6. On logistic regression analysis, diabetes, HbA1c, collagen-induced large-sized aggregates, and prestroke administration of aspirin remained independent predictors of clinical outcomes in atherothrombotic stroke. In cardioembolic and lacunar stroke, no relations with clinical outcomes were found. CONCLUSIONS: High plasma level of HbA1c is involved in enhanced platelet aggregability in acute atherothrombotic stroke patients, and prestroke administration of aspirin may be beneficial to clinical outcomes.


Assuntos
Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Diabetes Mellitus/sangue , Hemoglobina A Glicada/metabolismo , Inibidores da Agregação de Plaquetas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária/métodos , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Aspirina/efeitos adversos , Biomarcadores/sangue , Plaquetas/metabolismo , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Comorbidade , Estudos Transversais , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Avaliação da Deficiência , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/efeitos adversos , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
9.
Biomed Res Int ; 2019: 8078230, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058193

RESUMO

This in vitro study was designed to evaluate the effect of sol-gel derived TiO2 coating on blood coagulation, blood protein adsorption, and platelet response on zirconia surfaces. Square-shaped zirconia (n=96) (10x10x2 mm) was cut, ground, sintered, and finally cleansed ultrasonically in each of acetone and ethanol for 5 minutes. Three experimental groups (n=32) were fabricated: (a) zirconia coated with sol-gel derived TiO2, (b) zirconia coated with sol-gel derived TiO2 and treated with ultraviolet (UV) irradiation for 1 hour, and (c) non-coated zirconia as control. The coatings were prepared from tetraisopropyl orthotitanate solution by dip-coating. The thrombogenicity of the specimens was evaluated using a whole blood kinetic clotting time method where the extent of blood clotting was evaluated at 10, 20, 30, 40, 50, and 60 minutes (n=4/time point, total n=24/group). Scanning electron microscope images were taken to observe platelet morphologies after 1-hour incubation with platelet-rich plasma (PRP) (n=5/group). Surface characteristics were visualized using atomic force microscopy (n=1/group). Adsorption of plasma proteins and fibronectin on each surface was studied by gel electrophoresis (n=2/group). Significant differences were observed in blood coagulation between the test groups at 20-, 30-, 40-, and 50-minute time points (p<0.005). UV treated TiO2 coated specimens showed fastest blood coagulation followed by TiO2 coated and non-coated specimens. Furthermore, platelets appeared at a higher activation state on coated specimens. Gel electrophoresis revealed no difference in protein adsorption among the experimental groups. In summary, TiO2 coatings promoted blood coagulation, and it was further enhanced by UV treatment, which has the potential to hasten the wound healing process in vivo.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Materiais Dentários/química , Titânio/química , Zircônio/química , Plaquetas/efeitos dos fármacos , Plaquetas/ultraestrutura , Materiais Dentários/uso terapêutico , Humanos , Teste de Materiais , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Resistência ao Cisalhamento/efeitos dos fármacos , Titânio/uso terapêutico , Raios Ultravioleta , Zircônio/uso terapêutico
10.
Nat Commun ; 10(1): 2051, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053712

RESUMO

Blood clotting at the vascular injury site is a complex process that involves platelet adhesion and clot stiffening/contraction in the milieu of fluid flow. An integrated understanding of the hemodynamics and tissue mechanics regulating this process is currently lacking due to the absence of an experimental system that can simultaneously model clot formation and measure clot mechanics under shear flow. Here we develop a microfluidic-integrated microclot-array-elastometry system (clotMAT) that recapitulates dynamic changes in clot mechanics under physiological shear. Treatments with procoagulants and platelet antagonists and studies with diseased patient plasma demonstrate the ability of the system to assay clot biomechanics associated with common antiplatelet treatments and bleeding disorders. The changes of clot mechanics under biochemical treatments and shear flow demonstrate independent yet equally strong effects of these two stimulants on clot stiffening. This microtissue force sensing system may have future research and diagnostic potential for various bleeding disorders.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Hemorragia/diagnóstico , Microfluídica/métodos , Tromboelastografia/métodos , Análise Serial de Tecidos/métodos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Feminino , Voluntários Saudáveis , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Inibidores da Agregação de Plaquetas/farmacologia , Estresse Mecânico , Doença de von Willebrand Tipo 2/sangue
11.
Medicina (Kaunas) ; 55(4)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959829

RESUMO

Background and objectives: The clinical use of non-steroidal anti-inflammatory drugs is limited due to high incidence of adverse drug reactions. The pyrrole heterocycle is included in the chemical structure of a number of drugs with various activities and shows relatively good tolerability and safety. The objectives of our study were to evaluate the analgesic and anti-inflammatory activity, as well as possible organ toxicity, of 2-[3-acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid (compound 3g), a novel N-pyrrolylcarboxylic acid structurally similar to celecoxib. Materials and methods: All experiments were performed on 6-week-old male Wistar rats divided into parallel groups (n = 8). Antinociception was assessed using animal pain models with thermal and chemical stimuli (paw withdrawal, tail-flick, and formalin tests). Criteria for the analgesic effect were increased latency in the paw withdrawal and tail-flick tests and decreased paw licking time in the formalin test compared to animals treated with saline (control). Anti-inflammatory activity was measured using a carrageenan-induced paw edema model; the criterion for anti-inflammatory effect was decreased edema compared to control. Blood samples were obtained after animals were sacrificed to assess possible organ toxicity. Statistical analysis was performed with IBM SPSS 20.0. Results: 2-[3-Acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid had analgesic action against chemical stimulus after single and multiple administration and against thermal stimulus after single administration. Compound 3g significantly suppressed carrageenan-induced paw edema after both single and continuous administration. After continuous administration, hematological tests showed that compound 3g decreased leukocyte and platelet levels and elevated serum creatinine levels. Conclusions: Antinociception with the tested compound is most likely mediated by spinal, peripheral, and anti-inflammatory mechanisms. Possible tolerance of the analgesic action at the spinal level develops after continuous administration. Anti-inflammatory activity is significant and probably the leading cause of antinociception. After multiple administration, compound 3g showed signs of potential nephrotoxicity and antiplatelet activity, as well as suppression of leukocyte levels.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Celecoxib/análogos & derivados , Celecoxib/farmacologia , Avaliação Pré-Clínica de Medicamentos , Indóis/química , Indóis/farmacologia , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Carragenina/administração & dosagem , Carragenina/farmacologia , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Eritrócitos/efeitos dos fármacos , Hemoglobinas/análise , Leucócitos/efeitos dos fármacos , Masculino , Modelos Animais , Medição da Dor , Pirróis/química , Ratos , Ratos Wistar
12.
J Mater Sci Mater Med ; 30(4): 44, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30929088

RESUMO

Hydroxyapatite is an ideal biomaterial for bone tissue engineering due to its biocompatibility and hemocompatibility which have been widely studied by many researchers. The incorporation of nanoporosity into hydroxyapatite could transform the biomaterial into an effective adsorbent for uremic toxins removal especially in artificial kidney system. However, the effect of nanoporosity incorporation on the hemocompatibility of hydroxyapatite has yet to be answered. In this study, nanoporous hydroxyapatite was synthesized using hydrothermal technique and its hemocompatibility was determined. Non-ionic surfactants were used as soft templates to create porosity in the hydroxyapatite. The presence of pure hydroxyapatite phase in the synthesized samples is validated by X-ray diffraction analysis and Fourier transform infrared spectroscopy. The TEM images show that the hydroxyapatite formed rod-like particles with the length of 21-90 nm and diameter of 11-70 nm. The hydroxyapatite samples exhibit BET surface area of 33-45 m2 g-1 and pore volume of 0.35-0.44 cm3 g-1. The hemocompatibility of the hydroxyapatite was determined via hemolysis test, platelet adhesion, platelet activation and blood clotting time measurement. The nanoporous hydroxyapatite shows less than 5% hemolysis, suggesting that the sample is highly hemocompatible. There is no activation and morphological change observed on the platelets adhered onto the hydroxyapatite. The blood clotting time demonstrates that the blood incubated with the hydroxyapatite did not coagulate. This study summarizes that the synthesized nanoporous hydroxyapatite is a highly hemocompatible biomaterial and could potentially be utilized in biomedical applications.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Durapatita/química , Durapatita/farmacologia , Hemólise/efeitos dos fármacos , Nanoporos , Plaquetas/fisiologia , Fenômenos Químicos , Humanos , Teste de Materiais , Nanoporos/ultraestrutura , Ativação Plaquetária/efeitos dos fármacos , Adesividade Plaquetária/efeitos dos fármacos , Porosidade , Espectroscopia de Infravermelho com Transformada de Fourier , Estresse Mecânico , Propriedades de Superfície , Difração de Raios X
13.
Ann Vasc Surg ; 59: 244-247, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31009712

RESUMO

BACKGROUND: Inflammation and endothelial dysfunction are implicated in the onset of atherosclerosis. Inflammasome activation takes part in the pathogenesis of the atherosclerotic disease. This study investigated the influence of platelet inflammatory inhibition on the transcription of intracitosolic nucleotide-binding oligomerization domain-like receptor protein 1 (NLRP-1) inflammasome in endothelial cells. METHODS: This experimental study enrolled 10 healthy volunteers with no cardiovascular risk factors and normal results on vascular examination. They received low doses of aspirin (100 mg/day) for seven days. A venous blood sample was collected in all subjects before aspirin intake and after the experimental week. Human aortic endothelial cell (HAEC) cultures were exposed to baseline plasma and plasma from subjects after aspirin intake. NLRP-1 gene expression was analyzed in these cultures. RESULTS: HAEC cultures that were exposed to plasma from subjects at baseline showed higher expression of NLRP-1 than HAECs exposed to plasma of healthy volunteers after one week on salicilate intake (relative quantification, 1.077 ± 0.05 vs. 1.002 ± 0.06; odds ratio, 1.8; 95 confidence interval, 1.1-2.9; P < 0.01). CONCLUSIONS: Data observed in the our study indicate that in HAECs, the intracytosolic NLRP-1 expression is attenuated by the auto/paracrine platelet inhibition by aspirin, without direct platelet-endothelial cell interaction.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Anti-Inflamatórios/administração & dosagem , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Inflamassomos/antagonistas & inibidores , Inibidores da Agregação de Plaquetas/administração & dosagem , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Plaquetas/metabolismo , Comunicação Celular/efeitos dos fármacos , Células Cultivadas , Estudos Clínicos como Assunto , Regulação para Baixo , Células Endoteliais/metabolismo , Voluntários Saudáveis , Humanos , Inflamassomos/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Artigo em Chinês | MEDLINE | ID: mdl-30929354

RESUMO

Objective: To investigate the effect of glyphosate on blood routine of occupational exposure population. Methods: The workers who were occupationally exposed to glyphosate were selected as exposure group, and administrative staffs who were not exposed to glyphosate were selected as control group. Occupational health examination was conducted on all the subjects, and personal monitoring was applied to detect the concentration of glyphosate in the air of workplace. Time weighted average (TWA) concentration was calculated by the result of determination. Statistical methods were employed to compare the difference of blood routine results between the contact group and the control group, as well as between different posts. Results: 178 glyphosate workers were included in the contact group, and 203 non-contact persons were included in the control group. There was no statistically significant difference in the equilibrium test between the two groups(P>0.05). The abnormal rate of blood routine in the exposure group and the control group were 70.8% and 69.0%, respectively, but the difference was not statistically significant (P>0.05). Compared with the control group, the red blood cell count and platelet distribution width difference (P<0.05) were significant difference. There was no significant difference between different positions (P>0.05). Conclusion: When TWA value is below 9.40 mg/m(3), glyphosate has effect on the results of platelet distribution width and red blood cell count, but has no effect on the abnormal rate of blood routine.


Assuntos
Plaquetas/efeitos dos fármacos , Contagem de Eritrócitos , Glicina/análogos & derivados , Exposição Ocupacional/efeitos adversos , Estudos de Casos e Controles , Glicina/toxicidade , Humanos
15.
Nat Med ; 25(4): 641-655, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30936549

RESUMO

Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.


Assuntos
Plaquetas/metabolismo , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Grânulos Citoplasmáticos/efeitos dos fármacos , Grânulos Citoplasmáticos/metabolismo , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos Transgênicos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Contagem de Plaquetas
16.
Am J Vet Res ; 80(5): 505-512, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31034271

RESUMO

OBJECTIVE: To determine pharmacokinetics and pharmacodynamics after oral administration of a single dose of clopidogrel to horses. ANIMALS: 6 healthy adult horses. PROCEDURES: Blood samples were collected before and at various times up to 24 hours after oral administration of clopidogrel (2 mg/kg). Reactivity of platelets from each blood sample was determined by optical aggregometry and phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Concentrations of clopidogrel and the clopidogrel active metabolite derivative (CAMD) were measured in each blood sample by use of liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were determined with a noncompartmental model. RESULTS: Compared with results for preadministration samples, platelet aggregation in response to 12.5µM ADP decreased significantly within 4 hours after clopidogrel administration for 5 of 6 horses. After 24 hours, platelet aggregation was identical to that measured before administration. Platelet aggregation in response to 25µM ADP was identical between samples obtained before and after administration. Phosphorylation of VASP in response to ADP (20µM) and prostaglandin E1 (3.3µM) was also unchanged by administration of clopidogrel. Time to maximum concentration of clopidogrel and CAMD was 0.54 and 0.71 hours, respectively, and calculated terminal-phase half-life of clopidogrel and CAMD was 1.81 and 0.97 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Clopidogrel or CAMD caused competitive inhibition of ADP-induced platelet aggregation during the first 24 hours after clopidogrel administration. Because CAMD was rapidly eliminated from horses, clopidogrel administration may be needed more frequently than in other species in which clopidogrel causes irreversible platelet inhibition. (Am J Vet Res 2019;80:505-512).


Assuntos
Plaquetas/efeitos dos fármacos , Clopidogrel/farmacocinética , Cavalos/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Difosfato de Adenosina/farmacologia , Administração Oral , Animais , Área Sob a Curva , Plaquetas/metabolismo , Moléculas de Adesão Celular/metabolismo , Clopidogrel/administração & dosagem , Feminino , Masculino , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/administração & dosagem
17.
Vet Clin Pathol ; 48(1): 11-18, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30924545

RESUMO

BACKGROUND: Dogs with Babesia rossi infection display a normocoagulable thromboelastogram, despite being markedly thrombocytopenic, which is purportedly due to large-scale platelet activation. Thromboelastographic platelet mapping (TEG-PM) evaluates individual contributions of thrombin, fibrinogen, and platelets to clot formation, and may elucidate some of the pathomechanisms of thrombocytopenia-associated hemostatic alterations. OBJECTIVE: This study investigated potential differences in TEG-PM variables in dogs with complicated B rossi infection compared with healthy controls, and whether these variables correlated with platelet activation indices. METHODS: The maximum amplitude (MA) following thrombin generation (MAThrombin ) was determined using kaolin-activated TEG. The TEG-PM variables included MA following the addition of platelet agonists arachidonic acid (MAAA ) and adenosine diphosphate (MAADP ), and MA due to fibrin alone (MAFibrin ). In addition, platelet indices and fibrinogen concentrations were determined. RESULTS: Thirteen dogs with complicated B rossi infection and five healthy controls were included. The median MAFibrin and fibrinogen concentrations were significantly higher (P < 0.01 for both) and median platelet count was significantly lower (P < 0.01) in the babesiosis group vs the control group. No significant differences were found for MAThrombin and MAAA/ADP . maximum amplitude due to fibrin alone was positively correlated with fibrinogen concentration (r = 0.735), mean platelet volume (r = 0.517), and mean platelet mass (r = 0.498), and negatively correlated with hematocrit (r = -0.685), platelet count (r = -0.476), and plateletcrit (r = -0.479) (P < 0.05 for all). CONCLUSIONS: This study suggests that the presence of hyperfibrinogenemia offsets the severe thrombocytopenia associated with B rossi to result in normal thromboelastograms and lack of overt clinical bleeding.


Assuntos
Babesia , Babesiose/sangue , Plaquetas/fisiologia , Doenças do Cão/sangue , Tromboelastografia/veterinária , Animais , Apirase/farmacologia , Ácido Araquidônico/farmacologia , Plaquetas/química , Plaquetas/efeitos dos fármacos , Estudos de Casos e Controles , Doenças do Cão/parasitologia , Cães , Feminino , Fibrinogênio/análise , Masculino
18.
Chin Med J (Engl) ; 132(9): 1053-1062, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30896564

RESUMO

BACKGROUND: High on-treatment platelet reactivity (HTPR) has been suggested as a risk factor for patients with ischemic vascular disease. We explored a predictive model of platelet reactivity to clopidogrel and the relationship with clinical outcomes. METHODS: A total of 441 patients were included. Platelet reactivity was measured by light transmittance aggregometry after receiving dual antiplatelet therapy. HTPR was defined by the consensus cutoff of maximal platelet aggregation >46% by light transmittance aggregometry. CYP2C19 loss-of-function polymorphisms were identified by DNA microarray analysis. The data were compared by binary logistic regression to find the risk factors. The primary endpoint was major adverse clinical events (MACEs), and patients were followed for a median time of 29 months. Survival curves were constructed with Kaplan-Meier estimates and compared by log-rank tests between the patients with HTPR and non-HTPR. RESULTS: The rate of HTPR was 17.2%. Logistic regression identified the following predictors of HTPR: age, therapy regimen, body mass index, diabetes history, CYP2C192, or CYP2C193 variant. The area under the curve of receiver operating characteristic for the HTPR predictive model was 0.793 (95% confidence interval: 0.738-0.848). Kaplan-Meier analysis showed that patients with HTPR had a higher incidence of MACE than those with non-HTPR (21.1% vs. 9.9%; χ = 7.572, P = 0.010). CONCLUSIONS: Our results suggest that advanced age, higher body mass index, treatment with regular dual antiplatelet therapy, diabetes, and CYP2C192 or CYP2C193 carriers are significantly associated with HTPR to clopidogrel. The predictive model of HTPR has useful discrimination and good calibration and may predict long-term MACE.


Assuntos
Plaquetas/efeitos dos fármacos , Clopidogrel/farmacologia , Clopidogrel/uso terapêutico , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/prevenção & controle , Idoso , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/prevenção & controle , Citocromo P-450 CYP2C19/metabolismo , Feminino , Genótipo , Hemoglobina A Glicada/metabolismo , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão
19.
Vascul Pharmacol ; 116: 4-7, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30876967

RESUMO

The pharmacological and clinical differences of the three recommended oral P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor) enable physicians to switch from one agent to another that it is considered more appropriate in the specific clinical setting. Moreover, the recent availability of cangrelor, the only intravenous P2Y12 inhibitor with a rapid onset and offset of its antiplatelet action, makes it necessary to switch from this agent to an oral P2Y12 inhibitor for a continued platelet inhibition after percutaneous coronary intervention. Several pharmacodynamic studies have provided information on how to change drug, in terms of timing and dosage, without running the risk of a temporary impairment of platelet inhibition. In addition, several studies have assessed the impact of the switching between P2Y12 inhibitors on clinical outcomes. Overall, these evidences have prompted the development of an extensive expert consensus document, have set the basis for recent practice guidelines recommendations, and have stimulated several systematic overviews. The present article provides a brief and schematic summary on the topic of switching between P2Y12 inhibitors, focusing on three main practical issues: why and how to switch therapies and what are the clinical consequences of such strategy.


Assuntos
Plaquetas/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Substituição de Medicamentos , Inibidores da Agregação de Plaquetas/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/análogos & derivados , Administração Intravenosa , Administração Oral , Plaquetas/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Tomada de Decisão Clínica , Clopidogrel/administração & dosagem , Substituição de Medicamentos/efeitos adversos , Humanos , Inibidores da Agregação de Plaquetas/efeitos adversos , Cloridrato de Prasugrel/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Receptores Purinérgicos P2Y12/sangue , Ticagrelor/administração & dosagem , Resultado do Tratamento
20.
N Engl J Med ; 380(19): 1825-1833, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-30883047

RESUMO

BACKGROUND: Ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction. Spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with ticagrelor, as with other antiplatelet drugs. The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. A rapid-acting reversal agent would be useful. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay. RESULTS: Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P<0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site. CONCLUSIONS: In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.).


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Plaquetas/efeitos dos fármacos , Coagulantes/uso terapêutico , Inibidores da Agregação de Plaquetas , Ticagrelor/antagonistas & inibidores , Adulto , Anticorpos Neutralizantes/efeitos adversos , Plaquetas/fisiologia , Coagulantes/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Ticagrelor/efeitos adversos , Ticagrelor/uso terapêutico
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