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1.
Yonsei Med J ; 62(1): 75-85, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33381937

RESUMO

PURPOSE: Antiplatelet drugs are essential in patients with cardiovascular disease who undergo stent placement. We hypothesized that risks of mortality would differ according to adherence to antiplatelet agents, number of antiplatelet agents, and antiplatelet regimens in patients undergoing stent placement or angioplasty. MATERIALS AND METHODS: Between 2002 and 2013, we initially enrolled 8671 subjects who underwent stent placement or angioplasty in the National Health Insurance Service-National Sample Cohort in Korea. Using the International Classification of Diseases, 10th revision, the incidence of all-cause death, including cardiovascular disease, cerebrovascular disease, and cancer, was defined. Using a nested case-control study design, controls were matched to cases at a ratio of 4:1, and a total of 5415 subjects were eligible for this study. RESULTS: During a median follow-up period of 3.51 years, the incidence rate of all-cause death was 40 per 1000 person-years. We found that adherence to antiplatelet monotherapy significantly decreased risk of death by cerebro-cardiovascular disease, compared with discontinuation of antiplatelets [adjusted odds ratio (OR) 0.62, 95% confidence interval (CI) (0.41-0.96)]. Compared with dual antiplatelet therapy (DAPT), aspirin and clopidogrel monotherapy significantly reduced death by cerebro-cardiovascular disease [adjusted OR 0.65, 95% CI (0.44-0.95) and adjusted OR 0.58, 95% CI (0.35-0.96), respectively]. There was no significant difference of mortality between aspirin monotherapy and clopidogrel monotherapy. CONCLUSION: Our study demonstrated that adherence to antiplatelet therapy and antiplatelet monotherapy, compared with DAPT, in patients with stent placement or angioplasty may have a beneficial effect on mortality in cerebro-cardiovascular disease.


Assuntos
Angioplastia/efeitos adversos , Stents Farmacológicos/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacologia , Idoso , Angioplastia/mortalidade , Aspirina/uso terapêutico , Estudos de Casos e Controles , Clopidogrel/efeitos adversos , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Resultado do Tratamento
2.
Phytomedicine ; 80: 153363, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33070081

RESUMO

BACKGROUND: The ingestion of flavonoids has been reported to be associated with reduced cardiovascular disease risk. Quercitrin is a common flavonoid in nature, and it exhibits antioxidant properties. Although the process of thrombogenesis is intimately related to cardiovascular disease risk, it is unclear whether quercitrin plays a role in thrombogenesis. PURPOSE: The aim of this study was to examine the antiplatelet effect of quercitrin in platelet activation. METHODS: Platelet aggregation, granule secretion, calcium mobilization, and integrin activation were used to assess the antiplatelet activity of quercitrin. Antithrombotic effect was determined in mouse using ferric chloride (FeCl3)-induced arterial thrombus formation in vivo and thrombus formation on collagen-coated surfaces under arteriolar shear in vitro. Transection tail bleeding time was used to evaluate whether quercitrin inhibited primary hemostasis. RESULTS: Quercitrin significantly impaired collagen-related peptide-induced platelet aggregation, granule secretion, reactive oxygen species generation, and intracellular calcium mobilization. Outside-in signaling of αIIbß3 integrin was significantly inhibited by quercitrin in a concentration-dependent manner. The inhibitory effect of quercitrin resulted from inhibition of the glycoprotein VI-mediated platelet signal transduction during cell activation. Further, the antioxidant effect is derived from decreased phosphorylation of components of the TNF receptor-associated factor 4/p47phox/Hic5 axis signalosome. Oral administration of quercitrin efficiently blocked FeCl3-induced arterial thrombus formation in vivo and thrombus formation on collagen-coated surfaces under arteriolar shear in vitro, without prolonging bleeding time. Studies using a mouse model of ischemia/reperfusion-induced stroke indicated that treatment with quercitrin reduced the infarct volume in stroke. CONCLUSIONS: Our results demonstrated that quercitrin could be an effective therapeutic agent for the treatment of thrombotic diseases.


Assuntos
Fibrinolíticos/farmacologia , Hemostasia/efeitos dos fármacos , Quercetina/análogos & derivados , Trombose/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Artérias , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Quercetina/efeitos adversos , Quercetina/farmacologia , Traumatismo por Reperfusão/induzido quimicamente , Trombose/induzido quimicamente , Trombose/metabolismo
4.
Medicine (Baltimore) ; 99(46): e23236, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181711

RESUMO

BACKGROUND: Butylphthalide is widely used for the adjunctive treatment of vascular dementia; however, the clinical evidences are not well synthesized yet. METHODS: We proposed a systematic review and meta-analysis to evaluate the efficacy and safety of butylphthalide as adjunctive therapy for vascular dementia. Seven electronic databases (China National Knowledge Infrastructure, Wanfang database, Chongqing VIP database, China Biomedical Literature Database, Pubmed, EMBASE and Cochrane library) will be searched for eligible randomized controlled trials (RCTs). Required data of included studies will be collected. Quality of studies will be evaluated using Cochrane risk of bias assessment tool. Data synthesis will be performed using Review Manager software. Subgroup analysis and sensitivity analysis will also be carried. RESULTS: Synthesis results of current available RCTs regarding the efficacy and safety of butylphthalide for the treatment vascular dementia will be provided by this systematic review and meta-analysis. CONCLUSION: This systematic review and meta-analysis will provide high level evidence of butylphthalide clinical application. REGISTRATION: PROSPERO CRD42020168947.


Assuntos
Benzofuranos/uso terapêutico , Protocolos Clínicos , Demência Vascular/tratamento farmacológico , Benzofuranos/farmacologia , Benzofuranos/normas , Demência Vascular/fisiopatologia , Humanos , Metanálise como Assunto , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/normas , Inibidores da Agregação de Plaquetas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto , Resultado do Tratamento
5.
Environ Health Prev Med ; 25(1): 70, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33160329

RESUMO

BACKGROUND: Resveratrol has been shown to inhibit platelet aggregation. However, the mechanism for this action of resveratrol remains to be clarified. The purpose of this study was to elucidate the Ca2+-related mechanism for the inhibitory action of resveratrol on platelet aggregation. METHODS: Ca2+ entry and subsequent aggregation of human platelets induced by different stimulants including thrombin, thapsigargin, and 1-oleoyl-2-acetylglycerol (OAG) were measured by the fluorescence method and light transmittance method, respectively. Each stimulant was added to a nominally Ca2+-free medium containing platelets, and then CaCl2 was added to the medium to induce Ca2+ influx into platelets. RESULTS: Thapsigargin-induced Ca2+ entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 6.25 µM or higher concentrations, while OAG-induced Ca2+ entry and subsequent platelet aggregation were not affected by resveratrol at concentrations up to 50 µM. In the nominally Ca2+-free medium, thrombin induced a small transient increase in intracellular Ca2+ concentrations, which was attenuated in the presence of resveratrol at 12.5 µM or higher concentrations. Thrombin-induced Ca2+ entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 12.5 µM or higher concentrations. CONCLUSIONS: The results suggest that resveratrol inhibits thrombin-induced platelet aggregation through decreasing Ca2+ release from its stores and inhibiting store-operated Ca2+ influx into platelets.


Assuntos
Cálcio/fisiologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antioxidantes/administração & dosagem , Humanos , Inibidores da Agregação de Plaquetas/administração & dosagem , Resveratrol/administração & dosagem
6.
PLoS One ; 15(10): e0240541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33035271

RESUMO

BACKGROUND: Ethyl pyruvate (EP), the ethyl ester of pyruvate, has proven antiinflammatory and antioxidative properties. Additionally, anticoagulant properties have been suggested recently. EP, therefore, is a potentially antiatherosclerotic drug. We aimed to investigate whether EP possesses antiplatelet and anticoagulant properties particularly in the physiological environment of whole blood. METHODS: We investigated the effects of increasing concentrations of EP on platelet function, on the course of clot development, and on standard coagulation times. Additionally, clot ultrastructure using scanning electron microscopy was analysed. RESULTS: EP exerted significant antiplatelet actions: i) Impedance aggregometry amplitudes (11.7 ± 3.0 ohm, 0 µg/mL EP) dose dependently decreased (7.8 ± 3.1 ohm, 1000 µg/mL EP; -33.3%). ATP exocytosis (0.87 ± 0.24 nM, 0 µg/mL EP) measured by the luminiscent method dose-dependently decreased (0.56 ± 0.14 nM, 1000 µg/mL; -35.6%). ii) Closure times (104.4 ± 23.8 s, 0 µg/mL EP) using the Platelet function analyzer were dose-dependently prolonged (180.5 ± 82.5 s, 1000 µg/mL EP; +72.9%) using membranes coated with collagen/ADP. iii) Surface coverage (15.9 ± 5.1%, 0 µg/mL EP) dose-dependently decreased (9.0 ± 3.7%, 1000 µg/mL EP; -43.4%) using the Cone and Platelet analyzer. EP also exerted significant anticoagulant actions: Coagulation times (177.9 ± 37.8, 0 µg/mL EP) evaluated by means of thrombelastometry were dose-dependently prolonged (212.8 ± 57.7 s, 1000 µg/mL EP; +19.6%). Activated partial thromboplastin times (31.5 ± 1.8 s, 0 µg/mL EP) were dose-dependently prolonged (35.6 ± 2.3 s, 1000 µg/mL EP; +13.0%). Prothrombin times (0.94 ± 0.02 INR, 0 µg/mL EP) were dose-dependently prolonged (1.09 ± 0.04 INR, 1000 µg/mL EP; +16.0%). CONCLUSION: We found that EP possesses antiplatelet and anticoagulant properties in whole blood. Together with its proven anti-inflammatory and antioxidative properties, EP is a potentially antiatherogenic drug.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Piruvatos/farmacologia , Adulto , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade
7.
Anesth Analg ; 131(5): 1373-1379, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33079858

RESUMO

BACKGROUND: Postpartum hemorrhage is a leading cause of maternal mortality. Antifibrinolytic therapy has the potential to influence outcomes in postpartum hemorrhage, but the incidence of elevated fibrinolytic activity in postpartum hemorrhage is unknown. METHODS: We retrospectively reviewed thromboelastography (TEG) results obtained for postpartum hemorrhage from 118 deliveries at The University of Chicago. TEG results were obtained as part of our postpartum hemorrhage protocol when blood loss exceeded 500 mL after vaginal delivery or 1000 mL after cesarean delivery. Our primary outcome was the incidence of elevated fibrinolytic activity, which we predefined as clot lysis ≥3% at 30 minutes (Ly30) on kaolin TEG. Platelet-mediated clot retraction can also lead to an elevated Ly30 on kaolin TEG. Therefore, to distinguish between fibrinolysis and clot retraction, we evaluated clot lysis using functional fibrinogen TEG, which contains a platelet inhibitor. We considered a kaolin TEG Ly30 ≥3% in conjunction with a nonzero functional fibrinogen TEG Ly30 suggestive of elevated fibrinolytic activity. We also recorded quantitative blood loss, primary etiology of hemorrhage, standard laboratory measurements of coagulation, and demographic and obstetric characteristics of the study population. RESULTS: The median kaolin TEG Ly30 was 0.2% (interquartile range: 0%-0.8%). Fifteen of 118 women (12.7%; 95% confidence interval, 7.9%-19.9%) had kaolin TEG Ly30 values ≥3%. Of 15 patients with elevated Ly30 values, functional fibrinogen TEG Ly30 was available for 13, of which none demonstrated detectable clot lysis. CONCLUSIONS: Our observation that none of the patients in our sample with kaolin TEG Ly30 values ≥3% had a nonzero functional fibrinogen TEG Ly30 value suggests that the observed elevations in kaolin TEG Ly30 may have been secondary to platelet-mediated clot retraction as opposed to fibrinolysis. Platelet-mediated clot retraction should be distinguished from fibrinolysis when assayed using viscoelastic techniques in postpartum hemorrhage. Further research is necessary to determine the optimal methods to assess fibrinolytic activity in postpartum hemorrhage.


Assuntos
Fibrinólise , Hemorragia Pós-Parto/sangue , Hemorragia Pós-Parto/epidemiologia , Tromboelastografia/métodos , Adulto , Testes de Coagulação Sanguínea , Viscosidade Sanguínea , Retração do Coágulo , Parto Obstétrico , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Incidência , Inibidores da Agregação de Plaquetas/farmacologia , Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
8.
Phytomedicine ; 79: 153330, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32932202

RESUMO

BACKGROUND: Compound Dan Zhi tablet (DZT) is a commonly used traditional Chinese medicine formula. It has been used for the treatment of ischemic stroke for many years in clinical. However, its pharmacological mechanism is unclear. PURPOSE: The aim of the current study was to understand the protective effects and underlying mechanisms of DZT on ischemic stroke. METHODS: Fifteen representative chemical markers in DZT were determined by ultra-performance liquid chromatography coupled with tandem quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). The protective effect of DZT against ischemic stroke was studied in a rat model of middle cerebral artery occlusion (MCAO), and the mechanism was further explored through a combination of network pharmacology and experimental verification. RESULTS: Quantitative analysis showed that the contents of phenolic acids, furan sulfonic acids, tanshinones, flavonoids, saponins and phthalides in DZT were calculated as 7.47, 0.788, 0.627, 0.531 and 0.256 mg/g, respectively. Phenolic acids were the most abundant constituents. Orally administered DZT (1.701 g kg-1) significantly alleviated the infarct size and neurological scores in MCAO rats. The network analysis predicted that 53 absorbed active compounds in DZT-treated plasma targeted 189 proteins and 47 pathways. Ten pathways were associated with anti-platelet activity. In further experiments, DZT (0.4 and 0.8 mg mL-1) markedly inhibited in vitro prostaglandin G/H synthase 1 (PTGS1) activity. DZT (0.4 and 0.8 mg mL-1) significantly inhibited in vitro platelet aggregation in response to ADP or AA. DZT (113 and 226 mg kg-1, p.o.) also produced a marked inhibition of ADP- or AA-induced ex vivo platelet aggregation with a short duration of action. DZT decreased the level of thromboxane A2 (TXA2) in MCAO rats. In the carrageenan-induced tail thrombosis model and ADP-induced acute pulmonary thromboembolism mice model, DZT (113 and 226 mg kg-1, p.o.) prevented thrombus formation. Importantly, DZT (113 and 226 mg kg-1, p.o.) exhibited a low bleeding liability. CONCLUSION: DZT protected against cerebral ischemic injury. The inhibition of TXA2 level, platelet aggregation and thrombosis formation might involve in the protective mechanism.


Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Trombose/tratamento farmacológico , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacocinética , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Camundongos Endogâmicos ICR , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Embolia Pulmonar/tratamento farmacológico , Coelhos , Ratos Sprague-Dawley , Comprimidos , Trombose/induzido quimicamente , Tromboxano A2/metabolismo
9.
Zhonghua Xin Xue Guan Bing Za Zhi ; 48(9): 765-771, 2020 Sep 24.
Artigo em Chinês | MEDLINE | ID: mdl-32957760

RESUMO

Objective: To investigate the effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of acute coronary syndrome(ACS) patients undergoing percutaneous coronary intervention(PCI). Methods: This study was a retrospective cohort study. ACS patients who underwent PCI in Beijing Anzhen Hospital from October 2015 to January 2017 were recruited. The inhibition rate of adenosine diphosphate(ADP) was monitored by thromboelastography. All of these patients were divided into clopidogrel resistance and non-resistance group according to the monitoring results. CYP2C19 genotype was detected by TaqMan probe-based real-time quantitative PCR. Patients were divided into slow, medium and fast metabolic group, according to the CYP2C19 genotype. After 12 months of follow-up, the end points included all-cause death, cardiac death, angina, myocardial infarction, stent thrombosis, ischemic stroke and hemorrhage were collected. Combined thrombotic events were defined as a composite of angina, myocardial infarction, stent thrombosis and ischemic stroke. The differences of the incidence of clinical events between groups were compared. Cox regression was used to analyze the effects of clopidogrel resistance and CYP2C19 genotype on the combined thrombotic events, cardiac death and hemorrhage. Results: A total of 1 696 patients were included, and the age was (59.4±9.6) years, with 1 280(75.5%) males. There were 471 cases(27.8%) in clopidogrel resistance group, and 1 225 cases(72.2%) in clopidogrel non-resistance group. There were 218 patients(12.9%) were in slow metabolic group, 668(39.4%) in medium metabolic group, and 810 (47.8%) in fast metabolic group. The median follow-up time was 13.3 months, and 131 cases were lost to follow-up, with a loss follow-up rate of 7.7%. Compared with the clopidogrel non-resistance group, the clopidogrel resistance group had a higher incidence of myocardial infarction(7.6%(36/471) vs. 5.1%(62/1 225), P=0.041), a lower incidence of hemorrhage (13.2%(62/471) vs. 17.9%(219/1 225), P=0.020) and minor hemorrhage(11.5%(54/471) vs. 15.8% (194/1 225), P=0.022). There were no statistically significant difference in all-cause death, cardiac death, angina, stent thrombosis, ischemic stroke and severe bleeding between clopidogrel resistance and non-resistance group(all P>0.05). There was no statistically significant difference in the incidence of endpoint events among different CYP2C19 genotypes (all P>0.05). Cox regression analysis showed that clopidogrel resistance was an independent factor of combined thrombotic events (OR=2.334, 95%CI 1.215-4.443, P=0.016) and bleeding events (OR=0.481, 95%CI 0.174-0.901, P=0.023). While CYP2C19 genotype was not independent factor for combined thrombotic events, cardiac death and hemorrhage (all P>0.05). Conclusion: For ACS patients after PCI, clopidogrel resistance can increase the risk of combined thrombotic events, but also reduce the risk of bleeding; while CYP2C19 genotype is not an independent factor for clinical prognosis.


Assuntos
Síndrome Coronariana Aguda , Clopidogrel , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/genética , Clopidogrel/farmacologia , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/genética , Genótipo , Humanos , Masculino , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
10.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1865(12): 158804, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32853794

RESUMO

Platelet 12-lipoxygenase(p-12-LOX) is highly expressed in human platelets, and the development of p-12-LOX inhibitors has the potential to be a novel antithrombotic tool by inhibiting thrombosis without prolonging hemostasis. A chiral liquid chromatography-mass spectrometry(LC-MS/MS) method was used to assess the impact of three commercially available LOX inhibitors[esculetin(6,7-dihydroxycoumarin), ML-355(N-2-benzothiazolyl-4-[[(2-hydroxy-3-methoxyphenyl)methyl]amino]-benzenesulfonamide), CDC(cinnamyl-3,4-dihydroxy-α-cyanocinnamate) and acetylsalicylic acid(ASA; a cyclooxygenase-1 inhibitor) on the generation of prostanoids and HETEs(hydroxyeicosatetraenoic acids) in human whole blood allowed to clot for 1 h at 37 °C(serum), platelet-rich plasma(PRP) stimulated with collagen or TRAP-6(a peptide activating thrombin receptor) and washed platelets. In serum, ML-355 did not affect eicosanoid generation, while CDC caused an incomplete reduction of 12S-HETE levels; esculetin inhibited both 12S-HETE and thromboxane(TX)B2 production; ASA selectively affected TXB2 production. In washed platelets stimulated with thrombin, esculetin, and CDC inhibited both 12S-HETE and TXB2 while ML-355 was almost ineffective. In PRP, ML-355, CDC, and esculetin did not affect platelet aggregation associated with incomplete effects on eicosanoid biosynthesis. ASA alone or in combination with ticagrelor(a P2Y12 blocker) affected platelet aggregation associated with profound inhibition of TXB2 generation. P2Y12 receptor signaling contributed to platelet 12S-HETE biosynthesis in response to primary agonists. In conclusion, ML-355, esculetin, and CDC were not selective inhibitors of p-12-LOX in different cellular systems. They did not affect platelet aggregation induced in PRP by collagen or TRAP-6. The characterization of 12-LOX inhibitors on eicosanoids generated in human whole blood is useful for information on their enzyme selectivity, off-target effects, and the possible influence of plasma components on their pharmacological effects.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Inibidores da Agregação de Plaquetas/farmacologia , Prostaglandinas/metabolismo , Adulto , Aspirina/farmacologia , Plaquetas/metabolismo , Descoberta de Drogas , Humanos , Ácidos Hidroxieicosatetraenoicos/sangue , Lipidômica , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Prostaglandinas/sangue , Ticagrelor/farmacologia , Adulto Jovem
11.
Stroke ; 51(9): 2795-2800, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32772685

RESUMO

BACKGROUND AND PURPOSE: Hemorrhages are a serious complication of brain surgery, and magnesium has shown hemostatic properties in hemorrhagic stroke and non-neurological surgeries. External ventricular drain (EVD) insertion is an advantageous model of emergency neurosurgical hemorrhage risk because it is common, standardized, and the operator is blinded to the outcome during the procedure. We tested the hypothesis that low magnesium is associated with risk of hemorrhagic complications from EVD insertion. METHODS: Patients with spontaneous intracerebral hemorrhage and aneurysmal subarachnoid hemorrhage were enrolled in a prospective, observational study. Demographic and clinical variables were prospectively recorded, including serum magnesium measurements. Catheter tract hemorrhage (CTH) was measured on postoperative head computed tomography within 48 hours of EVD insertion. RESULTS: We observed 50 CTH among 327 EVD procedures (15.3%) distributed similarly among intracerebral hemorrhage (21/116 [18.1%]) and subarachnoid hemorrhage (29/211 [13.7%]). Magnesium was lower in patients with CTH compared with those without (median 1.8 versus 2.0 mg/dL, P<0.0001). Higher magnesium was associated with lower odds of CTH (odds ratio 0.67 per 0.1 mg/dL magnesium [95% CI, 0.56-0.78], P<0.0001) after adjustment for other risk factors, with similar effect in the intracerebral hemorrhage and subarachnoid hemorrhage subgroups. Preprocedural increase in magnesium (odds ratio 0.68 [0.52-0.85]) and dose of preprocedural magnesium sulfate (odds ratio 0.67 [0.40-0.97]) were associated with reduced CTH risk after adjustment for initial magnesium and other risk factors. CONCLUSIONS: Lower magnesium at the time of EVD insertion was an independent predictor of hemorrhagic complications. Baseline risk was attenuated by preprocedural increases in magnesium, suggesting a therapeutic opportunity.


Assuntos
Hemorragia Cerebral/etiologia , Deficiência de Magnésio/complicações , Sulfato de Magnésio/uso terapêutico , Ventriculostomia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Cateteres/efeitos adversos , Hemorragia Cerebral/diagnóstico por imagem , Feminino , Humanos , Deficiência de Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/farmacologia , Complicações Pós-Operatórias , Estudos Prospectivos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/diagnóstico por imagem , Tomografia Computadorizada por Raios X
12.
Arterioscler Thromb Vasc Biol ; 40(10): 2360-2375, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787516

RESUMO

OBJECTIVE: Platelet activation by stimulatory factors leads to an increase in intracellular calcium concentration ([Ca2+]i), which is essential for almost all platelet functions. Modulation of Ca2+ influx and [Ca2+]i in platelets has been emerging as a possible strategy for preventing and treating platelet-dependent thrombosis. Voltage-gated potassium 1.3 channels (Kv1.3) are highly expressed in platelets and able to regulate agonist-evoked [Ca2+]i increase. However, the role of Kv1.3 channels in regulating platelet functions and thrombosis has not yet been elucidated. In addition, it is difficult to obtain a specific blocker for this channel, since Kv1.3 shares identical drug-binding sites with other K+ channels. Here, we investigate whether specific blockade of Kv1.3 channels by monoclonal antibodies affects platelet functions and thrombosis. Approach and Results: In this study, we produced the anti-Kv1.3 monoclonal antibody 6E12#15, which could specifically recognize both human and mouse Kv1.3 proteins and sufficiently block Kv1.3 channel currents. We found Kv1.3 blockade by 6E12#15 inhibited platelet aggregation, adhesion, and activation upon agonist stimulation. In vivo treatment with 6E12#15 alleviated thrombus formation in a mesenteric arteriole thrombosis mouse model and protected mice from collagen/epinephrine-induced pulmonary thromboembolism. Furthermore, we observed Kv1.3 regulated platelet functions by modulating Ca2+ influx and [Ca2+]i elevation, and that this is mediated in part by P2X1. Interestingly, Kv1.3-/- mice showed impaired platelet aggregation while displayed no abnormalities in in vivo thrombus formation. This phenomenon was related to more megakaryocytes and platelets produced in Kv1.3-/- mice compared with wild-type mice. CONCLUSIONS: We showed specific inhibition of Kv1.3 by the novel monoclonal antibody 6E12#15 suppressed platelet functions and platelet-dependent thrombosis through modulating platelet [Ca2+]i elevation. These results indicate that Kv1.3 could act as a promising therapeutic target for antiplatelet therapies.


Assuntos
Anticorpos Monoclonais/farmacologia , Plaquetas/efeitos dos fármacos , Fibrinolíticos/farmacologia , Canal de Potássio Kv1.3/antagonistas & inibidores , Inibidores da Agregação de Plaquetas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Embolia Pulmonar/prevenção & controle , Trombose/prevenção & controle , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/metabolismo , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Canal de Potássio Kv1.3/sangue , Canal de Potássio Kv1.3/deficiência , Canal de Potássio Kv1.3/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ativação Plaquetária/efeitos dos fármacos , Embolia Pulmonar/sangue , Embolia Pulmonar/genética , Embolia Pulmonar/metabolismo , Transdução de Sinais , Trombose/sangue , Trombose/genética , Trombose/metabolismo
13.
Arterioscler Thromb Vasc Biol ; 40(10): 2376-2390, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787519

RESUMO

OBJECTIVES: Carbon monoxide (CO) produced by haem oxygenases or released by CO-releasing molecules (CORM) affords antiplatelet effects, but the mechanism involved has not been defined. Here, we tested the hypothesis that CO-induced inhibition of human platelet aggregation is mediated by modulation of platelet bioenergetics. Approach and Results: To analyze the effects of CORM-A1 on human platelet aggregation and bioenergetics, a light transmission aggregometry, Seahorse XFe technique and liquid chromatography tandem-mass spectrometry-based metabolomics were used. CORM-A1-induced inhibition of platelet aggregation was accompanied by the inhibition of mitochondrial respiration and glycolysis. Interestingly, specific inhibitors of these processes applied individually, in contrast to combined treatment, did not inhibit platelet aggregation considerably. A CORM-A1-induced delay of tricarboxylic acid cycle was associated with oxidized nicotinamide adenine dinucleotide (NAD+) depletion, compatible with the inhibition of oxidative phosphorylation. CORM-A1 provoked an increase in concentrations of proximal (before GAPDH [glyceraldehyde 3-phosphate dehydrogenase]), but not distal glycolysis metabolites, suggesting that CO delayed glycolysis at the level of NAD+-dependent GAPDH; however, GAPDH activity was directly not inhibited. In the presence of exogenous pyruvate, CORM-A1-induced inhibition of platelet aggregation and glycolysis were lost, but were restored by the inhibition of lactate dehydrogenase, involved in cytosolic NAD+ regeneration, pointing out to the key role of NAD+ depletion in the inhibition of platelet bioenergetics by CORM-A1. CONCLUSIONS: The antiplatelet effect of CO is mediated by inhibition of mitochondrial respiration-attributed to the inhibition of cytochrome c oxidase, and inhibition of glycolysis-ascribed to cytosolic NAD+ depletion.


Assuntos
Trifosfato de Adenosina/metabolismo , Plaquetas/efeitos dos fármacos , Boranos/farmacologia , Monóxido de Carbono/farmacologia , Carbonatos/farmacologia , Glicólise/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , NAD/metabolismo , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Plaquetas/metabolismo , Respiração Celular/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Masculino , Mitocôndrias/metabolismo
14.
Br J Pharmacol ; 177(21): 4971-4974, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32639031

RESUMO

In the search to rapidly identify effective therapies that will mitigate the morbidity and mortality of COVID-19, attention has been directed towards the repurposing of existing drugs. Candidates for repurposing include drugs that target COVID-19 pathobiology, including agents that alter angiotensin signalling. Recent data indicate that key findings in COVID-19 patients include thrombosis and endotheliitis. Activation of proteinase-activated receptor 1 (PAR1), in particular by the serine protease thrombin, is a critical element in platelet aggregation and coagulation. PAR1 activation also impacts on the actions of other cell types involved in COVID-19 pathobiology, including endothelial cells, fibroblasts and pulmonary alveolar epithelial cells. Vorapaxar is an approved inhibitor of PAR1, used for treatment of patients with myocardial infarction or peripheral arterial disease. We discuss evidence for a possible beneficial role for vorapaxar in the treatment of COVID-19 patients and other as-yet non-approved antagonists of PAR1 and proteinase-activated receptor 4 (PAR4). LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Lactonas/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Piridinas/administração & dosagem , Receptor PAR-1/antagonistas & inibidores , Animais , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Humanos , Lactonas/farmacologia , Pandemias , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/farmacologia , Pneumonia Viral/virologia , Piridinas/farmacologia , Receptor PAR-1/metabolismo , Receptores de Trombina/antagonistas & inibidores , Receptores de Trombina/metabolismo
15.
BMC Complement Med Ther ; 20(1): 204, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32615977

RESUMO

BACKGROUND: Omega-3 and acetylsalicylic acid (ASA) are two widely used "over-the-counter" drugs. Previous research has shown multiple electrode aggregometry (MEA) can detect ASA and varying Omega-3 platelet inhibiting effects. Synergistic platelet inhibiting effects of ASA and Omega-3 have been found using other methods than MEA. The aim of this study was to investigate the antiplatelet effects of Omega-3, and ASA synergism with MEA. METHODS: Ten healthy male volunteers ingested Omega-3 (1260 mg/day) for 5 days. MEA was used to analyse platelet function before and after Omega-3 intake. Aggregation was initiated using three different agonists and measured as area under the curve (AUC): adenosine diphosphate (ADP), thrombin receptor activating peptide (TRAP) and arachidonic acid (ASPI). Two concentrations of ASA were dose titrated ex vivo to 2 out of 3 ASPI test cells in order to measure synergism between Omega-3 and ASA. RESULTS: Following 5 days Omega-3 intake, ADP, TRAP and ASPI AUC did not change significantly. In vitro ASA before Omega-3 intake, reduced ASPI AUC < 30 U, indicating a strong platelet inhibiting effect. Below this AUC level, the 5 days Omega-3 intake increased ASPI-AUC with the ex vivo added low dose ASA (P = 0.02) and high dose ASA (P = 0.04). CONCLUSIONS: No synergism between ASA and Omega-3 was found using the MEA ASPI test. The surprising increase in ASPI-AUC following Omega-3 intake and ex vivo ASA suggest that there are methodological issuses with the MEA ASPI test. TRIAL REGISTRATION: Trial registration ISRCTN78027929 . Registered 19 May 2015.


Assuntos
Aspirina/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/metabolismo , Adulto , Ácido Araquidônico/metabolismo , Aspirina/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Ácidos Graxos Ômega-3/administração & dosagem , Humanos , Masculino , Fragmentos de Peptídeos/metabolismo , Inibidores da Agregação de Plaquetas/administração & dosagem , Adulto Jovem
16.
Biochem Pharmacol ; 181: 114149, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32663453

RESUMO

Snake venoms consist of a complex mixture of many bioactive molecules. Among them are disintegrins, which are peptides without enzymatic activity, but with high binding affinity for integrins, transmembrane receptors that function to connect cells with components of the extracellular matrix. Integrin-mediated cell attachment is critical for cell migration and dissemination, as well as for signal transduction pathways involved in cell growth. During tumor development, integrins play key roles by supporting cancer cell proliferation, angiogenesis, and metastasis. The recognition that snake venom disintegrins can block integrin functions has spawned a number of studies to explore their cancer therapeutic potential. While dozens of different disintegrins have been isolated, none of them as yet has undergone clinical evaluation in cancer patients. Among the best-characterized and preclinically most advanced disintegrins is vicrostatin (VCN), a recombinant disintegrin that was rationally designed by fusing 62 N-terminal amino acids derived from the disintegrin contortrostatin with 6 C-terminal amino acids from echistatin, the disintegrins from another snake species. Bacterially produced VCN was shown to target multiple tumor-associated integrins, achieving potent anti-tumor and anti-angiogenic effects in in vitro and in vivo models in the absence of noticeable toxicity. This review will introduce the field of snake venom disintegrins as potential anticancer agents and illustrate the translational development and cancer-therapeutic potential of VCN as an example.


Assuntos
Antineoplásicos/farmacologia , Desintegrinas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Desintegrinas/química , Desintegrinas/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Venenos de Serpentes/química , Venenos de Serpentes/metabolismo
17.
Sci Rep ; 10(1): 12135, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699337

RESUMO

While the patency of vascular access is essential for hemodialysis patients, optimal pharmaceutical treatment to maintain arteriovenous fistula (AVF) patency remains lacking. As cardiovascular diseases are highly prevalent in patients with end-stage renal disease, various cardiovascular medications have also been used to maintain AVF patency. However, previous studies revealed inconsistent therapeutic effects and a comprehensive evaluation of this issue is needed. The present retrospective, longitudinal cohort study included patients receiving successful AVF creation. The evaluated cardiovascular medications included antiplatelet agents, antihypertensive agents, nitrates and nitrites, statins, dipyridamole, and pentoxifylline. The outcome was AVF primary patency. All laboratory data and medication profiles were recorded at baseline and followed at 3-month interval, until the end of the 2-year study period. Cox proportional regression model with time-dependent covariates was used to evaluate the risk for AVF patency loss. A total of 349 patients were included in the present study, in which 57% were men and the mean age was 65 ± 14 years. Among the included patients, 40% used antiplatelet agents, 27% used dipyridamole and 36% used statins at baseline. Of all the evaluated cardiovascular medications, only dipyridamole showed significant association with a higher risk for loss of AVF patency. To evaluate the effect of combination of antiplatelet agents and dipyridamole, the patients were classified into four groups, I: combine use of antiplatelet agents and dipyridamole, II: antiplatelet only, III: dipyridamole only; IV: none of both were used. Of the four groups, group IV exhibited highest AVF patency (52.4%), which was followed by group III (42.7%), group II (40%), and group I (28.6%), respectively. Compared with group IV, only group I showed a significantly higher risk for AVF patency loss. None of the cardiovascular medications evaluated in the present study showed a beneficial effect on AVF patency. Furthermore, dipyridamole showed an association with a higher risk of AVF patency loss. We do not suggest a beneficial effect of dipyridamole on maintaining AVF patency, particularly in combination with antiplatelet agents.


Assuntos
Fístula Arteriovenosa/etiologia , Dipiridamol/efeitos adversos , Inibidores da Agregação de Plaquetas/efeitos adversos , Idoso , Fístula Arteriovenosa/diagnóstico , Doença da Artéria Coronariana/tratamento farmacológico , Dipiridamol/farmacologia , Dipiridamol/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Falência Renal Crônica/patologia , Falência Renal Crônica/terapia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Modelos de Riscos Proporcionais , Diálise Renal , Estudos Retrospectivos , Fatores de Risco , Grau de Desobstrução Vascular/efeitos dos fármacos
19.
Food Chem ; 332: 127384, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32615384

RESUMO

Dairy polar lipids (PL) seem to exhibit antiplatelet effects. However, it is not known what molecular species may be responsible. In this study, we confirmed using C30 reversed-phase (C30RP) ultra-high-performance liquid chromatography (UHPLC) coupled to high resolution accurate mass tandem mass spectrometry (HRAM-MS/MS) that fermentation of yoghurts from ovine milk using specific starter cultures altered the PL composition. These lipid alterations occurred concomitant with increased antithrombotic properties of the yoghurts PL fractions against platelet-activating factor (PAF) and thrombin-induced platelet aggregation. Specifically, elevation in phosphatidylethanolamine (PE), sphingomyelin (SM), phosphatidylcholine (PC) and their molecular species were observed following yoghurt fermentation. Furthermore, PC(18:0/18:1), PE(18:1/18:2), SM(d18:0/22:0) and several other molecular species were significantly inversely correlated with the inhibition of PAF and thrombin. These molecular species were abundant in the most bioactive yoghurts fermented by S. thermophilus and L. acidophilus, which suggest that fermentation by these microorganisms increases the antithrombotic properties of ovine milk PL.


Assuntos
Lipídeos/análise , Leite/metabolismo , Inibidores da Agregação de Plaquetas/análise , Iogurte/análise , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Cromatografia Líquida de Alta Pressão , Fermentação , Lipídeos/farmacologia , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Ovinos , Esfingomielinas/metabolismo , Espectrometria de Massas em Tandem , Trombina/farmacologia
20.
Arterioscler Thromb Vasc Biol ; 40(9): 2127-2142, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32698684

RESUMO

OBJECTIVE: Atherothrombosis occurs upon rupture of an atherosclerotic plaque and leads to the formation of a mural thrombus. Computational fluid dynamics and numerical models indicated that the mechanical stress applied to a thrombus increases dramatically as a thrombus grows, and that strong inter-platelet interactions are essential to maintain its stability. We investigated whether GPVI (glycoprotein VI)-mediated platelet activation helps to maintain thrombus stability by using real-time video-microscopy. Approach and Results: We showed that GPVI blockade with 2 distinct Fab fragments promoted efficient disaggregation of human thrombi preformed on collagen or on human atherosclerotic plaque material in the absence of thrombin. ACT017-induced disaggregation was achieved under arterial blood flow conditions, and its effect increased with wall shear rate. GPVI regulated platelet activation within a growing thrombus as evidenced by the loss in thrombus contraction when GPVI was blocked, and the absence of the disaggregating effect of an anti-GPVI agent when the thrombi were fully activated with soluble agonists. The GPVI-dependent thrombus stabilizing effect was further supported by the fact that inhibition of any of the 4 key immunoreceptor tyrosine-based motif signalling molecules, src-kinases, Syk, PI3Kß, or phospholipase C, resulted in kinetics of thrombus disaggregation similar to ACT017. The absence of ACT017-induced disaggregation of thrombi from 2 afibrinogenemic patients suggests that the role of GPVI requires interaction with fibrinogen. Finally, platelet disaggregation of fibrin-rich thrombi was also promoted by ACT017 in combination with r-tPA (recombinant tissue plasminogen activator). CONCLUSIONS: This work identifies an unrecognized role for GPVI in maintaining thrombus stability and suggests that targeting GPVI could dissolve platelet aggregates with a poor fibrin content.


Assuntos
Afibrinogenemia/sangue , Plaquetas/efeitos dos fármacos , Fibrinogênio/metabolismo , Fragmentos Fab das Imunoglobulinas/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Trombose/tratamento farmacológico , Afibrinogenemia/diagnóstico , Afibrinogenemia/genética , Plaquetas/metabolismo , Simulação por Computador , Fibrinogênio/genética , Fibrinolíticos/farmacologia , Humanos , Cinética , Microscopia de Vídeo , Modelos Biológicos , Glicoproteínas da Membrana de Plaquetas/metabolismo , Transdução de Sinais , Estresse Mecânico , Trombina/metabolismo , Trombose/sangue , Trombose/diagnóstico , Trombose/genética
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