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1.
Toxicon ; 187: 223-231, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32971099

RESUMO

Snake venom metalloproteinases (SVMPs) are an important component in viperid and crotalid venoms, and these SVMPs play important and versatile roles in the pathogenesis of snakebite envenoming. The SVMPs from elapid venoms are not well elucidated compared with those from viperid and crotalid venoms. Atrase B is a nonhemorrhagic P-III SVMP purified from the Naja atra venom, which possesses a weak fibrinogenolytic activity. In this paper, the activity and mechanism of atrase B against platelet aggregation and blood coagulation were investigated. The in vitro assay showed that atrase B remarkably inhibited ristocetin- and thrombin-induced platelet aggregation by cleavage of the platelet membrane glycoprotein Ib, and the coagulation of normal human plasma, which may be caused by inhibiting coagulation factor VIII predominantly. When atrase B was intravenously injected into rats at doses of 0.05 and 0.30 mg/kg, the activated partial thromboplastin and the thrombin times were significantly prolonged in a dose-dependent manner. Similarly, the fibrinogen level decreased, but only a high dose of atrase B showed remarkable activity against platelet aggregation. Results suggested that anticoagulation was a more important function of atrase B compared with its activity against platelet aggregation. These results indicated that atrase B may play an important role in the anticoagulant properties of Naja atra venom. In addition, atrase B may be a potent anticoagulant agent because its effectiveness in vivo against platelet aggregation and blood coagulation.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Venenos Elapídicos/toxicidade , Metaloproteases/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Animais , Humanos , Ratos
2.
Chem Biol Interact ; 329: 109223, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32781033

RESUMO

Thromboembolism is a major cause of morbidity and mortality worldwide. Most therapeutic drugs for treating thrombosis can cause hemorrhage and have short half-lives within human blood circulation resulting in a need to discover and develop novel anticoagulants/antithrombotics. EuRP-61 has been isolated from a plant latex (Euphorbia resinifera) and characterized as a serine protease. In this study, EuRP-61 was able to hydrolyze all chains of human fibrin clots. The enzyme may have long term stability in blood circulation as its fibrinogenolytic activity was not affected by human blood circulating inhibitors such as α2-macroglobulin and antithrombin III. The enzyme may affect the extrinsic, intrinsic or common pathways of the human blood coagulation cascade as evidenced by its prolonged of both prothrombin (PT) and activated partial thromboplastin (APTT) time. Moreover, the enzyme inhibited platelet aggregation via the ADP-receptor pathway. EuRP-61 was not toxic to human red blood cells in the 4 common blood groups (A, B, O and AB) (all Rh+) or human peripheral blood mononuclear cells (hPBMCs). The enzyme may protect human peripheral blood cells from aggregation without destroying them. This study provides evidence that EuRP-61 may have potential as an agent for the treatment of thrombosis.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Euphorbia/enzimologia , Fibrinolíticos/farmacologia , Peptídeo Hidrolases/farmacologia , Proteínas de Plantas/farmacologia , Anticoagulantes/isolamento & purificação , Antitrombina III/antagonistas & inibidores , Antitrombina III/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Fibrinolíticos/isolamento & purificação , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Peptídeo Hidrolases/isolamento & purificação , Proteínas de Plantas/isolamento & purificação , Agregação Plaquetária/efeitos dos fármacos , alfa 2-Macroglobulinas Associadas à Gravidez/antagonistas & inibidores , alfa 2-Macroglobulinas Associadas à Gravidez/metabolismo
3.
Vasc Endovascular Surg ; 54(8): 712-717, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32856558

RESUMO

BACKGROUND: Platelet inhibitory therapy is prescribed to prevent arterial thromboembolism in patients with atherosclerotic disease. Although taken by millions of people, around 30% are resistant to the treatment they are being prescribed. AIMS: To determine whether symptoms of cerebral ischemia, or pre-operative cerebral emboli, in patients admitted for a carotid endarterectomy were associated with resistance to aspirin or clopidogrel. METHODS: Venous blood from 133 patients immediately before carotid endarterectomy (CEA) was analyzed for resistance to aspirin and clopidogrel by multiplate impedance aggregometry. The number of emboli/hour entering the ipsilateral middle cerebral artery was counted by transcranial Doppler (TCD) on the day before surgery in 33 of these patients. RESULTS: Resistance was found in 21 (26.3%) of 100 patients taking aspirin and 14 (42%) of 33 taking clopidogrel. Mean (sd) residual platelet aggregation was significantly higher at 41.9(32) Au in patients who had suffered recent symptoms of cerebral ischemia compared with 30.8(16) Au in asymptomatic patients (p = 0.012). Residual platelet aggregation also correlated significantly with the number of emboli/hour counted by TCD in the ipsilateral middle cerebral artery (r = 0.45, p = 0.009). CONCLUSION: Antiplatelet resistance was associated with the frequency of cerebral emboli and recent symptoms of cerebral ischemia in patients with carotid disease. Definitive clinical studies are needed to explore whether testing for antiplatelet resistance should be undertaken routinely in patients starting platelet inhibitory therapy for cardiovascular disease.


Assuntos
Aspirina/uso terapêutico , Doenças das Artérias Carótidas/tratamento farmacológico , Clopidogrel/uso terapêutico , Resistência a Medicamentos , Infarto da Artéria Cerebral Média/prevenção & controle , Embolia Intracraniana/prevenção & controle , Inibidores da Agregação de Plaquetas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Aspirina/efeitos adversos , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico por imagem , Clopidogrel/efeitos adversos , Feminino , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/etiologia , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/etiologia , Masculino , Inibidores da Agregação de Plaquetas/efeitos adversos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia Doppler Transcraniana
4.
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
5.
J Pharmacol Sci ; 144(1): 43-51, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32653340

RESUMO

Platelet activation is the primary cause of thrombosis. The P2X7 receptor (P2X7R) is a therapeutic target of thrombosis. However, it is still unknown whether P2X7R activation affects platelet thrombus. Our molecular docking results showed that entecavir as a P2X7R antagonist interacted perfectly with the human P2X7R (hP2X7R) in silico simulation studies. Furthermore, our experimental data revealed that entecavir could act as a P2X7R antagonist to exert cytoprotective effects against platelet activation via protecting mitochondrial function, improving lipid peroxidation and increasing antioxidant activity. Correlated with this, entecavir inhibited platelet aggregation, dense-granule secretion, P-selectin expression, integrin activation and Ca2+ increase. In experimental mouse model, entecavir could significantly inhibit arteriovenous thrombosis and prolong the bleeding time. Furthermore, we found that entecavir had no significant effect on prothrombin time (PT), activated partial thrombin time (APTT), thrombin time (TT), fibrinogen (FIB), mean platelet volume (MPV) and platelet counts (PLT). This study demonstrates that entecavir markedly prevents platelet activation and thrombosis through inhibiting P2X7R without affecting coagulation system. Therefore, entecavir may be a potential candidate for treating thrombosis disease.


Assuntos
Guanina/análogos & derivados , Ativação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Receptores Purinérgicos P2X7 , Trombose/prevenção & controle , Animais , Antioxidantes , Tempo de Sangramento , Coagulação Sanguínea/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Modelos Animais de Doenças , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Agregação Plaquetária/efeitos dos fármacos , Trombose/sangue
6.
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
8.
Adv Rheumatol ; 60(1): 32, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: covidwho-591986

RESUMO

Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.


Assuntos
Antimaláricos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Cloroquina/farmacologia , Hidroxicloroquina/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Infecções por Coronavirus/tratamento farmacológico , Erupção por Droga/etiologia , Interações Medicamentosas , Feminino , Glucose/metabolismo , Cardiopatias/induzido quimicamente , Humanos , Lipídeos/sangue , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/mortalidade , Masculino , Pandemias , Agregação Plaquetária/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Gravidez , Insuficiência Renal/prevenção & controle , Doenças Retinianas/induzido quimicamente , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia
9.
Adv Rheumatol ; 60(1): 32, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517786

RESUMO

Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.


Assuntos
Antimaláricos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Cloroquina/farmacologia , Hidroxicloroquina/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Infecções por Coronavirus/tratamento farmacológico , Erupção por Droga/etiologia , Interações Medicamentosas , Feminino , Glucose/metabolismo , Cardiopatias/induzido quimicamente , Humanos , Lipídeos/sangue , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/mortalidade , Masculino , Pandemias , Agregação Plaquetária/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Gravidez , Insuficiência Renal/prevenção & controle , Doenças Retinianas/induzido quimicamente , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia
10.
Platelets ; 31(6): 825-826, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32367749

RESUMO

EDTA dependent pseudothrombocytopenia (EDTA-PCTP) is a phenomenon that characterized by a spurious decrease of platelets in vitro due to the aggregation of platelets in EDTA anticoagulant blood samples. We report the first case of a transient appearance of EDTA-PCTP in a patient with 2019 novel coronavirus pneumonia (COVID-19). A 59-year-old woman was admitted to the isolated ward for severe type of 2019 novel coronavirus pneumonia. At the time of admission, her platelet count was in a normal range. Two days later, her platelet count decreased gradually without any signs or symptoms of bleeding. Since the peripheral blood smear showed a platelet aggregation, a blood sample anticoagulanted with citrate was tested and the number of platelet was normal. The phenomenon disappeared after 17 days when the patient was cured. This case emphasized the importance of peripheral blood smear and clinical manifestation, especially in the differential diagnosis of thrombocytopenia.


Assuntos
Betacoronavirus , Plaquetas/efeitos dos fármacos , Infecções por Coronavirus/sangue , Erros de Diagnóstico , Ácido Edético/farmacologia , Pandemias , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Pneumonia Viral/sangue , Trombocitopenia/diagnóstico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Reações Falso-Positivas , Feminino , Humanos , Pessoa de Meia-Idade , Transfusão de Plaquetas , Pneumonia Viral/complicações , Procedimentos Desnecessários
11.
Stroke ; 51(6): 1886-1890, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32404037

RESUMO

Background and Purpose- Previous experimental studies found that the infusion of human purified nascent HDL (high-density lipoprotein) significantly reduced infarct volume and hemorrhagic transformation rate by decreasing neutrophil recruitment. ApoA1-M (apolipoprotein A1-Milano) is a natural variant of human ApoA1 that confers protection against atherosclerosis. Recombinant ApoA1-M has been formulated as a complex with phospholipids to mimic the properties of nascent HDL. The aim of this study was to assess the impact of intravenous ApoA1-M in a transient middle cerebral artery occlusion stroke model in rats. Methods- In a first experiment, rats were subjected to 120-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused immediately or 4 hours after occlusion. In a second experiment, rats were subjected to 240-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused with or without recombinant tPA (tissue-type plasminogen activator) immediately after recanalization. Primary outcome criteria were the infarct volume and hemorrhagic transformation rate measured at 24 hours. Platelets, coagulation, and neutrophil activation biomarkers were measured in brain homogenates and plasma. Additional in vitro experiments studied the effects of ApoA1-M on platelet aggregation and platelet-neutrophil interactions. Results- The infusion of ApoA1-M immediately or 4 hours after 120-minute transient middle cerebral artery occlusion significantly reduced the infarct volume compared with saline (P=0.034 and P=0.036, respectively). Compared with tPA alone, co-administration of ApoA1-M and tPA showed similar rates of hemorrhagic transformation. ApoA1-M had no significant inhibition effect on neutrophil activation biomarkers. Platelet activation was slightly decreased in rats treated with ApoA1-M compared with saline. In vitro, the incubation of human and rat platelet-rich plasma with ApoA1-M significantly reduced ADP-induced platelet aggregation (P=0.001 and P=0.02, respectively). Conclusions- ApoA1-Milano significantly decreased the infarct volume through an inhibition of platelet aggregation but did not reduce hemorrhagic transformation and neutrophils activation as expected after previous experimental studies with nascent HDL. Visual Overview- An online visual overview is available for this article.


Assuntos
Apolipoproteína A-I/farmacologia , Aterosclerose/prevenção & controle , Infarto da Artéria Cerebral Média/prevenção & controle , Animais , Aterosclerose/sangue , Aterosclerose/patologia , Biomarcadores/sangue , Plaquetas/metabolismo , Plaquetas/patologia , Modelos Animais de Doenças , Humanos , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/patologia , Masculino , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Agregação Plaquetária/efeitos dos fármacos , Ratos , Proteínas Recombinantes/farmacologia
12.
J Stroke Cerebrovasc Dis ; 29(7): 104877, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32414579

RESUMO

OBJECTIVES: To assess the prevalence of high on-clopidogrel platelet reactivity (HCPR) in patients with ischaemic stroke or transient ischaemic attack (IS/TIA), their outcome and genetic basis of on-treatment response variability in IS/TIA patients. METHODS: We conducted a comprehensive search of PubMed and EMBASE from their inceptions to March 9, 2019. Studies that reported absolute numbers/percentages of HCRP at any time point after IS/TIA onset evaluated with any type of platelet function tests, clinical outcomes and genotyping data were included. RESULTS: Among 21 studies of 4312 IS/TIA patients treated with clopidogrel, the pooled prevalence of HCPR was 28% (95%CI: 24-32%; high heterogeneity: I2 = 88.2%, p < 0.001). Heterogeneity degree diminished across groups defined by the HCPR testing method. Clopidogrel non-responder IS/TIA patients had poorer outcome compared to responders (RR = 2.09, 95%CI: 1.61-2.70; p = 0.036; low heterogeneity across studies: I2 = 27.4%, p = 0.210). IS/TIA carriers of CYP2C19*2 or CYP2C19*3 loss of function alleles had a higher risk of HCPR compared to wild type (RR = 1.69, 95%CI: 1.47-1.95; p < 0.001; I2 = 0.01%, p = 0.475). CONCLUSIONS: This systematic review shows a high prevalence of clopidogrel resistance in IS/TIA and poor outcome in these patients. CYP2C19 polymorphisms may potentially influence clopidogrel resistance.


Assuntos
Plaquetas/efeitos dos fármacos , Clopidogrel/uso terapêutico , Resistência a Medicamentos , Ataque Isquêmico Transitório/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Plaquetas/metabolismo , Clopidogrel/efeitos adversos , Clopidogrel/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Resistência a Medicamentos/genética , Humanos , Ataque Isquêmico Transitório/sangue , Ataque Isquêmico Transitório/diagnóstico , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Polimorfismo Genético , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Resultado do Tratamento
13.
Am J Chin Med ; 48(2): 259-286, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32345058

RESUMO

Many cultivated and wild plants are used for the management of various diseases, specifically renal and hepatic diseases and those of the immune and cardiovascular systems. In China, medicinal plants from ancient to modern history have been used in patients with angina pectoris, congestive heart failure (CHF), systolic hypertension, arrhythmia, and venous insufficiency for centuries. The latest increase in the fame of natural products and alternative medicine has revived interest in conventional remedies that have been consumed in the management of CVD. The cardio-protective properties of the various herbs are possibly due to their anti-oxidative, antihypercholesterolemic, anti-ischemic activities, and inhibition of platelet aggregation that reduce the risk of CVD. Ethno-pharmacological and biological properties of these plants are explored, based upon published scientific literature. Although a majority of medicinal plants having a biological mechanism that linked with CVD management, to date, published literature pertaining to their promising scientific properties are still poorly understood. Compared with synthetic medicines, alternative medicines do not need scientific studies before their formal approval from the government sector and due to this purpose; their safety, as well as efficacy, still remain elusive. Taken together, we addressed all accessible evidence on alternative medicines commonly consumed in CVD management. Our comprehensive analysis of the scientific literature indicated that many TCMs are available and valuable herbal medication would be the best alternative for the management of CVD as a complementary therapy. Furthermore, practitioners should always discuss possible benefits-risks of alternative medicines with patients so that they are aware of the consumption of alternative medications.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Fitoterapia , Extratos Vegetais/uso terapêutico , Plantas Medicinais/química , Medição de Risco , Antioxidantes , Cardiotônicos , Terapias Complementares , Humanos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Agregação Plaquetária/efeitos dos fármacos
14.
Comput Methods Biomech Biomed Engin ; 23(10): 611-626, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32310682

RESUMO

In our previous works, the transport of activated platelets (APs) on orifice flow has been simulated by finite difference method (FDM). And the distribution of AP concentration on the flow was obtained. However, the effect of platelet aggregation on the distribution of AP concentration can't be investigated by FDM because FDM can't simulate platelet aggregation. On the other hand, platelet aggregation has been simulated by dissipative particle dynamics (DPD). In this paper, a hybrid method combining FDM and DPD is proposed to investigate the effect of platelet aggregation on the distribution of AP concentration. And the hybrid method is used to simulate thrombus formation on orifice flow. As for the effect of platelet aggregation, it is found that the distribution of AP concentration in the hybrid method is different from the distribution in FDM at the places of platelet aggregation. It is considered that the difference is induced by platelet aggregation. As for the distribution of thrombus, higher AP concentration and more aggregated APs are found around the reattachment point and in the recirculation area. It is considered that thrombus is mainly distributed at these places in the simulation. And according to our previous experimental results, thrombus is mainly distributed around the reattachment point and in the recirculation area. It is concluded that the effect of platelet aggregation on the distribution of AP concentration can be investigated by the hybrid method, and the computational results agree with our previous experimental results.


Assuntos
Algoritmos , Circulação Sanguínea , Simulação por Computador , Trombose/sangue , Plaquetas/patologia , Humanos , Agregação Plaquetária/efeitos dos fármacos
15.
BMC Neurol ; 20(1): 159, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345264

RESUMO

BACKGROUND: Early neurological deterioration (END) is common in acute ischemic stroke (IS). However, the underlying mechanisms for END are unclear. The aim of this study was to evaluate the associations of 16 variants in clopidogrel-relevant genes and interactions among these variants with END in acute IS patients receiving clopidogrel treatment. METHODS: We consecutively enrolled 375 acute IS patients between June 2014 and January 2015. Platelet aggregation was measured on admission and after the 7-10 days of clopidogrel treatment. The 16 variants in clopidogrel-relevant genes were examined using mass spectrometry. The primary outcome was END within the 10 days of admission. Gene-gene interactions were analyzed by generalized multifactor dimensionality reduction (GMDR) methods. RESULTS: Among the 375 patients, 95 (25.3%) patients developed END within the first 10 days of admission. Among the 16 variants, only CYP2C19*2 (rs4244285) AA/AG was associated with END using single-locus analytical approach. GMDR analysis revealed that there was a synergistic effect of gene-gene interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 on the risk for END. The high-risk interactions among the three variants were associated with the higher platelet aggregation and independent predictor for END after adjusting for the covariates (hazard ratio: 2.82; 95% confidence interval: 1.36-7.76; P = 0.003). CONCLUSIONS: END is very common in patients with acute IS. The mechanisms leading to END are most likely multifactorial. Interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 may confer a higher risk for END. It was very important to modify clopidogrel therapy for the patients carrying the high-risk interactive genotypes. CLINICAL TRIAL REGISTRATION INFORMATION: The study described here is registered at http://www.chictr.org/ (unique Identifier: ChiCTR-OCH-14004724). The date of trial registration was May 30, 2014.


Assuntos
Isquemia Encefálica/genética , Clopidogrel/efeitos adversos , Citocromo P-450 CYP2C19/genética , Epistasia Genética/genética , Integrina beta3/genética , Agregação Plaquetária/genética , Receptores Purinérgicos P2Y12/genética , Recidiva , Acidente Vascular Cerebral/genética , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Clopidogrel/uso terapêutico , Genótipo , Humanos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/efeitos adversos , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico
16.
Arterioscler Thromb Vasc Biol ; 40(6): 1533-1542, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32268786

RESUMO

OBJECTIVE: Clopidogrel is a commonly used P2Y12 inhibitor to treat and prevent arterial thrombotic events. Clopidogrel is a prodrug that requires bioactivation by CYP (cytochrome P450) enzymes to exert antiplatelet activity. Diabetes mellitus is associated with an increased risk of ischemic events, and impaired ability to generate the active metabolite (AM) from clopidogrel. The objective of this study is to identify the mechanism of clopidogrel resistance in a murine model of diet-induced obesity (DIO). Approach and Results: C57BL/6J mice and IL-1R-/- mice were given high-fat diet for 10 weeks to generate a murine model of diet-induced obesity. Platelet aggregation and carotid arterial thrombosis were assessed in response to clopidogrel treatment. Wild-type DIO mice exhibited resistance to antiplatelet and antithrombotic effects of clopidogrel that was associated with reduced hepatic expression of CYP genes and reduced generation of the AM. IL (Interleukin)-1 receptor-deficient DIO (IL1R-/- DIO) mice showed no resistance to clopidogrel. Lack of resistance was accompanied by increased exposure of the clopidogrel AM. This resistance was also absent when wild-type DIO mice were treated with the conjugate of the clopidogrel AM, DT-678. CONCLUSIONS: These findings indicate that antiplatelet effects of clopidogrel may be impaired in the setting of diabetes mellitus due to reduced prodrug bioactivation related to IL-1 receptor signaling. Therapeutic targeting of P2Y12 in patients with diabetes mellitus using the conjugate of clopidogrel AM may lead to improved outcomes.


Assuntos
Clopidogrel/farmacocinética , Clopidogrel/uso terapêutico , Resistência a Medicamentos , Obesidade/complicações , Receptores de Interleucina-1/fisiologia , Animais , Trombose das Artérias Carótidas/prevenção & controle , Clopidogrel/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Diabetes Mellitus , Dieta Hiperlipídica , Modelos Animais de Doenças , Fibrinolíticos , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/enzimologia , Obesidade/etiologia , Obesidade/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Receptores de Interleucina-1/deficiência
17.
J Med Chem ; 63(11): 6164-6178, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32345019

RESUMO

Antagonists for the ATP-gated ion channel receptor P2X1 have potential as antithrombotics and for treating hyperactive bladder and inflammation. In this study, salicylanilide derivatives were synthesized based on a screening hit. P2X1 antagonistic potency was assessed in 1321N1 astrocytoma cells stably transfected with the human P2X1 receptor by measuring inhibition of the ATP-induced calcium influx. Structure-activity relationships were analyzed, and selectivity versus other P2X receptor subtypes was assessed. The most potent compounds, N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (1, IC50 0.0192 µM) and N-[3,5-bis(trifluoromethyl)phenyl]-4-chloro-2-hydroxybenzamide (14, IC50 0.0231 µM), displayed >500-fold selectivity versus P2X2 and P2X3, and 10-fold selectivity versus P2X4 and P2X7 receptors, and inhibited collagen-induced platelet aggregation. They behaved as negative allosteric modulators, and molecular modeling studies suggested an extracellular binding site. Besides selective P2X1 antagonists, compounds with ancillary P2X4 and/or P2X7 receptor inhibition were discovered. These compounds represent the first potent, non-acidic, allosteric P2X1 receptor antagonists reported to date.


Assuntos
Antagonistas do Receptor Purinérgico P2X/química , Receptores Purinérgicos P2X1/metabolismo , Salicilanilidas/química , Regulação Alostérica/efeitos dos fármacos , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Sítios de Ligação , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Cálcio/metabolismo , Linhagem Celular , Colágeno , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Dinâmica Molecular , Agregação Plaquetária/efeitos dos fármacos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Antagonistas do Receptor Purinérgico P2X/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X1/química , Salicilanilidas/metabolismo , Salicilanilidas/farmacologia , Relação Estrutura-Atividade
18.
Transfusion ; 60(5): 1050-1059, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32187695

RESUMO

BACKGROUND: Our previous study showed that ultraviolet C (UVC) from xenon (Xe) flash without any photoreactive compounds inactivated bacteria in platelet concentrates (PCs) with less damage to platelets (PLTs) as compared with Xe flash containing ultraviolet A, ultraviolet B, and visible light. Here, we report a UVC irradiation system for PCs under flow conditions consisting of a flow path-irradiation sheet, a peristaltic pump, and a collection bag. STUDY DESIGN AND METHODS: Platelet concentrates containing Ringer's solution (R-PCs) inoculated with bacteria were injected into a flow path sheet using a peristaltic pump, being irradiated with UVC from Xe flash. The quality of the irradiated PCs containing platelet additive solution (PAS-PCs) was assessed based on PC variables, PLT surface markers, and aggregation ability. RESULTS: Streptococcus dysgalactiae (12 tests) and Escherichia coli (11) were all negative on bacterial culture, while Staphylococcus aureus (12) and Klebsiella pneumoniae (14) grew in one and two R-PCs, respectively. Bacillus cereus spores were inactivated in 7 of 12 R-PCs. PC variables became significantly different between irradiated and nonirradiated PAS-PCs. P-selectin, first procaspase-activating compound (PAC-1) binding, and phosphatidylserine increased by irradiation. Aggregability stimulated by adenosine diphosphate, collagen, or thromboxane A2 increased in the irradiated PAS-PCs, while that by thrombin became smaller compared with nonirradiated controls. CONCLUSION: This newly developed system inactivated bacteria including spores in R-PCs. PAS-PCs irradiated by this system retained acceptable in vitro quality and aggregability. Usage of a peristaltic pump instead of agitator during irradiation may enable this system to be directly combined with an apheresis blood cell separator.


Assuntos
Plaquetas/citologia , Preservação de Sangue , Desinfecção/instrumentação , Viabilidade Microbiana , Raios Ultravioleta , Xenônio/farmacologia , Bacillus cereus/efeitos dos fármacos , Bacillus cereus/fisiologia , Bacillus cereus/efeitos da radiação , Bactérias/efeitos dos fármacos , Bactérias/efeitos da radiação , Remoção de Componentes Sanguíneos , Plaquetas/efeitos dos fármacos , Plaquetas/efeitos da radiação , Preservação de Sangue/instrumentação , Preservação de Sangue/métodos , Segurança do Sangue/instrumentação , Segurança do Sangue/métodos , Desinfecção/métodos , Contaminação de Medicamentos/prevenção & controle , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Escherichia coli/efeitos da radiação , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/fisiologia , Klebsiella pneumoniae/efeitos da radiação , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Viabilidade Microbiana/efeitos da radiação , Soluções para Preservação de Órgãos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/fisiologia , Agregação Plaquetária/efeitos da radiação , Controle de Qualidade , Solução de Ringer/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Staphylococcus aureus/efeitos da radiação , Streptococcus/efeitos dos fármacos , Streptococcus/fisiologia , Streptococcus/efeitos da radiação
19.
Transfusion ; 60(5): 1042-1049, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32187700

RESUMO

BACKGROUND: Some jurisdictions require leukoreduction of cellular blood components. The only whole blood collection set with a platelet-saving filter uses citrate-phosphate-dextrose (CPD) as storage solution. Substituting CPD with citrate-phosphate-dextrose-adenine (CPDA-1) increases shelf life from 21 to 35 days. This would simplify prehospital and rural resupply and reduce wastage. We investigated in vitro quality and hemostatic properties of CPDA-1 whole blood leukoreduced with a platelet-saving filter. STUDY DESIGN AND METHODS: CPDA-1 whole blood was leukoreduced using a platelet-saving filter and stored 35 days. EDQM requirements, hematology, metabolic parameters, thromboelastography, light transmission aggregometry, fibrinogen, factor VIII, and interleukin-6 were measured on Days 0, 1, 14, 21, and 35 and compared to non-leukoreduced blood. RESULTS: All units met EDQM requirements. Leukoreduction yielded residual white blood cell count <1 × 106 and 87% platelet recovery on Day 1. It caused reduction in thromboelastography parameters, but not aggregometry response. No hemolysis >0.8% was observed. Factor VIII was higher on Day 35 in the leukoreduced group, 37.9 (95% CI: 26.0, 49.8) versus 13.8 (9.4, 18.2) IU/dL. In both groups, aggregation was significantly reduced by Day 14. Thromboelastography showed remaining platelet activity on Day 35, MA 46.9 (42.1, 51.7) in the leukoreduced and 44.3 (39.6, 49.0) mm in the non-leukoreduced group. Fibrinogen was within reference ranges at Day 35 (>2 g/dL). Interleukin-6 was not detectable. CONCLUSION: Leukoreducing CPDA-1 whole blood with a platelet-saving filter did not compromise hemostatic properties. We encourage development of a single bag CPDA-1 whole blood collection set with in-line platelet-saving filter.


Assuntos
Adenina/química , Preservação de Sangue/métodos , Coleta de Amostras Sanguíneas/métodos , Citratos/química , Temperatura Baixa , Glucose/química , Procedimentos de Redução de Leucócitos/métodos , Fosfatos/química , Adenina/farmacologia , Sangue/efeitos dos fármacos , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Preservação de Sangue/normas , Coleta de Amostras Sanguíneas/normas , Citratos/farmacologia , Filtração/métodos , Glucose/farmacologia , Hemólise/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Humanos , Técnicas In Vitro , Procedimentos de Redução de Leucócitos/normas , Fosfatos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Controle de Qualidade , Refrigeração/métodos
20.
Carbohydr Polym ; 235: 115975, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32122506

RESUMO

The control of blood flow from breached blood vessels during surgery or trauma is challenging. With the existing treatment options being either expensive or ineffective, the development of a haemostat that overcome such drawbacks would be beneficial. With an aim to develop an ideal haemostat, the potential of sodium starch glycolate (SSG), a commonly used pharmaceutical disintegrant was modified to obtain porous microparticles (pSSG). The biodegradability, cyto-compatibility and haemo-compatibility of the modified particles were confirmed using appropriate studies. In comparison to starch and SSG, the irregular shaped pSSG demonstrated spontaneous and significant fluid absorption (3500+500 %) and formed a physical barrier to blood flow. In addition, significant blood cells aggregation and platelet activation was observed in the modified micoparticles leading to rapid clot formation. In-vivo studies on liver and abdominal artery injury models in rats indicated the superior haemostatic potential of pSSG over SSG and starch. The results indicated that pSSG can be explored further in clinical evaluation as a hemostat.


Assuntos
Hemostáticos/farmacologia , Amido/análogos & derivados , Eritrócitos/efeitos dos fármacos , Hemostáticos/síntese química , Hemostáticos/química , Humanos , Tamanho da Partícula , Agregação Plaquetária/efeitos dos fármacos , Porosidade , Amido/síntese química , Amido/química , Amido/farmacologia , Propriedades de Superfície
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