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1.
Angiol. (Barcelona) ; 72(4): 186-197, jul.-ago. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-193581

RESUMO

Los pacientes infectados por el nuevo coronavirus COVID-19 presentan un riesgo incrementado de enfermedad tromboembólica venosa (ETEV). La presente guía de práctica clínica del Capítulo Español de Flebología y Linfología y la Sociedad Española de Angiología y Cirugía Vascular pretende dar una serie de recomendaciones sobre profilaxis y tratamiento de la ETEV en los pacientes infectados por COVID-19, tanto a nivel hospitalario como ambulatorio, y consejos sobre su seguimiento clínico y ecográfico. Se recomienda que todos los pacientes con infección por COVID-19 hospitalizados, tengan o no factores de riesgo protrombótico asociados, reciban profilaxis antitrombótica, si no existe contraindicación. En caso de pacientes ambulatorios, según perfil clínico e historial médico, se recomienda valorar tromboprofilaxis con heparina de bajo peso molecular (HBPM), en ausencia de contraindicación. Ante el diagnóstico de TVP en paciente con COVID-19, tanto hospitalizado o ambulatorio, debe iniciarse el tratamiento anticoagulante con HBPM a dosis terapéuticas. No existen interacciones farmacológicas descritas de las HPBM con los fármacos empleados contra el COVID-19. Los niveles elevados de dímero-D son un hallazgo común en pacientes con COVID-19, por lo que este parámetro, de forma aislada, no es indicativo para realizar una ecografía Doppler de rutina. Se aconseja la realización de ecografía Doppler a un paciente COVID-19 positivo (con las medidas de protección necesarias) para descartar TVP solo en pacientes con alta sospecha clínica de TVP y cuando se dé una de las dos situaciones clínicas: alto riesgo de sangrado, o que exista un incremento brusco e inesperado de los niveles de dímero-D


Patients infected with the new coronavirus COVID-19 have an increased risk of venous thromboembolic disease (VTEV). The present clinical practice guide of the Spanish Chapter of Phlebology and Lymphology and the Spanish Society of Angiology and Vascular Surgery, aims to give a series of recommendations on prophylaxis and treatment of VTE in patients infected with COVID-19, both at the hospital and outpatient, and advice on their clinical and ultrasound monitoring. It is recommended that all hospitalized patients with COVID-19 infection, whether or not they have associated prothrombotic risk factors, should receive antithrombotic prophylaxis, if there is no contraindication. In the case of outpatients, according to clinical profile and medical history, it is recommended to evaluate thromboprophylaxis with low molecular weight heparin (LMWH), in the absence of contraindication. Given the diagnosis of DVT in a patient with COVID19, both hospitalized and outpatient, anticoagulant treatment with LMWH should be started at therapeutic doses. There are no described pharmacological interactions of HPBMs with the drugs used against COVID19. High levels of D-dimer are a common finding in patients with COVID-19, so this parameter, in isolation, is not indicative for routine Doppler ultrasound. Doppler ultrasound is recommended for a COVID-19 positive patient (with the necessary protective measures), to rule out DVT, only in patients with high clinical suspicion of DVT, and when one of the two clinical situations occurs: high risk of bleeding, or a sudden and unexpected increase in D-dimer levels


Assuntos
Humanos , Anticoagulantes/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/tratamento farmacológico , Fibrinolíticos/farmacologia , Pneumonia Viral/tratamento farmacológico , Embolia Pulmonar/tratamento farmacológico , Sociedades Médicas/normas , Pandemias , Fatores de Risco , Heparina de Baixo Peso Molecular/uso terapêutico , Ultrassonografia , Infecções por Coronavirus/fisiopatologia , Serviços de Assistência Domiciliar/normas
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.
Stroke ; 51(9): 2834-2843, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32772681

RESUMO

BACKGROUND AND PURPOSE: Rapamycin is a clinically approved mammalian target of rapamycin inhibitor that has been shown to be neuroprotective in animal models of stroke. However, the mechanism of rapamycin-induced neuroprotection is still being explored. Our aims were to determine if rapamycin improved leptomeningeal collateral perfusion, to determine if this is through eNOS (endothelial nitric oxide synthase)-mediated vessel dilation and to determine if rapamycin increases immediate postreperfusion blood flow. METHODS: Wistar and spontaneously hypertensive rats (≈14 weeks old, n=22 and n=15, respectively) were subjected to ischemia by middle cerebral artery occlusion (90 and 120 minutes, respectively) with or without treatment with rapamycin at 30-minute poststroke. Changes in middle cerebral artery and collateral perfusion territories were measured by dual-site laser Doppler. Reactivity to rapamycin was studied using isolated and pressurized leptomeningeal anastomoses. Brain injury was measured histologically or with triphenyltetrazolium chloride staining. RESULTS: In Wistar rats, rapamycin increased collateral perfusion (43±17%), increased reperfusion cerebral blood flow (16±8%) and significantly reduced infarct volume (35±6 versus 63±8 mm3, P<0.05). Rapamycin dilated leptomeningeal anastomoses by 80±9%, which was abolished by nitric oxide synthase inhibition. In spontaneously hypertensive rats, rapamycin increased collateral perfusion by 32±25%, reperfusion cerebral blood flow by 44±16%, without reducing acute infarct volume 2 hours postreperfusion. Reperfusion cerebral blood flow was a stronger predictor of brain damage than collateral perfusion in both Wistar and spontaneously hypertensive rats. CONCLUSIONS: Rapamycin increased collateral perfusion and reperfusion cerebral blood flow in both Wistar and comorbid spontaneously hypertensive rats that appeared to be mediated by enhancing eNOS activation. These findings suggest that rapamycin may be an effective acute therapy for increasing collateral flow and as an adjunct therapy to thrombolysis or thrombectomy to improve reperfusion blood flow.


Assuntos
Circulação Colateral/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Fibrinolíticos/farmacologia , Ataque Isquêmico Transitório/diagnóstico por imagem , Ataque Isquêmico Transitório/patologia , Fluxometria por Laser-Doppler , Masculino , Meninges/irrigação sanguínea , Meninges/diagnóstico por imagem , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Reperfusão
4.
J Stroke Cerebrovasc Dis ; 29(9): 105073, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807475

RESUMO

OBJECTIVE: Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral and intraventricular haemorrhage (ICH and IVH). However, the MISTIE III and CLEAR III trial failed to show significant improvement of favourable outcomes. Besides experimental and clinical trials revealed neurotoxic effects of rtPA. The demand for optimization of fibrinolytic therapy persists. Herein, we used our recently devised clot model of ICH to systematically analyse fibrinolytic properties of rtPA, tenecteplase and urokinase. METHODS: In vitro clots of human blood (size: 25 ml and 50 ml; age: 1.5 tenecteplase, 24 tenecteplase and 48 tenecteplase) were produced and equipped with a catheter into the clot core for drug delivery and drainage. Various doses of tenecteplase and urokinase with different treatment periods were examined (overall 117 clots), assessing the optimal dose and treatment time of these fibrinolytics. Clots were weighed before and at the end of treatment. These results were compared with clots treated with 1 mg rtPA or with 0.9% sodium chloride solution. RESULTS: The optimal treatment scheme of tenecteplase was found to be 100 IU with an incubation time of 30 min, for urokinase it was 50 000 IU with an incubation time of 20 min. The relative clot end weight of tenecteplase and urokinase (31.3±11.9%, 34.8 ±7.7%) was comparable to rtPA (36.7±10.7%). Larger clots were more effectively treated with tenecteplase compared to the control group (P=0.0013). urokinase and tenecteplase had similar lysis rates in aged clots and 90 min clots. One and two repetitive treatments with tenecteplase were as effective as two and three cycles of urokinase. CONCLUSIONS: In our in vitro clot model we could determine optimal treatment regimens of tenecteplase (100 IU, 30 min) and urokinase (50 000 IU, 20 min). Urokinase and tenecteplase were comparable in their fibrinolytic potential compared to 1mg rtPA in small clots and showed an effective lysis in aged clots. tenecteplase was more effective in larger clots.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/farmacologia , Tenecteplase/farmacologia , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/farmacologia , Hemorragia Cerebral/sangue , Relação Dose-Resposta a Droga , Humanos , Fatores de Tempo
5.
Eur Rev Med Pharmacol Sci ; 24(13): 7494-7496, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32706089

RESUMO

Although most patients with coronavirus disease 2019 (COVID-19) have a good prognosis, in some cases, the disease progresses rapidly, and the mortality rate is high. Some evidence suggests that infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produces a 'cytokine storm', which is related to acute respiratory distress syndrome or multi-organ dysfunction leading to physiological deterioration and death. It is important to highlight the state of hypercoagulability that can be triggered, involving microvascular thrombosis and vascular occlusive events, which are relevant to such poor outcomes. At present, no specific antiviral drug or vaccine is available for SARS-CoV-2 infection, and current research is aimed at preventing and mitigating damage to the target organs, mainly the lungs. In seeking therapies for patients with COVID-19, immunomodulators, cytokine antagonists and early anti-coagulation therapies have been tested in attempts to reduce the mortality rate. Pentoxifylline, a non-specific phosphodiesterase inhibitor widely used to improve the rheological properties of blood, has beneficial anti-inflammatory properties and can significantly reduce the serum levels of pro-inflammatory cytokines such as interleukin (IL)-6, IL-1, tumour necrosis factor-alpha, C-reactive protein and other immunoregulators. It has also been found to exert anti-thrombotic, antioxidant and anti-fibrogenic actions. These properties could help to prevent or mitigate the inflammatory response and hypercoagulability that develop with SARS-CoV-2 infection, decreasing multi-organ dysfunction manifesting primarily as acute lung injury.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Fibrinolíticos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Pandemias , Pentoxifilina/farmacologia
6.
Biomed Pharmacother ; 130: 110536, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32688139

RESUMO

In the last three months, the whole scientific community has shifted its focus to the fight against the COVI-2 infection (COVID-19) trying to use different medications to save the patients' life. In some studies, the results were completely inconclusive, as in the case of chloroquine. However, the recent discovery on benefits deriving from use of such anticoagulants for Covid-19 patients, has increased the success of patients' treatment. Among lots of old and new drugs, PARP-inhibitors were not considered as possible option in the treatment of Covi-2 infection, being the latter able to induce the inflammatory and thrombotic cascades. Since PARP-inhibitors are able to reduce and block mechanisms leading to thrombosis and inflammation, they could be used as antithrombotic medications. Therefore, the present brief report is aimed to open the discussion on the potentials of PARP-inhibitors in non-oncological settings, like Covid-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/sangue , Fibrinolíticos/uso terapêutico , Pandemias , Pneumonia Viral/sangue , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Trombofilia/tratamento farmacológico , Trombose/prevenção & controle , Anti-Inflamatórios/farmacologia , Infecções por Coronavirus/complicações , Reposicionamento de Medicamentos , Fibrinolíticos/farmacologia , Humanos , Inflamação , Pneumonia Viral/complicações , Poli(ADP-Ribose) Polimerase-1/fisiologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/fisiologia , Trombofilia/etiologia
7.
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
8.
Stroke ; 51(7): 2236-2239, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32568648

RESUMO

BACKGROUND AND PURPOSE: A recombinant engineered variant of APC (activated protein C), 3K3A-APC, lacks anticoagulant properties (<10%) while preserving APCs anti-inflammatory, anti-apoptotic, and neuroprotective functions and is very promising in clinical trials for ischemic stroke. Therapeutic intervention with single bolus administration of the third-generation tPA (tissue-type plasminogen activator), tenecteplase, is anticipated to be widely adopted for treatment of acute ischemic stroke. 3K3A-APC is well-tolerated in stroke patients dosed with alteplase, and in vitro studies show 3K3A-APC does not interfere with alteplase-induced clot lysis. The purpose of this in vitro study was to assess the influence of 3K3A-APC on tenecteplase-induced clot lysis. METHODS: Tenecteplase-mediated lysis of thrombin generated plasma clots of human normal pooled plasma was monitored in the presence of varying doses of 3K3A-APC. The effects on fibrinolysis by tenecteplase and alteplase were compared. RESULTS: The presence of 3K3A-APC shortened the time for clot lysis induced by tenecteplase at very low levels but not at higher therapeutic concentrations of tenecteplase. Comparisons of alteplase-mediated clot lysis to tenecteplase clot lysis showed that both thrombolytic agents behaved similarly in the presence of 3K3A-APC. CONCLUSIONS: These results indicate that 3K3A-APC does not interfere with tenecteplase's clot lysis function.


Assuntos
Fibrinólise/efeitos dos fármacos , Fibrinolíticos/farmacologia , Proteína C/farmacologia , Proteínas Recombinantes/farmacologia , Tenecteplase/farmacologia , Humanos , Técnicas In Vitro , Trombose
9.
J Am Coll Cardiol ; 75(23): 2950-2973, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: covidwho-547082

RESUMO

Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.


Assuntos
Anticoagulantes/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus , Fibrinolíticos/farmacologia , Pandemias , Inibidores da Agregação de Plaquetas/farmacologia , Pneumonia Viral , Tromboembolia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Humanos , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Tromboembolia/tratamento farmacológico , Tromboembolia/epidemiologia , Tromboembolia/etiologia , Tromboembolia/fisiopatologia , Resultado do Tratamento
10.
J Am Coll Cardiol ; 75(23): 2950-2973, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: covidwho-72088

RESUMO

Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.


Assuntos
Anticoagulantes/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus , Fibrinolíticos/farmacologia , Pandemias , Inibidores da Agregação de Plaquetas/farmacologia , Pneumonia Viral , Tromboembolia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Humanos , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Tromboembolia/tratamento farmacológico , Tromboembolia/epidemiologia , Tromboembolia/etiologia , Tromboembolia/fisiopatologia , Resultado do Tratamento
11.
J Am Coll Cardiol ; 75(23): 2950-2973, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32311448

RESUMO

Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.


Assuntos
Anticoagulantes/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus , Fibrinolíticos/farmacologia , Pandemias , Inibidores da Agregação de Plaquetas/farmacologia , Pneumonia Viral , Tromboembolia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Humanos , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Tromboembolia/tratamento farmacológico , Tromboembolia/epidemiologia , Tromboembolia/etiologia , Tromboembolia/fisiopatologia , Resultado do Tratamento
12.
Adv Exp Med Biol ; 1177: 101-131, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32246445

RESUMO

Thrombosis, the localized clotting of blood that affects arterial or venous circulation, is one of the leading causes of death worldwide. Arterial thrombosis is commonly initiated by vascular endothelial injury, while venous thrombosis mainly stems from blood stasis. Despite these differences, platelet adhesion, activation and aggregation, and fibrin formation as a result of coagulation constitute the fundamental processes of thrombus formation. Antithrombotic drugs permitted on the clinical currently can dramatically reduce major adverse cardiovascular events; however, they can also increase the bleeding risk. Discovery of antithrombotic drugs that can effectively prevent thrombosis while sparing bleeding side effects remains unmet medical need. In this chapter, we provide an overview on the pathophysiology of thrombosis, followed by introduction of each class of antithrombotic drugs including their pharmacology, clinical applications and limitations. Practical challenges and future perspectives of antithrombotic drugs are discussed in the last part of this chapter.


Assuntos
Fibrinolíticos/farmacologia , Trombose/prevenção & controle , Coagulação Sanguínea/efeitos dos fármacos , Hemorragia/induzido quimicamente , Humanos , Adesividade Plaquetária/efeitos dos fármacos
13.
Mar Drugs ; 18(4)2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32344720

RESUMO

Monostroma nitidum is a green single-cell layered algae that grows on the southwest coast of Japan. It is often used for salad ingredients, boiled tsukudani, soups, etc., due to its health benefits. M. nitidum is composed of many cell aggregates, and the various substances that fill the intercellular space are dietary fibers, vitamins, and minerals. Rhamnan sulfate (RS), a sulfated polysaccharide, is main the component of the fiber extracted from M. nitidum. Recently, some biological properties of RS have been demonstrated by in vitro and in vivo studies that probably protect human subjects from viruses and ameliorate vascular dysfunction caused by metabolic disorders, especially lifestyle-related diseases. In this review, we focus on the antithrombotic effects of RS and introduce its antiviral and other biological activities.


Assuntos
Clorófitas/química , Desoxiaçúcares/farmacologia , Mananas/farmacologia , Animais , Antivirais/isolamento & purificação , Antivirais/farmacologia , Desoxiaçúcares/isolamento & purificação , Fibrinolíticos/isolamento & purificação , Fibrinolíticos/farmacologia , Humanos , Japão , Mananas/isolamento & purificação , Sulfatos
14.
Blood Coagul Fibrinolysis ; 31(3): 179-185, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32271313

RESUMO

: Platelet aggregation inhibition and interfering with clot formation are essential tools for antithrombotic therapy and there is a need for discovering new antithrombotic agents. In this study, we synthesized a series of benzylidenepiperidine-3-carbohydrazide derivatives (1f-11f), bearing various selected substituents on both the piperidine ring nitrogen and the hydrazide nitrogen. The synthesized compounds were characterized by FTIR, HNMR spectroscopic techniques, CHN/O elemental analysis and electrospray ionization mass spectra. All new 1-benzyl-N'-benzylidenepiperidine-3-carbohydrazides were evaluated for their antiplatelet aggregation activities (against platelet aggregation induced by AA, ADP and collagen separately) and anticoagulant activities [protrombin time (PT) and partial thromboplastin time (PTT)]. Antiplatelet aggregation activity of the new derivatives was measured using human plasma on an APACT 4004 aggregometer. All the compounds were mainly effective on ADP pathway of platelet aggregation compared with collagen and AA pathways. The most potent compound on platelet aggregation induced by ADP is compound 2f with 87% aggregation inhibition activity at 0.5 mmol/l concentration. The synthesized compounds were further investigated for their anticoagulant action via the two PT and PTT models. They all showed higher PT and PTT values compared with the blank control sample. The most potent compounds are 5f, 6f, 7f and 1f. All compounds were obtained in good yield and further evaluated for their antiplatelet and anticoagulant activity.


Assuntos
Fibrinolíticos/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Fibrinolíticos/farmacologia , Humanos , Inibidores da Agregação de Plaquetas/farmacologia
15.
Int J Nanomedicine ; 15: 465-481, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021191

RESUMO

Background: 1-(4-isopropylphenyl)-ß-carboline-3-carboxylic acid (ICCA) was modified by Trp-Phe-Phe to form 1-(4-isopropylphenyl)-ß-carboline-3-carbonyl-Trp-Phe-Phe (ICCA-WFF). Purpose: The object of preparing ICCA-WFF was to enhance the in vivo efficacy of ICCA, to explore the possible targeting action, and to visualize the nano-feature. Methods: The advantages of ICCA-WFF over ICCA were demonstrated by a series of in vivo assays, such as anti-tumor assay, anti-arterial thrombosis assay, anti-venous thrombosis assay, P-selectin expression assay, and GPIIb/IIIa expression assay. The nano-features of ICCA-WFF were visualized by TEM, SEM and AFM images. The thrombus targeting and tumor-targeting actions were evidenced by FT-MS spectrum analysis. Results: The minimal effective dose of ICCA-WFF slowing tumor growth and inhibiting thrombosis was 10-fold lower than that of ICCA. ICCA-WFF, but not ICCA, formed nano-particles capable of safe delivery in blood circulation. In vivo ICCA-WFF, but not ICCA, can target thrombus and tumor. In thrombus and tumor, ICCA-WFF released Trp-Phe-Phe and/or ICCA. Conclusion: Modifying ICCA with Trp-Phe-Phe successfully enhanced the anti-tumor activity, improved the anti-thrombotic action, formed nano-particles, targeted tumor tissue and thrombus, and provided an oligopeptide modification strategy for heterocyclic compounds.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Fibrinolíticos/farmacologia , Peptídeos/química , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fibrinolíticos/química , Humanos , Masculino , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Nanopartículas/química , Selectina-P/química , Selectina-P/metabolismo , Peptídeos/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ratos Sprague-Dawley , Trombose/sangue , Trombose/tratamento farmacológico
16.
J Vasc Surg Venous Lymphat Disord ; 8(2): 268-278, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32067728

RESUMO

OBJECTIVE: There is an inter-relationship between thrombosis and inflammation. Previously, we have shown the importance of P-selectin in thrombogenesis and thrombus resolution in many preclinical animal models. The role of E-selectin has been explored in rodent models and in a small pilot study of clinical calf vein deep venous thrombosis. The purpose of this study was to determine the role of E-selectin in thrombosis in a primate model of proximal iliac vein thrombosis, a model close to the human condition. METHODS: Iliac vein thrombosis was induced with a well-characterized primate model. Through a transplant incision, the hypogastric vein and iliac vein branches were ligated. Thrombus was induced by balloon occlusion of the proximal and distal iliac vein for 6 hours. The balloons were then deflated, and the primates recovered. Starting on postocclusion day 2, animals were treated with the E-selectin inhibitor GMI-1271, 25 mg/kg subcutaneously, once daily until day 21 (n = 4). Nontreated control animals received no treatment (n = 5). All animals were evaluated by magnetic resonance venography (MRV); evaluation of vessel area by ultrasound, protein analysis, hematology (complete blood count), and coagulation tests (bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen, and thromboelastography) were performed at baseline, day 2, day 7, day 14, and day 21 with euthanasia. In addition, platelet function and CD44 expression on leukocytes were determined. RESULTS: E-selectin inhibition by GMI-1271 significantly increased vein recanalization by MRV vs control animals on day 14 (P < .05) and day 21 (P < .0001). GMI-1271 significantly decreased vein wall inflammation by MRV with gadolinium vein wall enhancement vs control also on day 14 (P < .0001) and day 21 (P < .0001). The thromboelastographic measure of clot strength (maximum amplitude) showed significant decreases in animals treated with GMI-1271 vs controls at day 2 (P < .05) and day 7 (P < .05). Animals treated with GMI-1271 had significant vessel area increase by day 21 vs controls (P < .05) by ultrasound. Vein wall intimal thickening (P < .001) and intimal fibrosis (P < .05) scores were significantly decreased in GMI-1271-treated animals vs controls. Importantly, no significant differences in hematology or coagulation test results were noted between all groups, suggesting that E-selectin inhibition carries no bleeding potential. GMI-1271 did not affect platelet function or aggregation or CD44 expression on leukocytes. In addition, no episodes of bleeding were noted in either group. CONCLUSIONS: This study suggests that E-selectin modulates venous thrombus progression and that its inhibition will increase thrombus recanalization and decrease vein wall inflammation, without affecting coagulation. The use of an E-selectin inhibitor such as GMI-1271 could potentially change how we treat deep venous thrombosis.


Assuntos
Anti-Inflamatórios/farmacologia , Selectina E/antagonistas & inibidores , Fibrinolíticos/farmacologia , Glicolipídeos/farmacologia , Veia Ilíaca/efeitos dos fármacos , Trombose Venosa/tratamento farmacológico , Animais , Modelos Animais de Doenças , Selectina E/metabolismo , Veia Ilíaca/diagnóstico por imagem , Veia Ilíaca/metabolismo , Papio , Transdução de Sinais , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/metabolismo
17.
Cardiovasc Drugs Ther ; 34(1): 15-23, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32062793

RESUMO

PURPOSE: Drugs inhibiting the platelet P2Y12 receptor, such as clopidogrel and prasugrel, are potent antithrombotic agents and are widely used in cardiovascular disease. However, the adverse effects of these drugs have limited their clinical use. For example, clopidogrel resistance occurs in approximately one third of patients, while prasugrel increases the risk of major bleeding. Therefore, new generations of such drugs are of clinical interest. METHODS: In this study, the pharmacodynamics of a new P2Y12 antagonist, CN-218, was compared with that of clopidogrel and prasugrel in rats and mice. The differences between CN-218 and clopidogrel include deuteration of the 7-position methyl carboxylate and the introduction of cinnamate in the 2-position of thiophene. RESULTS: CN-218 had an antiaggregatory efficacy that was at least five times more potent than that of clopidogrel but not as potent as that of prasugrel. It had a significant impact on activated partial thromboplastin time (APTT), whereby the APTT of CN-218-treated rats was approximately 9 s longer than that of the vehicle- or clopidogrel-treated group, while it had no impact on prothrombin time (PT) in rats. CN-218 had a similar potent antithrombotic effect to that of prasugrel and clopidogrel and also reduced the risk of bleeding compared to prasugrel. CONCLUSION: CN-218 may be a promising antithrombotic agent, with potent antiplatelet and significant anticoagulant activity, as well as a lower risk of bleeding compared to clopidogrel and prasugrel.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Fibrinolíticos/farmacologia , Piperidinas/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Tiofenos/farmacologia , Trombose/prevenção & controle , Animais , Plaquetas/metabolismo , Carragenina , Clopidogrel/farmacologia , AMP Cíclico/sangue , Modelos Animais de Doenças , Fibrinolíticos/toxicidade , Hemorragia/induzido quimicamente , Masculino , Camundongos , Piperidinas/toxicidade , Inibidores da Agregação de Plaquetas/toxicidade , Cloridrato de Prasugrel/farmacologia , Antagonistas do Receptor Purinérgico P2Y/toxicidade , Ratos Wistar , Receptores Purinérgicos P2Y12/sangue , Tiofenos/toxicidade , Trombose/sangue , Trombose/induzido quimicamente
18.
Arterioscler Thromb Vasc Biol ; 40(3): e65-e77, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31893947

RESUMO

OBJECTIVE: In patients with diabetes mellitus, increased platelet reactivity predicts cardiac events. Limited evidence suggests that DPP-4 (dipeptidyl peptidase 4) influences platelets via GLP-1 (glucagon-like peptide 1)-dependent effects. Because DPP-4 inhibitors are frequently used in diabetes mellitus to improve the GLP-1-regulated glucose metabolism, we characterized the role of DPP-4 inhibition and of native intact versus DPP-4-cleaved GLP-1 on flow-dependent thrombus formation in mouse and human blood. Approach and Results: An ex vivo whole blood microfluidics model was applied to approach in vivo thrombosis and study collagen-dependent platelet adhesion, activation, and thrombus formation under shear-flow conditions by multiparameter analyses. In mice, in vivo inhibition or genetic deficiency of DPP-4 (Dpp4-/-), but not of GLP-1-receptors (Glp1r-/-), suppressed flow-dependent platelet aggregation. In human blood, GLP-1(7-36), but not DPP-4-cleaved GLP-1(9-36), reduced thrombus volume by 32% and impaired whole blood thrombus formation at both low/venous and high/arterial wall-shear rates. These effects were enforced upon ADP costimulation and occurred independently of plasma factors and leukocytes. Human platelets did not contain detectable levels of GLP-1-receptor transcripts. Also, GLP-1(7-36) did not inhibit collagen-induced aggregation under conditions of stirring or stasis of platelets, pointing to a marked flow-dependent role. CONCLUSIONS: Native, intact GLP-1 is a natural suppressor of thrombus growth under physiological flow conditions, with DPP-4 inhibition and increased intact GLP-1 suppressing platelet aggregation under flow without a main relevance of GLP-1-receptor on platelets.


Assuntos
Plaquetas/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fibrinolíticos/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Linagliptina/farmacologia , Fosfato de Sitagliptina/farmacologia , Trombose/prevenção & controle , Animais , Plaquetas/metabolismo , Dipeptidil Peptidase 4/genética , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fragmentos de Peptídeos/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Transdução de Sinais , Trombose/enzimologia , Trombose/genética
19.
Vascular ; 28(3): 309-313, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31902309

RESUMO

OBJECTIVES: In cardiovascular disease, deep vein thrombosis is one of the vital symptoms causing pulmonary thromboembolism. However, the pathogenesis of deep vein thrombosis is still not clear. One of the critical factors leading to deep vein thrombosis is the platelet aggregation that is mediated by a set of key genes including platelet membrane protein coded by platelet glycoprotein Ib alpha chain (GPIBA). METHODS: Deep vein thrombosis model was established according to the previous protocol, and venous blood and thrombi were collected for further analysis. RESULTS: The dynamic changes of GPIBA and coagulation factor, von Willebrand factor, were observed in deep vein thrombosis models. Meanwhile, critical proteins participating in adhesion and binding of platelets such as epithelial membrane protein 2 (EMP2), vascular cell adhesion protein 1 (VCAM1), immunoreceptor tyrosine-based activation motif 1 (ITAM1), integrin subunit alpha M (ITGAM), or fibronectin were also differentially expressed in deep vein thrombosis models. CONCLUSIONS: Application of heparin could reverse these dynamic changes in deep vein thrombosis models. Thus, we explained the potential synergic role of GPIBA and von Willebrand factor in regulating the occurrence of deep vein thrombosis and provide therapeutic target against cardiovascular disease.


Assuntos
Coagulação Sanguínea , Plaquetas/metabolismo , Agregação Plaquetária , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Trombose Venosa/metabolismo , Fator de von Willebrand/metabolismo , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Antígeno CD11b/metabolismo , Modelos Animais de Doenças , Fibrinolíticos/farmacologia , Fibronectinas/metabolismo , Heparina/farmacologia , Motivo de Ativação do Imunorreceptor Baseado em Tirosina , Glicoproteínas de Membrana/metabolismo , Camundongos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Transdução de Sinais , Molécula 1 de Adesão de Célula Vascular/metabolismo , Trombose Venosa/sangue , Trombose Venosa/prevenção & controle
20.
Blood ; 135(9): 689-699, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31977000

RESUMO

Although thrombin is a key enzyme in the coagulation cascade and is required for both normal hemostasis and pathologic thrombogenesis, it also participates in its own negative feedback via activation of protein C, which downregulates thrombin generation by enzymatically inactivating factors Va and VIIIa. Our group and others have previously shown that thrombin's procoagulant and anticoagulant activities can be effectively disassociated to varying extents through site-directed mutagenesis. The thrombin mutant W215A/E217A (WE thrombin) has been one of the best characterized constructs with selective activity toward protein C. Although animal studies have demonstrated that WE thrombin acts as an anticoagulant through activated protein C (APC) generation, the observed limited systemic anticoagulation does not fully explain the antithrombotic potency of this or other thrombin mutants. AB002 (E-WE thrombin) is an investigational protein C activator thrombin analog in phase 2 clinical development (clinicaltrials.gov NCT03963895). Here, we demonstrate that this molecule is a potent enzyme that is able to rapidly interrupt arterial-type thrombus propagation at exceedingly low doses (<2 µg/kg, IV), yet without substantial systemic anticoagulation in baboons. We demonstrate that AB002 produces APC on platelet aggregates and competitively inhibits thrombin-activatable fibrinolysis inhibitor (carboxypeptidase B2) activation in vitro, which may contribute to the observed in vivo efficacy. We also describe its safety and activity in a phase 1 first-in-human clinical trial. Together, these results support further clinical evaluation of AB002 as a potentially safe and effective new approach for treating or preventing acute thrombotic and thromboembolic conditions. This trial was registered at www.clinicaltrials.gov as #NCT03453060.


Assuntos
Fibrinolíticos/farmacologia , Proteína C/efeitos dos fármacos , Trombina/análogos & derivados , Trombose/prevenção & controle , Adulto , Animais , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Papio , Proteínas Recombinantes/farmacologia
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