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1.
Clin Appl Thromb Hemost ; 26: 1076029620954913, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33030036

RESUMO

INTRODUCTION: Sulodexide represents a mixture of fast-moving heparin (FMH) and dermatan sulfate (DS) and has been used for the management of venous diseases such as DVT and related disorders. The purpose of this study is to compare sulodexide and its components with unfractionated heparin (UFH) to determine its suitability for the indications in which UFH is used. MATERIALS AND METHOD: Active pharmaceutical ingredients (API) versions of sulodexide, FMH and DS were obtained from Alfasigma. API versions of UFH were obtained from Medefil Inc. Normal human citrated plasma was obtained from blood bank of the Loyola University Medical Center. Each of the individual agents were supplemented in plasma at a graded concentration of 0.0-10 µg/mL. Clotting assays (PiCT, aPTT, PT and TT), anti-Xa and anti-IIa and thrombin generation studies were carried out. Results were compiled as mean ± SD of 3 individual determination. RESULT: In the clot based (PiCT, aPTT and TT), anti-Xa and IIa assays, both the UFH and FMH produced stronger activities in these assays followed by sulodexide. DS did not show any anticoagulant activity. In the thrombin generation assay, FMH and UFH produced comparable inhibition of thrombin generation as measured by various parameters. Sulodexide was slightly weaker in this assay, whereas DS produced relatively weaker effects. CONCLUSION: In comparison to sulodexide, both UFH and FMH exhibit comparable anticoagulant activity despite differences in their molecular weight. These results suggest that sulodexide can be developed as a parenteral anticoagulant for indications in which UFH is used.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Glicosaminoglicanos/farmacologia , Trombina/farmacologia , Anticoagulantes/administração & dosagem , Antitrombinas/administração & dosagem , Antitrombinas/farmacologia , Glicosaminoglicanos/administração & dosagem , Heparina/administração & dosagem , Heparina/farmacologia , Humanos , Itália , Sensibilidade e Especificidade , Trombina/administração & dosagem
2.
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
3.
Aging (Albany NY) ; 12(16): 15954-15961, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32826388

RESUMO

The COVID-19 pandemic has caused monumental mortality, and there are still no adequate therapies. Most severely ill COVID-19 patients manifest a hyperactivated immune response, instigated by interleukin 6 (IL6) that triggers a so called "cytokine storm" and coagulopathy. Hypoxia is also associated with COVID-19. So far overlooked is the fact that both IL6 and hypoxia depress the abundance of a key anticoagulant, Protein S. We speculate that the IL6-driven cytokine explosion plus hypoxemia causes a severe drop in Protein S level that exacerbates the thrombotic risk in COVID-19 patients. Here we highlight a mechanism by which the IL6-hypoxia curse causes a deadly hypercoagulable state in COVID-19 patients, and we suggest a path to therapy.


Assuntos
Infecções por Coronavirus , Síndrome da Liberação de Citocina , Hipóxia , Pandemias , Pneumonia Viral , Proteína S , Trombofilia/imunologia , Anticoagulantes/metabolismo , Anticoagulantes/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/virologia , Gerenciamento Clínico , Humanos , Hipóxia/sangue , Hipóxia/etiologia , Hipóxia/imunologia , Interleucina-6/sangue , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Proteína S/metabolismo , Proteína S/farmacologia , Índice de Gravidade de Doença
4.
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
5.
Nat Commun ; 11(1): 3890, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753636

RESUMO

Inhibiting thrombosis without generating bleeding risks is a major challenge in medicine. A promising solution may be the inhibition of coagulation factor XII (FXII), because its knock-out or inhibition in animals reduced thrombosis without causing abnormal bleeding. Herein, we have engineered a macrocyclic peptide inhibitor of activated FXII (FXIIa) with sub-nanomolar activity (Ki = 370 ± 40 pM) and a high stability (t1/2 > 5 days in plasma), allowing for the preclinical evaluation of a first synthetic FXIIa inhibitor. This 1899 Da molecule, termed FXII900, efficiently blocks FXIIa in mice, rabbits, and pigs. We found that it reduces ferric-chloride-induced experimental thrombosis in mice and suppresses blood coagulation in an extracorporeal membrane oxygenation (ECMO) setting in rabbits, all without increasing the bleeding risk. This shows that FXIIa activity is controllable in vivo with a synthetic inhibitor, and that the inhibitor FXII900 is a promising candidate for safe thromboprotection in acute medical conditions.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Fator XIIa/antagonistas & inibidores , Peptídeos Cíclicos/efeitos dos fármacos , Trombose/prevenção & controle , Animais , Cloretos/efeitos adversos , Clonagem Molecular , Modelos Animais de Doenças , Descoberta de Drogas , Oxigenação por Membrana Extracorpórea/métodos , Fator XII/antagonistas & inibidores , Feminino , Compostos Férricos/efeitos adversos , Humanos , Pulmão , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coelhos , Proteínas Recombinantes/farmacologia , Suínos
6.
Aging (Albany NY) ; 12(16): 15954-15961, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: covidwho-724169

RESUMO

The COVID-19 pandemic has caused monumental mortality, and there are still no adequate therapies. Most severely ill COVID-19 patients manifest a hyperactivated immune response, instigated by interleukin 6 (IL6) that triggers a so called "cytokine storm" and coagulopathy. Hypoxia is also associated with COVID-19. So far overlooked is the fact that both IL6 and hypoxia depress the abundance of a key anticoagulant, Protein S. We speculate that the IL6-driven cytokine explosion plus hypoxemia causes a severe drop in Protein S level that exacerbates the thrombotic risk in COVID-19 patients. Here we highlight a mechanism by which the IL6-hypoxia curse causes a deadly hypercoagulable state in COVID-19 patients, and we suggest a path to therapy.


Assuntos
Infecções por Coronavirus , Síndrome da Liberação de Citocina , Hipóxia , Pandemias , Pneumonia Viral , Proteína S , Trombofilia/imunologia , Anticoagulantes/metabolismo , Anticoagulantes/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/virologia , Gerenciamento Clínico , Humanos , Hipóxia/sangue , Hipóxia/etiologia , Hipóxia/imunologia , Interleucina-6/sangue , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Proteína S/metabolismo , Proteína S/farmacologia , Índice de Gravidade de Doença
7.
Lancet Haematol ; 7(8): e613-e623, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32735839

RESUMO

Lifelong anticoagulation with warfarin or alternative vitamin K antagonist is the standard anticoagulant treatment for thrombotic antiphospholipid syndrome. Anticoagulant-refractory thrombotic antiphospholipid syndrome can be broadly defined as breakthrough thrombosis while on standard oral anticoagulation treatment and its management is a major challenge given the serious nature of the thrombotic disease observed, which has become refractory to oral anticoagulation. The factors (genetic and cellular) that cause anticoagulant-refractory thrombotic antiphospholipid syndrome are now better understood. However, efforts to use this greater understanding have not yet transformed the capacity to treat it successfully in many patients. In this Viewpoint, we review the factors that are likely to be contributing to the cause of this syndrome and consider how they might be modified or inhibited. We also discuss management, including general strategies to minimise thrombotic risk, intensification of anticoagulation, addition of an antiplatelet agent, adjunctive treatment for thrombosis, immunomodulatory therapy, complement inhibition, vascular options, and future potential therapeutic targets.


Assuntos
Anticoagulantes/farmacologia , Síndrome Antifosfolipídica/terapia , Resistência a Medicamentos/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Terapia Trombolítica , Trombose/prevenção & controle , Síndrome Antifosfolipídica/patologia , Humanos , Trombose/patologia
8.
Fundam Clin Pharmacol ; 34(5): 530-547, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32603486

RESUMO

Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Medicamentos sob Prescrição/farmacologia , Analgésicos/farmacologia , Antiasmáticos/farmacologia , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Anticoagulantes/farmacologia , Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Antivirais/farmacologia , Betacoronavirus , Fármacos Cardiovasculares/farmacologia , Interações Medicamentosas , Humanos , Hidroxicloroquina/farmacologia , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Interferon beta-1b/farmacologia , Pandemias , Medicamentos sob Prescrição/farmacocinética , Psicotrópicos/farmacologia , Receptores de Interleucina/antagonistas & inibidores , Medição de Risco , Hormônios Tireóideos/farmacologia
10.
Fundam Clin Pharmacol ; 34(5): 530-547, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: covidwho-626969

RESUMO

Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Medicamentos sob Prescrição/farmacologia , Analgésicos/farmacologia , Antiasmáticos/farmacologia , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Anticoagulantes/farmacologia , Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Antivirais/farmacologia , Betacoronavirus , Fármacos Cardiovasculares/farmacologia , Interações Medicamentosas , Humanos , Hidroxicloroquina/farmacologia , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Interferon beta-1b/farmacologia , Pandemias , Medicamentos sob Prescrição/farmacocinética , Psicotrópicos/farmacologia , Receptores de Interleucina/antagonistas & inibidores , Medição de Risco , Hormônios Tireóideos/farmacologia
12.
Infez Med ; 28(suppl 1): 118-121, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32532948

RESUMO

A 71-year old gentleman with history of arterial hypertension treated with valsartan presented on was hospitalized at the Infectious Diseases Unit, University of Bologna (Italy) for severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2) and received treatment with hydroxychloroquine 200mg bid (400 mg bid the first day), azithromycin 400 mg qd, thrombotic prophylaxis with enoxaparin 4000 UI qd and Venturi mask oxygen delivering FiO2 of 31%. The case highlights the high frequency of coagulopathy in patients with moderate to severe cases of SARS-CoV-2 associated disease (COVID-19). After one week the patient significantly improved and the daily dose of enoxaparin was reduced and definitively discontinued four days later. The case highlights the high frequency of coagulopathy in patients with moderate to severe cases of SARS-CoV-2 associated disease (COVID-19). Considering the available information we believe that LMWH may represent a promising treatment for COVID-19 but further well-designed trials are needed to address these points.


Assuntos
Anticoagulantes/uso terapêutico , Infecções por Coronavirus/complicações , Enoxaparina/uso terapêutico , Pneumonia Viral/complicações , Trombofilia/tratamento farmacológico , Idoso , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anticoagulantes/farmacologia , Anti-Hipertensivos/uso terapêutico , Azitromicina/administração & dosagem , Azitromicina/uso terapêutico , Terapia Combinada , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Quimioterapia Combinada , Enoxaparina/farmacologia , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Masculino , Oxigenoterapia , Pandemias , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/terapia , Trombofilia/etiologia , Tomografia Computadorizada por Raios X , Valsartana/uso terapêutico
13.
Viruses ; 12(6)2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32532094

RESUMO

Although infection by SARS-CoV-2, the causative agent of coronavirus pneumonia disease (COVID-19), is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked Middle East respiratory syndrome coronavirus (MERS-CoV) S protein-mediated cell fusion by targeting transmembrane serine protease 2 (TMPRSS2), and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein, angiotensin I converting enzyme 2 (ACE2) and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an effective concentration (EC)50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. On the other hand, a significantly higher dose (EC50 around 30 mM) was required for VeroE6/TMPRSS2 cells, where the TMPRSS2-independent but cathepsin-dependent endosomal infection pathway likely predominates. Together, our study shows that nafamostat mesylate potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and also inhibits SARS-CoV-2 infection in vitro in a cell-type-dependent manner. These findings, together with accumulated clinical data regarding nafamostat's safety, make it a likely candidate drug to treat COVID-19.


Assuntos
Anticoagulantes/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Guanidinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Betacoronavirus/metabolismo , Linhagem Celular , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Gabexato/análogos & derivados , Gabexato/farmacologia , Células HEK293 , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero
14.
Nephron ; 144(8): 383-385, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32526763

RESUMO

In our opinion, the use of heparin could play a crucial role in these patients. In fact, recent studies have shown that heparin, the most commonly used anticoagulant during HD procedures, had anti-inflammatory properties and a direct antiviral action, due to its ability to prevent SARS-CoV-2 pseudovirus entry into host cells. These activities, together with its anticoagulant action, could explain the ability of heparin to ameliorate COVID-19 clinical course.


Assuntos
Anticoagulantes/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Heparina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Diálise Renal , Anticoagulantes/farmacologia , Heparina/farmacologia , Humanos , Pandemias
15.
Molecules ; 25(11)2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32485894

RESUMO

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than -8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.


Assuntos
Anticoagulantes/química , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Sequência de Aminoácidos , Anticoagulantes/farmacologia , Antivirais/farmacologia , Betacoronavirus/química , Betacoronavirus/enzimologia , Betacoronavirus/genética , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/química , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fator Xa/química , Fator Xa/genética , Fator Xa/metabolismo , Hepacivirus/química , Hepacivirus/enzimologia , Hepacivirus/genética , Humanos , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Homologia Estrutural de Proteína , Especificidade por Substrato , Termodinâmica , Trombina/antagonistas & inibidores , Trombina/química , Trombina/genética , Trombina/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
16.
Ann Vasc Surg ; 68: 88-92, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32589931

RESUMO

Heparin resistance is an uncommon phenomenon defined as the need for high-dose unfractionated heparin (UFH) of more than 35,000 IU/day to achieve the target activated partial-thromboplastin time ratio or the failure to achieve the desired activated clotting time after a full UFH dose. This rare phenomenon is being more commonly observed in Covid-19 patients in a hypercoagulable state. We describe a Covid-19 patient confirmed by reverse-transcriptase polymerase chain reaction assay, with acute limb ischemia, who developed heparin resistance. The patient was managed by the departments of vascular surgery, anesthesia and intensive care, and the Coagulation Service and Thrombosis Research from San Raffaele Scientific Institute, Milan, Italy.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Resistência a Medicamentos , Heparina/farmacologia , Isquemia/tratamento farmacológico , Extremidade Inferior/irrigação sanguínea , Pneumonia Viral/complicações , Doença Aguda , Idoso , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Humanos , Isquemia/sangue , Isquemia/etiologia , Masculino , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Tomografia Computadorizada por Raios X
17.
Molecules ; 25(11)2020 May 29.
Artigo em Inglês | MEDLINE | ID: covidwho-436971

RESUMO

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than -8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.


Assuntos
Anticoagulantes/química , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Sequência de Aminoácidos , Anticoagulantes/farmacologia , Antivirais/farmacologia , Betacoronavirus/química , Betacoronavirus/enzimologia , Betacoronavirus/genética , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/química , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fator Xa/química , Fator Xa/genética , Fator Xa/metabolismo , Hepacivirus/química , Hepacivirus/enzimologia , Hepacivirus/genética , Humanos , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Homologia Estrutural de Proteína , Especificidade por Substrato , Termodinâmica , Trombina/antagonistas & inibidores , Trombina/química , Trombina/genética , Trombina/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
18.
Nephron ; 144(8): 383-385, 2020.
Artigo em Inglês | MEDLINE | ID: covidwho-596483

RESUMO

In our opinion, the use of heparin could play a crucial role in these patients. In fact, recent studies have shown that heparin, the most commonly used anticoagulant during HD procedures, had anti-inflammatory properties and a direct antiviral action, due to its ability to prevent SARS-CoV-2 pseudovirus entry into host cells. These activities, together with its anticoagulant action, could explain the ability of heparin to ameliorate COVID-19 clinical course.


Assuntos
Anticoagulantes/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Heparina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Diálise Renal , Anticoagulantes/farmacologia , Heparina/farmacologia , Humanos , Pandemias
19.
Viruses ; 12(6)2020 06 10.
Artigo em Inglês | MEDLINE | ID: covidwho-592497

RESUMO

Although infection by SARS-CoV-2, the causative agent of coronavirus pneumonia disease (COVID-19), is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked Middle East respiratory syndrome coronavirus (MERS-CoV) S protein-mediated cell fusion by targeting transmembrane serine protease 2 (TMPRSS2), and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein, angiotensin I converting enzyme 2 (ACE2) and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an effective concentration (EC)50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. On the other hand, a significantly higher dose (EC50 around 30 mM) was required for VeroE6/TMPRSS2 cells, where the TMPRSS2-independent but cathepsin-dependent endosomal infection pathway likely predominates. Together, our study shows that nafamostat mesylate potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and also inhibits SARS-CoV-2 infection in vitro in a cell-type-dependent manner. These findings, together with accumulated clinical data regarding nafamostat's safety, make it a likely candidate drug to treat COVID-19.


Assuntos
Anticoagulantes/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Guanidinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Betacoronavirus/metabolismo , Linhagem Celular , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Gabexato/análogos & derivados , Gabexato/farmacologia , Células HEK293 , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero
20.
Ann Vasc Surg ; 68: 88-92, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: covidwho-612189

RESUMO

Heparin resistance is an uncommon phenomenon defined as the need for high-dose unfractionated heparin (UFH) of more than 35,000 IU/day to achieve the target activated partial-thromboplastin time ratio or the failure to achieve the desired activated clotting time after a full UFH dose. This rare phenomenon is being more commonly observed in Covid-19 patients in a hypercoagulable state. We describe a Covid-19 patient confirmed by reverse-transcriptase polymerase chain reaction assay, with acute limb ischemia, who developed heparin resistance. The patient was managed by the departments of vascular surgery, anesthesia and intensive care, and the Coagulation Service and Thrombosis Research from San Raffaele Scientific Institute, Milan, Italy.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Resistência a Medicamentos , Heparina/farmacologia , Isquemia/tratamento farmacológico , Extremidade Inferior/irrigação sanguínea , Pneumonia Viral/complicações , Doença Aguda , Idoso , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Humanos , Isquemia/sangue , Isquemia/etiologia , Masculino , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Tomografia Computadorizada por Raios X
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