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1.
Biochemistry (Mosc) ; 84(12): 1521-1528, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31870256

RESUMO

DNA aptamers (oligonucleotides) interacting with thrombin exosite I contain G-quadruplex, two T-T, and one T-G-T loops in their structure. They prevent exosite I binding with fibrinogen and thrombin receptors on platelet surface, thereby suppressing thrombin-stimulated formation of fibrin from fibrinogen and platelet aggregation. Earlier, we synthesized original antithrombin aptamer RE31 (5'-GTGACGTAGGTTGGTGTGGTTGGGGCGTCAC-3') that contained (in addition to G-quadruplex) a hinge region connected to six pairs of complementary bases (duplex region). In this study, we compared properties of RE31 aptamer and its analogues containing varying number of bases in the duplex region and nucleotide insertions in the hinge region. Reduction in the number of nucleotides in the duplex region by 1 to 4 pairs (in comparison with RE31 aptamer) resulted in the decrease of the structural stability of aptamers (manifested as lower melting temperatures) and their ability to inhibit thrombin-stimulated fibrin formation in human blood plasma in tests of thrombin, prothrombin, and activated partial thromboplastin times. However, an increase in the number of bases by 1 to 2 pairs did not cause significant changes in the stability and antithrombin activity of the aptamers. Insertions into the hinge region of RE31 aptamer decreased its antithrombin activity. Investigation of RE31 antithrombotic properties demonstrated that RE31 (i) slowed down thrombin formation in human blood plasma (thrombin generation test), (ii) accelerated lysis of fibrin clot by tissue plasminogen activator in in vitro model, and (iii) suppressed arterial thrombosis in in vivo model. Based on the obtained data, RE31 aptamer can be considered as a potentially effective antithrombotic compound.


Assuntos
Antitrombinas/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Trombina/efeitos dos fármacos , Aptâmeros de Nucleotídeos/química , Sítios de Ligação , Testes de Coagulação Sanguínea , Humanos , Agregação Plaquetária/efeitos dos fármacos , Relação Estrutura-Atividade
3.
J Clin Pathol ; 72(12): 817-824, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31366633

RESUMO

AIMS: Bivalent direct thrombin inhibitors (DTIs), hirudin and bivalirudin, bind to the active site and exosite 1 of thrombin irreversibly and reversibly, respectively. The present study aims to assess in vitro effects of hirudin and bivalirudin through clot waveform analysis (CWA) and enzyme kinetics in coagulation assays. METHODS: The pooled normal plasma and its dilutions were spiked with hirudin or bivalirudin. The activated partial thromboplastin time (APTT) assay and the Clauss fibrinogen assay were performed using the CS-5100 (Sysmex). The APTT-CWA data were automatically gained by the CS-5100 programme. RESULTS: In APTT-CWA, the maximum coagulation velocity, acceleration and deceleration were decreased dependently on the drug concentrations, demonstrating evidence for the blockade of thrombin-positive feedback by hirudin or bivalirudin. The Hill plot analysis was applied to the dose-dependent curves in bivalirudin. The Hill coefficients were greater than 1, showing positive anticoagulant cooperativity. Regarding the dose-dependent curves in hirudin, all the parameters dropped to almost zero without making an asymptotic line. In the Clauss fibrinogen assay, the Lineweaver-Burk plots demonstrated that both drugs exhibit mixed inhibition mimicking uncompetitive binding. The Dixon plots in bivalirudin were linear and supported the inhibition type described above. The Dixon plots in hirudin were non-linear and inappropriate to use for determination of the inhibition type. In addition, the inverse function of the clotting time appeared to drop to zero without making an asymptotic line, suggesting complete loss of thrombin activity by irreversible binding. CONCLUSIONS: The results provide insights into anticoagulation with bivalent DTIs.


Assuntos
Antitrombinas/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Hirudinas/farmacologia , Tempo de Tromboplastina Parcial , Fragmentos de Peptídeos/farmacologia , Trombina/antagonistas & inibidores , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Fibrinogênio/metabolismo , Humanos , Cinética , Modelos Biológicos , Proteínas Recombinantes/farmacologia , Trombina/metabolismo
4.
J Med Food ; 22(10): 976-981, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31211650

RESUMO

Fermentation has shown to be an effective technique in bioactive peptides release. That is why in this study antihypertensive, antithrombotic, and antioxidant activity was evaluated during amaranth proteins fermentation with Lactobacillus casei Shirota and Streptococcus thermophilus 54102 in mono and combined culture. During fermentation an increase of free amine groups was observed, and no statistical differences among monocultures were shown, getting higher concentration in combined culture. This was related to antihypertensive and antioxidant activities, where the highest values were also found in the combined process (45% of angiotensin-converting enzyme inhibition, and 168 µmol Trolox equivalents per liter [TE/L] for 2,2-diphenyl-1-picrylhydrazyl, 268 µmol TE/L for 2,2'-azino-bis 3-ethylbenzothiazoline-6-sulfonic acid, and 381 µmol Fe2E/L for ferric reducing ability of plasma). On the contrary, antithrombotic activity was not related to free amine groups during fermentation, having the highest bioactivity in different moments in each experiment. L. casei Shirota and S. thermophilus 54102 are strains that are able to release bioactive peptides from amaranth protein, although amaranth is not a common matrix for the development of lactic acid bacteria. In addition, in this study it was observed for the first time that lactic acid strains are able to release bioactive peptides from amaranth protein. In addition, this methodology could be part for the development of fermented beverages, different from fermented milk, to diversify matrix to obtain a novel functional food.


Assuntos
Amaranthus/química , Fermentação , Lactobacillales/metabolismo , Peptídeos/farmacologia , Proteínas de Plantas/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Antitrombinas/farmacologia , Ácido Láctico/metabolismo , Lactobacillus casei , Sementes/química , Streptococcus thermophilus
5.
Mater Sci Eng C Mater Biol Appl ; 102: 289-298, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147001

RESUMO

Hydrophobically modified poly(vinyl alcohol)s (hm-PVAs) with various alkyl chain lengths (3-12) were synthesized and were coated on poly(propylene) (PP) films. The blood compatibilities of the hm-PVAs-coated films were evaluated. The C6-PVA-coated PP film showed suppressed platelet adhesion as compared to the other hm-PVA-coated PP films, especially the 15C6-PVA-coated PP film, in which 30 mol% of OH groups were substituted by C6 groups. The fibrinogen adsorption was also inhibited on this film. The hydration water structure of the films was analyzed using differential scanning calorimetry (DSC). 15C6-PVA showed the highest (4.8 wt%) intermediate water (IW), and hence exhibited good blood compatibility. The fibrinogen γ chain activity of the 15C6-PVA-coated PP film was 18% lower than that of the PP film, indicating that hm-PVAs can inhibit fibrinogen γ chain activation. These results showed that by simple hydrophobic modification, PVA could be used as a blood contacting material.


Assuntos
Antitrombinas/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Álcool de Polivinil/química , Adsorção , Animais , Fibrinogênio/metabolismo , Humanos , Espectroscopia Fotoeletrônica , Adesividade Plaquetária , Polipropilenos/química , Espectroscopia de Prótons por Ressonância Magnética , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química
6.
PLoS One ; 14(4): e0215333, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002679

RESUMO

BACKGROUND: Staphylococcus aureus is the most frequent and fatal cause of left-sided infective endocarditis (IE). New treatment strategies are needed to improve the outcome. S. aureus coagulase promotes clot and fibrin formation. We hypothesized that dabigatran, could reduce valve vegetations and inflammation in S. aureus IE. METHODS: We used a rat model of severe aortic valve S. aureus IE. All infected animals were randomized to receive adjunctive dabigatran (10 mg/kg b.i.d., n = 12) or saline (controls, n = 11) in combination with gentamicin. Valve vegetation size, bacterial load, cytokine, cell integrins expression and peripheral platelets and neutrophils were assessed 3 days post-infection. RESULTS: Adjunctive dabigatran treatment significantly reduced valve vegetation size compared to controls (p< 0.0001). A significant reduction of the bacterial load in aortic valves was seen in dabigatran group compared to controls (p = 0.02), as well as expression of key pro-inflammatory markers keratinocyte-derived chemokine, IL-6, ICAM-1, TIMP-1, L-selectin (p< 0.04). Moreover, the dabigatran group had a 2.5-fold increase of circulating platelets compared to controls and a higher expression of functional and activated platelets (CD62p+) unbound to neutrophils. CONCLUSION: Adjunctive dabigatran reduced the vegetation size, bacterial load, and inflammation in experimental S. aureus IE.


Assuntos
Dabigatrana/farmacologia , Endocardite Bacteriana/tratamento farmacológico , Gentamicinas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Antitrombinas/farmacologia , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/microbiologia , Carga Bacteriana/efeitos dos fármacos , Quimioterapia Adjuvante , Modelos Animais de Doenças , Quimioterapia Combinada , Endocardite Bacteriana/microbiologia , Humanos , Masculino , Distribuição Aleatória , Ratos Wistar , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia
7.
Ren Fail ; 41(1): 104-112, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30880546

RESUMO

Immunoglobulin A nephropathy (IgAN) is characterized by mesangial IgA and IgG co-deposition. As the clinical course of IgAN is highly variable, a lot of patients will eventually develop to end-stage renal disease (ESRD) within years. Hirudin, a potent and specific thrombin inhibitor, has been reported to treat IgAN with hematuria, but the mechanism is unclear. Our study aims to explore the potential of hirudin and the underlying mechanism in the treatment of IgAN. The establishment of IgAN model was set up in rats through oral and intravenous immunization with bovine gamma-globulin (BGG). Results suggested that hirudin could reduce the increased level of proteinuria, serum creatinine and urea nitrogen in IgAN models. Besides that, hirudin ameliorated the elevated number of apoptotic bodies and expressions of apoptosis-related proteins (caspase-3 and caspase-9) in IgAN model. The fibrosis indexes (transforming growth factor ß-1 (TGF-ß1), Collagen-IV (CoI-IV) and Fibronectin-1) of kidney were remarkably suppressed in IgAN rats treated with hirudin compared with IgAN rats with no further treatment. IgAN rats exhibited remarkably increased inflammatory factors (IL-1ß, IL-6, and IL-18), while hirudin treatment significantly alleviated these alterations. Moreover, the reduced levels of CD4+CD25+Foxp3+ Treg and CD4+IFN-γ+ Th1/CD4+IL-4+ Th2 could be reversed by hirudin in IgAN model. Furthermore, in the process of IgAN, hirudin could inactivate various pathways (IκBα, NF-κB, TNF-α, and VCAM-1) compared with IgAN model group. Taken together, our study indicated that hirudin could ameliorate IgAN through suppressing fibrosis and inflammatory response. These findings provide a new therapeutic method to treat IgAN.


Assuntos
Antitrombinas/farmacologia , Glomerulonefrite por IGA/tratamento farmacológico , Terapia com Hirudina/métodos , Hirudinas/farmacologia , Rim/patologia , Animais , Antitrombinas/uso terapêutico , Creatinina/sangue , Modelos Animais de Doenças , Fibrose , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/urina , Hematúria/sangue , Hematúria/tratamento farmacológico , Hematúria/imunologia , Hematúria/urina , Humanos , Rim/efeitos dos fármacos , Masculino , Proteinúria/sangue , Proteinúria/tratamento farmacológico , Proteinúria/imunologia , Proteinúria/urina , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Resultado do Tratamento , gama-Globulinas/imunologia
8.
World Neurosurg ; 126: e731-e735, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30851469

RESUMO

BACKGROUND: Revascularization before infarct development after cerebral ischemia may affect morbidity. The success of revascularization can be less than expected because of spontaneous thrombosis or restenosis with intimal hyperplasia. The aim of this study was to compare dabigatran etexilate, a direct thrombin inhibitor, with bemiparin sodium, a second-generation low-molecular-weight heparin, after carotid artery anastomosis. METHODS: This study used 24 randomly selected Sprague-Dawley rats. The rats were separated into 3 equal groups: group 1 (control group); group 2 (dabigatran group), in which dabigatran 10 mg/kg was orally administered for 7 days; and group 3 (bemiparin group), in which bemiparin 250 IU/kg was subcutaneously administered for 7 days. The right-side carotid artery of rats was used for anastomosis and the left-side carotid artery was used for the control. The carotid artery was explored and transected. Anastomosis was applied using 10/0 polypropylene sutures. After 7 days of treatment, the right and left carotid arteries were removed. Lumen diameter, lumen area, tunica media thickness, edema, vessel wall injury, intimal hyperplasia, thrombus, and inflammation were evaluated in tissue biopsy specimens. RESULTS: Bemiparin used after anastomosis caused less thickening of tunica media and reduced intimal hyperplasia but did not decrease lumen diameter and area. Dabigatran increased edema and inflammation but did not prevent intimal hyperplasia. CONCLUSIONS: Bemiparin reduced intimal hyperplasia and prevented thrombosis angiogenesis, but dabigatran did not prevent intimal hyperplasia, and its anticoagulation effect was more than the antithrombotic effect.


Assuntos
Anticoagulantes/farmacologia , Antitrombinas/farmacologia , Artérias Carótidas/efeitos dos fármacos , Revascularização Cerebral/métodos , Dabigatrana/farmacologia , Heparina de Baixo Peso Molecular/farmacologia , Neointima/prevenção & controle , Trombose/prevenção & controle , Animais , Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Dabigatrana/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Ratos , Ratos Sprague-Dawley
9.
Clin Appl Thromb Hemost ; 25: 1076029619834350, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30836769

RESUMO

We aimed to evaluate the efficacy and safety of antithrombin (AT) supplementation and concomitant anticoagulation therapy in 65 children who met the Japanese Ministry of Health and Welfare (JMHW) disseminated intravascular coagulation (DIC) criteria and had received AT concentrate and/or other concomitant anticoagulants. The primary efficacy end point was to determine standardized mortality ratio (SMR). The secondary efficacy end points were DIC resolution rate and pediatric sequential organ failure assessment (pSOFA) score on day 3. The 28-day mortality rate was 6.8%; SMR was 0.55. Disseminated intravascular coagulation resolution rate on day 3 was 54.5%. The JMHW DIC scores at day 0 ( P = .005) and pSOFA scores at day 3 ( P = .018) were significantly lower in patients with resolution of DIC than in those without resolution of DIC. The target cutoff value for JMHW DIC score on day 0 was 6. No bleeding-related adverse events were associated with AT administration. In children with DIC, AT supplementation and concomitant anticoagulation therapy can be safely used as initial treatment when JMHW DIC score is 6; it may improve DIC resolution, organ failure, and mortality rates.


Assuntos
Antitrombinas/uso terapêutico , Coagulação Intravascular Disseminada/tratamento farmacológico , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Antitrombinas/administração & dosagem , Antitrombinas/farmacologia , Pré-Escolar , Coagulação Intravascular Disseminada/mortalidade , Coagulação Intravascular Disseminada/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Análise de Sobrevida
10.
Arterioscler Thromb Vasc Biol ; 39(4): 694-703, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30727756

RESUMO

Objective- PAR4 (protease-activated receptor 4), one of the thrombin receptors in human platelets, has emerged as a promising target for the treatment of arterial thrombotic disease. Previous studies implied that thrombin exosite II, known as a binding site for heparin, may be involved in thrombin-induced PAR4 activation. In the present study, a heparin octasaccharide analog containing the thrombin exosite II-binding domain of heparin was chemically synthesized and investigated for anti-PAR4 effect. Approach and Results- PAR4-mediated platelet aggregation was examined using either thrombin in the presence of a PAR1 antagonist or γ-thrombin, which selectively activates PAR4. SCH-28 specifically inhibits PAR4-mediated platelet aggregation, as well as the signaling events downstream of PAR4 in response to thrombin. Moreover, SCH-28 prevents thrombin-induced ß-arrestin recruitment to PAR4 but not PAR1 in Chinese Hamster Ovary-K1 cells using a commercial enzymatic complementation assay. Compared with heparin, SCH-28 is more potent in inhibiting PAR4-mediated platelet aggregation but has no significant anticoagulant activity. In an in vitro thrombosis model, SCH-28 reduces thrombus formation under whole blood arterial flow conditions. Conclusions- SCH-28, a synthetic small-molecular and nonanticoagulant heparin analog, inhibits thrombin-induced PAR4 activation by interfering with thrombin exosite II, a mechanism of action distinct from other PAR4 inhibitors that target the receptor. The characteristics of SCH-28 provide a new strategy for targeting PAR4 with the potential for the treatment of arterial thrombosis.


Assuntos
Antitrombinas/farmacologia , Heparina/química , Oligossacarídeos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Receptores de Trombina/antagonistas & inibidores , Animais , Antitrombinas/síntese química , Células CHO , Sinalização do Cálcio/efeitos dos fármacos , Simulação por Computador , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Modelos Moleculares , Proteínas Recombinantes/efeitos dos fármacos , Trombina/farmacologia , Trombose/prevenção & controle
11.
Acta Cir Bras ; 34(1): e20190010000006, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785507

RESUMO

PURPOSE: To investigate whether hirudin exerts its antithrombin action to decrease the ratio of Human Microvascular Endothelial Cells (HMVECs) apoptosis. METHODS: Human microvascular endothelial cells (HMVECs) cultured in the third and fifth generations were used. HMVECs were divided into normal group, thrombin group (T group), natrual hirudin group (H group), thrombin + natrual hirudin group (T + H group), AG490 group, thrombin + AG490 group (T + AG490 group), natrual hirudin + AG490 group (H + AG490 group), thrombin + natural hirudin + AG490 (T + H + AG490 group).Apart from the normal group, the other groups were exposed to the relevant drugs for 24 hours.HMVEC apoptosis was assessed by flow cytometric and double Immunofluorescence of phosphorylation of JAK (P-JAK2) and TUNEL assay. RESULTS: Compared with the normal group, in thrombin group the HMVECs apoptosis rate were significantly increased (P<0.05).The results indicated that the index of apoptosis and the apoptosis rate were improved in cultures treated by natural hirudin (T + H group), relative to cultures with thrombin only (T group). We found that the index of apoptosis and the apoptosis rate in the AG490 + thrombin group were higher than that in the hirudin + thrombin group (P<0.05). Double Immunofluorescence of p-JAK2 and TUNEL assays showed that cells were double positive for P-JAK2 uptake and TUNEL detection liquid binding. CONCLUSION: The natural hirudin and JAK2/STATs signal inhibitor AG490 could block the effects of thrombin. Natural hirudin could attenuate HMVECs apoptosis via antagonizing thrombin and it is suggested that this effect may occur by blocking the JAK2/STATs signaling pathway and this signaling pathways appears to be not the only pathway.


Assuntos
Antitrombinas/farmacologia , Apoptose/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Hirudinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Trombina/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Clin Drug Investig ; 39(4): 355-362, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30697670

RESUMO

BACKGROUND AND OBJECTIVES: Warfarin-related nephropathy is an unexplained acute kidney injury, and may occur in patients with supratherapeutic INR, in the absence of overt bleeding. Similar findings have been observed in rats treated with dabigatran etexilate. We conducted a prospective study in dabigatran etexilate-treated patients to assess the incidence of dabigatran-related nephropathy and to investigate the possible correlation between dabigatran plasma concentration (DPC) and worsening renal function. METHOD: One hundred and seven patients treated long term with dabigatran etexilate for non-valvular atrial fibrillation (NVAF) were followed up for 90 days. DPC, serum creatinine (SCr) and serum cystatin C were prospectively measured. Ninety five patients had complete follow-up data and were evaluable for primary endpoint. RESULTS: Eleven patients had supratherapeutic DPC, defined as DPC higher than 200 ng/ml at study enrolment, but at the end of follow-up no patient showed a persistent increase in SCr. No patients experienced acute kidney injury. CONCLUSIONS: Our study shows that no persistent renal detrimental effect is associated with dabigatran treatment. An increase in SCr during dabigatran treatment is reversible and it seems to be unrelated to dabigatran itself.


Assuntos
Antitrombinas/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/uso terapêutico , Rim/efeitos dos fármacos , Rim/fisiologia , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/farmacologia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Dabigatrana/farmacologia , Feminino , Seguimentos , Humanos , Testes de Função Renal/tendências , Masculino , Estudos Prospectivos
14.
J Cardiothorac Vasc Anesth ; 33(2): 396-402, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30072263

RESUMO

OBJECTIVES: To determine whether precardiopulmonary bypass (CPB) normalization of antithrombin levels in infants to 100% improves heparin sensitivity and anticoagulation during CPB and has beneficial effects into the postoperative period. DESIGN: Randomized, double-blinded, placebo-controlled prospective study. SETTING: Multicenter study performed in 2 academic hospitals. PARTICIPANTS: The study comprised 40 infants younger than 7 months with preoperative antithrombin levels <70% undergoing CPB surgery. INTERVENTIONS: Antithrombin levels were increased with exogenous antithrombin to 100% functional level intraoperatively before surgical incision. MEASUREMENTS AND MAIN RESULTS: Demographics, clinical variables, and blood samples were collected up to postoperative day 4. Higher first post-heparin activated clotting times (sec) were observed in the antithrombin group despite similar initial heparin dosing. There was an increase in heparin sensitivity in the antithrombin group. There was significantly lower 24-hour chest tube output (mL/kg) in the antithrombin group and lower overall blood product unit exposures in the antithrombin group as a whole. Functional antithrombin levels (%) were significantly higher in the treatment group versus placebo group until postoperative day 2. D-dimer was significantly lower in the antithrombin group than in the placebo group on postoperative day 4. CONCLUSION: Supplementation of antithrombin in infants with low antithrombin levels improves heparin sensitivity and anticoagulation during CPB without increased rates of bleeding or adverse events. Beneficial effects may be seen into the postoperative period, reflected by significantly less postoperative bleeding and exposure to blood products and reduced generation of D-dimers.


Assuntos
Deficiência de Antitrombina III/tratamento farmacológico , Antitrombina III/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Procedimentos Cirúrgicos Cardíacos/métodos , Cardiopatias Congênitas/cirurgia , Hemorragia Pós-Operatória/prevenção & controle , Cuidados Pré-Operatórios/métodos , Deficiência de Antitrombina III/sangue , Deficiência de Antitrombina III/complicações , Antitrombinas/farmacologia , Método Duplo-Cego , Feminino , Seguimentos , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/complicações , Humanos , Recém-Nascido , Masculino , Hemorragia Pós-Operatória/sangue , Estudos Prospectivos , Resultado do Tratamento
16.
Presse Med ; 48(2): 154-164, 2019 Feb.
Artigo em Francês | MEDLINE | ID: mdl-30528147

RESUMO

Vitamin-K antagonists (VKA) have been the standard for oral anticoagulation. However, they carry several problems in older patients: frequent bleeding complications, complex management, risk of interactions with multiple drugs. Two classes of direct oral anticoagulants (DOA) are currently available in France: (a) direct thrombin inhibitors: dabigatran; and (b) direct factor Xa inhibitors: rivaroxaban, apixaban and others. Their management is easier: quickly effective after administration, they are given at fixed doses and do not need regular laboratory monitoring. Several randomized trials have shown that DOA are non-inferior to VKA for treating venous thromboembolic disease (prophylactic or curative treatment) and atrial fibrillation (prevention of associated embolisms). DOA might be also effective for long-term treatment of coronary disease, in some cases. No trial has specifically studied older patients. In the context of atrial fibrillation, subgroup analysis show similar results between patients above and below 75-years-old. Lower doses of dabigatran and apixaban should be used in many older people. All DOA are eliminated at least partly by kidneys. Their dose must be reduced in moderate renal failure (filtration glomerular rate (FGR) 30 to 50mL/min) and they are contraindicated in older patients with severe renal failure (FGR<30mL/min). DOA also have other problems: (a) important drug interactions are still possible, (b) the clinical application of specific coagulation tests need to be defined, (c) their safety in some subgroups of elderly patients, very different from patients included in clinical trials, is not known.


Assuntos
Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Tromboembolia/prevenção & controle , Síndrome Coronariana Aguda/prevenção & controle , Idoso , Anticoagulantes/farmacologia , Antitrombinas/farmacologia , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Contraindicações de Medicamentos , Relação Dose-Resposta a Droga , Interações de Medicamentos , Inibidores do Fator Xa/farmacologia , Próteses Valvulares Cardíacas , Hemorragia/induzido quimicamente , Humanos , Insuficiência Renal Crônica/complicações , Fatores de Risco , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controle , Tromboembolia/tratamento farmacológico , Vitamina K/antagonistas & inibidores , Varfarina/farmacologia , Varfarina/uso terapêutico
17.
J Clin Pathol ; 72(3): 244-250, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30518630

RESUMO

AIMS: Clot waveform analysis (CWA) has been reported to extend the interpretation of clotting time measurement. The parameters obtained from successive derivatives of the clotting reaction curves reflect the rates of activation of individual coagulation factors, theoretically dissecting the cascade pathway. This study aims to assess the in vitro effects of direct thrombin inhibitors (DTIs) and activated factor X (FXa) inhibitors. METHODS: CWA was applied to the activated partial thromboplastin time (APTT) assay of plasma samples spiked with each drug. For CWA of APTT measurement curves (APTT-CWA), the positive mode of clotting reaction curves was defined as the direction towards fibrin generation. RESULTS: All the maximum positive values in the successive derivatives were decreased dependently on the concentrations of each drug. Moreover, the negative values in the second and third derivatives appeared putatively due to consumption of thrombin and factor FXa, respectively, to form complexes with plasma serine protease inhibitors. The decrease of the maximum negative values observed dependently on the concentrations of each drug appeared to be consistent with the decreased generation of thrombin and factor FXa. The analysis of Hill coefficients of each drug in the dose-response of changes in the APTT-CWA parameters revealed a difference in anticoagulant cooperativity between DTIs versus FXa inhibitors. CONCLUSIONS: The APTT-CWA demonstrated evidence for the blockade of thrombin-positive feedback by DTIs and FXa inhibitors and that for the differences in anticoagulant cooperativity between them. The results demonstrate the usability of CWA for assessment of anticoagulation and provide insights into direct anticoagulants.


Assuntos
Antitrombinas/farmacologia , Testes de Coagulação Sanguínea/métodos , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/farmacologia , Análise de Ondaletas , Humanos
18.
J Mol Graph Model ; 87: 165-171, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30551079

RESUMO

Recent computational simulations on protein-ligand binding/unbinding have precisely been uncovering the ligand-binding process at the atomic level. In the process, the non-specific binding of ligands to the target site is suggested to occur before binding to the target. We in this study analyzed the conformations of ligands under the non-specific binding on a protein surface to figure out the differences in the conformational characteristics in aqueous solution using the 55-ns molecular dynamic simulation. As for the protein surface, we constructed an artificial ß-sheet, composed of poly-alanine residues (Ala-sheet). For the ligands, the four α-thrombin inhibitors possessing two scaffolds with distinct hydrophobicity profiles were used. During the simulation, all the inhibitors kept interaction with Ala-sheet and had the limited conformational fluctuations compared with in aqueous solution. The representative conformations obtained from the cluster analysis showed that two of hydrophobic inhibitors adopted the extended conformations in aqueous solution and also on Ala-sheet. For the other two hydrophilic inhibitors, the conformations in aqueous solution adopted the bent conformation with two terminal hydrophobic rings closely packed. On Ala-sheet, contrarily, the two hydrophobic rings were open and took the extended conformations, which were placed on the sheet as a foothold. The charged moieties in the hydrophilic inhibitors were protruded into aqueous environment with the extended conformation. The conformational characteristics of the inhibitors in aqueous solution and Ala-sheet varied likely by chemical features or structures of the inhibitors, but each was considered to be physicochemically reasonable.


Assuntos
Antitrombinas/química , Antitrombinas/farmacologia , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Trombina/antagonistas & inibidores , Trombina/química , Análise por Conglomerados , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Estrutura Molecular , Conformação Proteica em Folha beta , Soluções
19.
Mol Cell Biochem ; 451(1-2): 69-78, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29971544

RESUMO

Chronic diabetes is associated with ventricular dysfunctions in the absence of hypertension and coronary artery diseases. This condition is termed as diabetic cardiomyopathy (DCM). There is no favourable treatment available for the management of diabetic cardiomyopathy. Recent studies have reported increase in circulating thrombin level among diabetic patients which is responsible for hypercoagulability of blood. Thrombin induces inflammation and fibrosis, and enhances cardiac cell growth and contractility in vitro. In this study, we have investigated the effects of argatroban; a direct thrombin inhibitor against DCM in streptozotocin-induced type-1 diabetes. Diabetes was induced by single dose of streptozotocin (STZ; 50 mg/kg, i.p.) in male Sprague-Dawley rats. After 4 weeks of diabetes induction, the animals were treated with argatroban (0.3 and 1 mg/kg, i.p. daily) for the next 4 weeks. The effect of argatroban was evaluated against diabetes-associated cardiac dysfunction, structural alteration and protein expression. STZ-induced diabetic rats exhibited significant decline in left ventricular functions. Four weeks of treatments with argatroban significantly improved ventricular functions without affecting heart rate. Further, it also protected heart against structural changes induced by diabetes as shown by reduction in fibrosis, hypertrophy and apoptosis. The improvement in cardiac functions and structural changes was associated with significant reduction in left ventricular expression of thrombin receptor also termed as protease-activated receptor-1 or PAR1, p-AKT (ser-473), p-50 NFκB and caspase-3 proteins. This study demonstrates beneficial effects of argatroban via improvement in cardiac functions and structural changes in STZ-induced DCM. These effects may be attributed through reduction in cardiac inflammation, fibrosis and apoptosis.


Assuntos
Antitrombinas/farmacologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
20.
Dig Dis Sci ; 64(1): 102-112, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30288660

RESUMO

BACKGROUND: Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis. METHODS: Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls. RESULTS: In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension. CONCLUSIONS: By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.


Assuntos
Antitrombinas/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dabigatrana/farmacologia , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Tioacetamida , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colágeno/metabolismo , Citoproteção , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrina/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hipertensão Portal/induzido quimicamente , Hipertensão Portal/fisiopatologia , Hipertensão Portal/prevenção & controle , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Neovascularização Patológica , Fosforilação , Pressão na Veia Porta/efeitos dos fármacos , Ratos Sprague-Dawley
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