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1.
J Ethnopharmacol ; 301: 115744, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36181984

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Lippia alba (Mill.) N.E.Br. ex Britton & P. Wilson is traditionally used in Brazil as an adjunct in the relief of mild anxiety, as an antispasmodic, and as an antidyspeptic. This medicinal species was included in the Phytotherapeutic Form of the Brazilian Pharmacopeia 2nd edition (2021) and has already been described as the most used medicinal plant in a study with patients from an Anticoagulation Clinic in Brazil. Meanwhile, no studies were found that support the safety of the use of L. alba in patients using anticoagulants, a drug with several safety limitations. AIM OF THE STUDY: Provide scientific evidence to ensure the safety of the concomitant use of L. alba and warfarin and support the management of these patients by evaluating its in vitro anticoagulant effect and chemical composition. And, as a timely complementation, evaluate the potential of this medicinal species in the development of new antithrombotics. METHODS: The chemical profile of L. alba derivatives was analyzed by chromatographic methods such as Ultra-Performance Liquid Chromatography (UPLC) coupled with electrospray ionization mass spectrometry (ESI-MS), qualitative UPLC using Diode-Array Detection, and Thin Layer Chromatography. The anticoagulant activity was evaluated by the innovative Thrombin Generation Assay by Calibrated Automated Thrombogram method and using traditional coagulometric tests: prothrombin time, activated partial thromboplastin time, and plasma fibrinogen measurement. RESULTS: Extracts and fractions prolonged the coagulation time in all the tests and reduced thrombin formation in thrombin generation assay. Coagulation times with the addition of ethanloic extract (2.26 mg/mL) was 17.78s, 46.43s and 14.25s respectively in prothrombin time, activated partial thromboplastin time and fibrinogren plasma measurement. In thrombin generation test, this same extract showed ETP as 323 nM/min compared to control (815 nM/min) with high tissue factor and 582 nM/min compared to control (1147 nM/min) using low tissue factor. Presence of flavonoids, phenylpropanoids, and triterpenes were confirmed by chromatographic methods and 13 compounds were identified by UPLC-ESI-MS. Based on these results and on the scientific literature, it is possible to propose that phenylpropanoids and flavonoids are related to the anticoagulant activity observed. CONCLUSION: The results demonstrate the in vitro anticoagulant activity of L. alba, probably due to the activation of intrinsic and extrinsic pathways. It is concluded, then, that there is a potential for interaction, which needs to be further studied, between L. alba and warfarin. Also, this medicinal species shows a great potential for use in the development of new antithrombotics.


Assuntos
Lippia , Humanos , Lippia/química , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Varfarina , Trombina , Tromboplastina , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química
2.
Biomolecules ; 12(11)2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36358949

RESUMO

Natural monoterpenes and their derivatives are widely considered as effective ingredients for the design and production of new biologically active compounds with high antioxidant, antimicrobial and anti-protozoa properties. In this study, we synthesized two series of thiotherpenoids "sulfide-sulfoxide-sulfone", with different bicyclic monoterpene skeleton (bornane and pinane) structures. The effect of the obtained compounds on platelet aggregation was investigated by using the molecular docking technique. The obtained data revealed that all the synthesized compounds may act as potential inhibitors of platelet aggregation. Moreover, the studied sulfides have shown high antioxidant activity as revealed by lipid peroxidation (LPO) process inhibition in a non-cellular substrate containing animal lipids. The sulfides were able to inhibit erythrocyte oxidative hemolysis, to reduce the accumulation of secondary LPO products in cells and to prevent the oxidation of native oxyhemoglobin. Additionally, the corresponding sulfones and sulfoxides exhibited insignificant antioxidant activity. However, the sulfides were found to exhibit significant antiaggregant and anticoagulant effects. These findings suggest as well that the sulfides could serve as a leader compound for future research and possible practical applications.


Assuntos
Antioxidantes , Fibrinolíticos , Animais , Antioxidantes/farmacologia , Antioxidantes/química , Simulação de Acoplamento Molecular , Fibrinolíticos/farmacologia , Anticoagulantes/farmacologia , Sulfóxidos/química , Sulfonas/química , Sulfetos/química
3.
Medicina (Kaunas) ; 58(11)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36363548

RESUMO

Background and objectives: Cementless total hip arthroplasty is a common surgical procedure and perioperative thromboprophylaxis is used to prevent deep vein thrombosis or pulmonary embolism. Osseointegration is important for long-term implant survival, and there is no research on the effect of different thromboprophylaxis agents on the process of osseointegration. Materials and Methods: Seventy rats were allocated as follows: Group I (control group), Group II (enoxaparin), Group III (nadroparin), and Group IV (fondaparinux). Ovariectomy was performed on all subjects, followed by the introduction of an intramedullary titanium implant into the femur. Thromboprophylaxis was administered accordingly to each treatment group for 35 days postoperatively. Results: Group I had statistically significantly lower anti-Xa levels compared to treatment groups. Micro-CT analysis showed that nadroparin had lower values compared to control in bone volume (0.12 vs. 0.21, p = 0.01) and percent bone volume (1.46 vs. 1.93, p = 0.047). The pull-out test showed statistically significant differences between the control group (8.81 N) compared to enoxaparin, nadroparin, and fondaparinux groups (4.53 N, 4 N and 4.07 N, respectively). Nadroparin had a lower histological cortical bone tissue and a higher width of fibrous tissue (27.49 µm and 86.9 µm) at the peri-implant area, compared to control (43.2 µm and 39.2 µm), enoxaparin (39.6 µm and 24 µm), and fondaparinux (36.2 µm and 32.7 µm). Conclusions: Short-term administration of enoxaparin, nadroparin, and fondaparinux can reduce the osseointegration of titanium implants, with nadroparin having the most negative effect. These results show that enoxaparin and fondaparinux are preferred to be administered due to a lesser negative impact on the initial implant fixation.


Assuntos
Nadroparina , Tromboembolia Venosa , Feminino , Ratos , Animais , Nadroparina/farmacologia , Nadroparina/uso terapêutico , Fondaparinux , Enoxaparina/farmacologia , Enoxaparina/uso terapêutico , Titânio/uso terapêutico , Osseointegração , Fator X , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico
4.
Int J Mol Sci ; 23(21)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36361963

RESUMO

Venous thromboembolism (VTE) is the third leading cardiovascular cause of death and is conventionally treated with anticoagulants that directly antagonize coagulation. However, recent data have demonstrated that also platelets play a crucial role in VTE pathophysiology. In the current review, we outline how platelets are involved during all stages of experimental venous thrombosis. Platelets mediate initiation of the disease by attaching to the vessel wall upon which they mediate leukocyte recruitment. This process is referred to as immunothrombosis, and within this novel concept inflammatory cells such as leukocytes and platelets directly drive the progression of VTE. In addition to their involvement in immunothrombosis, activated platelets can directly drive venous thrombosis by supporting coagulation and secreting procoagulant factors. Furthermore, fibrinolysis and vessel resolution are (partly) mediated by platelets. Finally, we summarize how conventional antiplatelet therapy can prevent experimental venous thrombosis and impacts (recurrent) VTE in humans.


Assuntos
Tromboembolia Venosa , Trombose Venosa , Humanos , Plaquetas , Tromboinflamação , Coagulação Sanguínea , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico
6.
Parasit Vectors ; 15(1): 411, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36335395

RESUMO

BACKGROUND: Haemaphysalis flava is a hematophagous ectoparasite that acquires the nutrition needed for development and reproduction by sucking blood and digesting the blood meal. During blood-sucking and blood-meal digestion, the prevention of blood coagulation is important for this tick. Previous studies have shown that heat shock cognate 70 (HSC70) protein has certain anticoagulant activities, but its immunogenicity remains unclear. Also, whether the mutation of individual bases of the TKD-like peptide of HSC70 through the overlap extension method can change its anticoagulant activities and immunogenicity remains to be investigated. METHODS: The gene encoding the HSC70 protein was cloned from a complementary DNA library synthesized from H. flava. The coding gene of the TKD-like peptide of HSC70 was mutated into a TKD peptide coding gene (HSC70TKD) using the overlap extension method. Escherichia coli prokaryotic expression plasmids were constructed to obtain the recombinant proteins of HSC70 (rHSC70) and HSC70TKD (rHSC70TKD). The purified rHSC70 and rHSC70TKD were evaluated at different concentrations for anticoagulant activities using four in vitro clotting assays. Emulsifying recombinant proteins with complete and incomplete Freund's adjuvants were subcutaneously immunized in Sprague Dawley rats. The serum antibody titers and serum concentrations of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) were detected using an indirect enzyme-linked immunosorbent assay to assess the immunogenicity of rHSC70 and rHSC70TKD. RESULTS: The open reading frame of HSC70 was successfully amplified and found to have a length of 1958 bp. The gene encoding the TKD-like peptide of HSC70 was artificially mutated, with the 1373-position adenine (A) of the original sequence mutated into guanine (G), the 1385-position cytosine (C) mutated into G and the 1386-position G mutated into C. rHSC70 and rHSC70TKD that fused with His-tag were obtained using the expression plasmids pET-28a-HSC70 and pET-28a-HSC70TKD, respectively. rHSC70 and rHSC70TKD prolonged the thrombin time (TT) and reduced the fibrinogen (FIB) content in the plasma, but did not affect the prothrombin time (PT) or activated partial thromboplastin time (APTT) when compared to the negative control. Interestingly, the ability of rHSC70TKD to prolong the TT and reduce the FIB content in the plasma was better than that of rHSC70. The specific antibody titers of both rHSC70 and rHSC70TKD in rat serum reached 1:124,000 14 days after the third immunization. The serum concentration of IFN-γ in the rHSC70TKD group was higher than that in the rHSC70 group. The rHSC70 group has the highest serum concentration of IL-4, and the serum concentration of IL-4 in the rHSC70TKD group was higher than that in the negative group. CONCLUSIONS: rHSC70 and rHSC70TKD exhibited anticoagulant activities by prolonging the TT and reducing the FIB content in vitro. rHSC70TKD had better anticoagulant activities than rHSC70. Both rHSC70 and rHSC70TKD had good immunogenicity and induced humoral and cellular immunity.


Assuntos
Interleucina-4 , Ixodidae , Animais , Ratos , Anticoagulantes/farmacologia , Anticoagulantes/metabolismo , Escherichia coli/metabolismo , Resposta ao Choque Térmico , Proteínas de Choque Térmico HSC70/genética , Proteínas de Choque Térmico HSC70/metabolismo , Ixodidae/genética , Ratos Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
7.
Molecules ; 27(20)2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36296562

RESUMO

In recent decades, heparin, as the most important anticoagulant drug, has been widely used in clinical settings to prevent and treat thrombosis in a variety of diseases. However, with in-depth research, the therapeutic potential of heparin is being explored beyond anticoagulation. To date, heparin and its derivatives have been tested in the protection against and repair of inflammatory, antitumor, and cardiovascular diseases. It has also been explored as an antiangiogenic, preventive, and antiviral agent for atherosclerosis. This review focused on the new and old applications of heparin and discussed the potential mechanisms explaining the biological diversity of heparin.


Assuntos
Doenças Cardiovasculares , Trombose , Humanos , Heparina/farmacologia , Heparina/uso terapêutico , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Trombose/tratamento farmacológico , Trombose/prevenção & controle , Doenças Cardiovasculares/tratamento farmacológico , Antivirais/uso terapêutico
8.
Biopharm Drug Dispos ; 43(5): 192-200, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36195699

RESUMO

It was reported that high-dose cyclosporine at 500 mg daily increases edoxaban exposure. We investigated whether cyclosporine <500 mg daily leads to edoxaban-induced bleeding in the clinical setting. This case series study included patients receiving edoxaban and cyclosporine at Mie University Hospital. The outcomes were bleeding and anticoagulant markers, including activated partial thromboplastin time (APTT), prothrombin time (PT), and the international normalized ratio of prothrombin time (PT-INR). We examined the genotypes of cytochrome P450 3A5 (CYP3A5), multidrug resistance 1 (ABCB1), and solute carrier organic anion transporter 1B1 (SLCO1B1). Trends in anticoagulant markers were analyzed. Thirteen patients received edoxaban (standard dose; n = 3 and reduced dose; n = 10) and cyclosporine (1.94 ± 1.42 mg/kg). A bleeding event occurred in one patient receiving a standard dose of edoxaban plus cyclosporine of 25 mg daily (HAS-BLED score of 2 and genotypes; CYP3A5*3/*3, ABCB1 3435CT, and SLCO1B1*1a/*1b). After edoxaban treatment, anticoagulant markers were prolonged (APTT; 27.95 ± 3.64 s vs. 31.11 ± 3.90 s, p < 0.001, PT; 11.53 ± 1.01 s vs. 13.03 ± 0.98 s, p = 0.002, PT-INR; 0.98 ± 0.09 vs. 1.11 ± 0.11, p = 0.007). In summary, the genotypes of CYP3A5, ABCB1, and SLCO1B1 and the dosage of edoxaban may affect the risk of bleeding by edoxaban when co-administered with cyclosporine, even at low doses.


Assuntos
Citocromo P-450 CYP3A , Inibidores do Fator Xa , Humanos , Citocromo P-450 CYP3A/genética , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Ciclosporina/efeitos adversos , Anticoagulantes/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado
9.
Dokl Biochem Biophys ; 506(1): 177-180, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36303047

RESUMO

The involvement of nitric oxide in the responses of the hemostasis system to the appearance of proline-containing peptides in the blood was studied in experiments on rats. It was shown that a single intranasal administration of peptides PGP, RPGP, and PGPL to rats led to an increase in fibrinolytic, anticoagulant, and antiplatelet potential of blood. The use of the non-selective NO-synthase blocker L-NAME almost completely inhibited the anticoagulant effects of the glyprolines. It was found that the mechanism of the anticoagulant-fibrinolytic and antiplatelet action of glyproline peptides is determined by the activation of the enzymatic pathway of nitric oxide formation. The obtained results revealed the involvement of nitric oxide in the implementation of hemostatic and vascular-endothelial functions of the organism.


Assuntos
Hemostáticos , Óxido Nítrico , Ratos , Animais , Hemostasia , Peptídeos/farmacologia , Anticoagulantes/farmacologia , NG-Nitroarginina Metil Éster/farmacologia
10.
Int J Mol Sci ; 23(20)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36293094

RESUMO

In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 Mpro. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds. Moreover, a quantum mechanical study was also conducted which helped us to attest to some of the molecular docking and dynamics findings. A biological evaluation (in vitro) of the most promising compounds was also performed by carrying out the MTT cytotoxicity assay and the crystal violet assay in order to assess inhibitory concentration 50 (IC50). It is worth noting that ticagrelor displayed the highest intrinsic potential for the inhibition of SARS-CoV-2 with an IC50 value of 5.60 µM and a safety index of 25.33. In addition, fondaparinux sodium and dabigatran showed promising inhibitory activities with IC50 values of 8.60 and 9.40 µM, respectively, and demonstrated safety indexes of 17.60 and 15.10, respectively. Moreover, the inhibitory potential of the SARS-CoV-2 Mpro enzyme was investigated by utilizing the SARS-CoV-2 Mpro assay and using tipranavir as a reference standard. Interestingly, promising SARS-CoV-2 Mpro inhibitory potential was attained for fondaparinux sodium with an IC50 value of 2.36 µM, surpassing the reference tipranavir (IC50 = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 Mpro inhibitory potential was attained for dabigatran with an IC50 value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/tratamento farmacológico , Simulação de Acoplamento Molecular , Proteases 3C de Coronavírus , Simulação de Dinâmica Molecular , Fondaparinux , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Dabigatrana , Ticagrelor , Eptifibatida , Violeta Genciana , Inibidores de Proteases/química , Proteínas não Estruturais Virais/metabolismo , Heparina/farmacologia , Antivirais/farmacologia , Antivirais/química
11.
Int J Mol Sci ; 23(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36293332

RESUMO

Recent research has contributed significantly to our understanding of the pathogenesis of acute disseminated intravascular coagulation. COVID-19 can be considered as a new underlying condition of disseminated intravascular coagulation. In this narrative review, current evidence is presented regarding biomarker differences between sepsis-induced and COVID-19-associated coagulopathies, supporting the importance of acquired antithrombin deficiency in the early differential diagnosis of septic coagulopathy and its potential impact on treatment with endogenous anticoagulants. Establishing new scoring systems for septic coagulopathy in combination with endogenous anticoagulant biomarker activities may allow for the identification of those in the heterogeneous population of sepsis patients who are more likely to benefit from targeted specific treatment interventions.


Assuntos
Transtornos da Coagulação Sanguínea , COVID-19 , Coagulação Intravascular Disseminada , Sepse , Humanos , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/etiologia , Antitrombinas/uso terapêutico , COVID-19/complicações , Anticoagulantes/uso terapêutico , Anticoagulantes/farmacologia , Transtornos da Coagulação Sanguínea/complicações , Sepse/complicações , Antitrombina III , Biomarcadores
12.
Carbohydr Polym ; 297: 120002, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36184134

RESUMO

Low molecular weight heparin (LMWH), an anionic polysaccharide, has been widely used as a clinical anticoagulant. However, repeated subcutaneous injection is sometimes required due to its short half-life. To reduce the dosing frequency, the injectable polypseudorotaxane hydrogel was fabricated by inclusion complexation formation between Tween 80 and α-Cyclodextrin (αCD) for sustained release of LMWH. The physicochemical properties of such hydrogel were characterized by SEM, XRD, DSC, and FTIR. This hydrogel showed shear-thinning and thixotropic behavior and was easily injected through standard syringe needles. The gelation time, mechanical strength, shear viscosity, in vitro drug release rate, in vitro hydrogel dissolution rate, and in vivo hydrogel retention could be tuned by αCD concentration in the hydrogel. In vivo safety evaluation indicated that the polypseudorotaxane hydrogel was biocompatible. Most importantly, this polypseudorotaxane hydrogel could sustain release of LMWH after subcutaneous injection.


Assuntos
alfa-Ciclodextrinas , Anticoagulantes/farmacologia , Ciclodextrinas , Preparações de Ação Retardada , Heparina de Baixo Peso Molecular , Hidrogéis/química , Poloxâmero , Polissorbatos , Rotaxanos , alfa-Ciclodextrinas/química
13.
Yakugaku Zasshi ; 142(10): 1125-1127, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-36184446

RESUMO

A 55-year-old man with hypertrophic cardiomyopathy and a pacemaker was admitted with coronavirus disease 2019 (COVID-19). Before admission, the patient's medications included amiodarone, diltiazem, bisoprolol, atorvastatin, etizolam, and warfarin (WF). After admission, dexamethasone (DXM) and remdesivir (RDV) were initiated for treating COVID-19. The international normalized ratio (INR) on admission was 1.8, which increased to 3.4 on day 5 and to 6.9 on day 10 after admission. Although there have been reports that RDV may occasionally prolong prothrombin time and that the degree of prolongation is often less severe, the mechanism of action has not been elucidated till date. There are reports of prolonged INR when WF is co-administered with RDV and DXM, suggesting that drug interactions may be a potential cause for the prolongation. A similar drug interaction may have potentially occurred in the case reported here. In addition, this case used amiodarone (AMD), and it has been reported that the RDV concentration increases when used in combination with AMD. Further investigations are needed to elucidate the cause of INR prolongation. Thus, close monitoring of the patient is recommended when RDV is co-administered with high-risk agents to avoid unnecessary side effects.


Assuntos
Amiodarona , COVID-19 , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Amiodarona/efeitos adversos , Anticoagulantes/farmacologia , Atorvastatina , Bisoprolol , COVID-19/tratamento farmacológico , Dexametasona/efeitos adversos , Diltiazem , Interações Medicamentosas , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Varfarina/farmacologia
14.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232517

RESUMO

Current guidelines recommend monitoring the anticoagulant effect of unfractionated heparin (UFH) by measuring anti-Xa activity rather than activated partial thromboplastin time (aPTT) in intensive care unit (ICU) patients. The primary objective of this study was to evaluate the correlation of aPTT, anti-Xa activity, and thrombin generation in UFH-treated ICU patients. A prospective observational pilot study was conducted in adult surgical ICU patients treated with UFH. aPTT and anti-Xa activity were monitored daily. The therapeutic target was aPTT between 50 s and 84 s, and/or anti-Xa between 0.3 and 0.7 U/mL. Correlation among aPTT, anti-Xa activity, and thrombin generation was determined by measuring endogenous thrombin potential (ETP), with the inflammatory response evaluated. C-reactive protein (CRP) was used as a marker of inflammatory response. The plasma of 107 samples from 30 ICU patients was analyzed. The correlation between aPTT and anti-Xa activity was 0.66, CI95% [0.54;0.76] (p < 0.0001). Although thrombin generation, aPTT, and anti-Xa were correlated with inflammatory responses, the correlation was higher with thrombin generation and anti-Xa activity compared to aPTT. When aPTT was in a therapeutic range, a low thrombin generation was observed but was 50% inhibited when anti-Xa was in a therapeutic range. Coagulation testing with aPTT, anti-Xa correlated with thrombin generation. A 50% decrease in thrombin generation was observed when anti-Xa was within a therapeutic range. Further work is needed to evaluate coagulation biomarker responses and clinical outcomes in specific ICU populations.


Assuntos
Heparina , Trombina , Adulto , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Biomarcadores , Proteína C-Reativa , Monitoramento de Medicamentos , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Heparina/farmacologia , Heparina de Baixo Peso Molecular , Humanos , Unidades de Terapia Intensiva , Tempo de Tromboplastina Parcial , Estudos Prospectivos
15.
Ter Arkh ; 94(7): 876-883, 2022 Aug 12.
Artigo em Russo | MEDLINE | ID: mdl-36286946

RESUMO

AIM: Analysis of the dynamics of different stages of clot formation and its lysis in patients with different COVID-19 severity. MATERIALS AND METHODS: We prospectively included 58 patients with COVID-19 (39 patients with moderate disease severity and 18 patients with severe disease) and 47 healthy volunteers as a control group. All participants underwent the assessment of flow-mediated dilation (FMD) of brachial artery, impedance aggregometry, rotational thromboelastometry and thrombodynamics. Von Willebrand factor antigen (vWF:Ag) quantification was also performed in patients with COVID-19. Measurements were repeated on the 3rd and 9th day of hospitalization. RESULTS: Compared to the control group, patients with COVID-19 showed reduced values of platelet aggregation and greater values of the clot growth rate, as well as its size and density. On the first day of hospitalization, we found no differences in the activity of plasma hemostasis and endogenous fibrinolysis between subgroups of patients. With the progression of the disease, the growth rate and size of the clot were higher in the severe subgroup, even despite higher doses of anticoagulants in this subgroup. An increase in platelet aggregation was noted during the progression of the disease, especially in the severe subgroup. There were no differences in the results of the FMD test by subgroups of patients. The vWF:Ag level was significantly higher in the severe subgroup. CONCLUSION: Thus, plasma hemostasis followed by secondary platelet activation correlates with the severity of COVID-19. Patients with moderate to severe coronavirus infection have predominantly local rather than generalized endothelial dysfunction.


Assuntos
COVID-19 , Trombose , Humanos , Fator de von Willebrand , Hemostasia , Agregação Plaquetária , Anticoagulantes/farmacologia
17.
Org Biomol Chem ; 20(42): 8323-8330, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36239281

RESUMO

A chemoenzymatic approach, mimicking the biosynthetic pathway of heparin and heparan sulfate (HS), has been well developed to prepare a series of structurally well-defined heparin oligosaccharides with excellent anticoagulant activity in good overall yields. The current chemoenzymatic synthesis typically begins with an unnatural glycosyl acceptor, p-nitrophenyl glucuronide (GlcA-PNP), which is convenient for detection recovery and purification, although it affords heparin molecules with undesirable structure characteristics. Herein, we describe a facile chemoenzymatic strategy assisted by the specific cleavage of heparinase III for the highly efficient synthesis of an unmodified heparin heptasaccharide which demonstrated potent anticoagulant activity in vitro and commensurate pharmacokinetic profiles with fondaparinux. This successful generic strategy is applicable to the scalable synthesis of diverse HS/heparin molecules with completely natural structural features as promising therapeutic agents.


Assuntos
Anticoagulantes , Heparina de Baixo Peso Molecular , Anticoagulantes/farmacologia , Anticoagulantes/química , Heparina/química , Heparitina Sulfato/química , Oligossacarídeos/química
18.
Biomater Sci ; 10(22): 6570-6582, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36222175

RESUMO

Indwelling needles are widely used in the clinic for their advantages of reducing the pain and discomfort caused by repeated venipuncture. Achieving anticoagulation and hemostasis with one single indwelling needle is highly desired from perspective of implantation patency and the prevention of needle-withdrawal-induced uncontrolled bleeding. Herein, we develop a sophisticated indwelling needle with an anticoagulant/hemostatic dual function by anchoring an anticoagulant heparin coating and a hemostatic hydrogel coating on the inner surface and the outer surface of the indwelling needle, respectively. The results of in vitro tests and continuous blood collections from the rabbit ear vein indicate that the anticoagulant coating can resist the adhesion of proteins and blood cells, and its anticoagulant effect can maintain the patency of the indwelling needle for 3 hours after implantation. Meanwhile, the xerogel-hydrogel transition of the hemostatic coating upon contacting blood promotes the aggregation of blood cells, thus sealing the puncture site to achieve complete hemostasis after needle removal. Importantly, this anticoagulant/hemostatic indwelling needle can replace traditional repeated puncture, and can be used to monitor blood glucose concentration changes in diabetic rats through continuous blood collection, portending its promising application in the oral glucose tolerance test.


Assuntos
Diabetes Mellitus Experimental , Hemostáticos , Ratos , Coelhos , Animais , Hemostáticos/farmacologia , Anticoagulantes/farmacologia , Agulhas , Teste de Tolerância a Glucose , Hemostasia , Hidrogéis/farmacologia
19.
Small ; 18(46): e2203751, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36192159

RESUMO

Despite nearly a century of clinical use as a blood thinner, heparin's rapid serum clearance and potential to induce severe bleeding events continue to urge the development of more effective controlled delivery strategies. Subcutaneous depots that steadily release the anticoagulant into circulation represent a promising approach to reducing overdose frequency, sustaining therapeutic concentrations of heparin in plasma, and prolonging anticoagulant activity in a safe and effective manner. Subcutaneously deliverable heparin-peptide nanogranules that allow for long-lasting heparin bioavailability in the circulatory system, while enabling on-demand activation of heparin's anticoagulant effects in the thrombus microenvironment, are reported. Biophysical studies demonstrate this responsive behavior is due to the sequestration of heparin within self-assembling peptide nanofibrils and its mechanically actuated decoupling to elicit antithrombotic effects at the clotting site. In vivo studies show these unique properties converge to allow subcutaneous nanogranule depots to extend heparin serum concentrations for an order of magnitude longer than standard dosing regimens while enabling prolonged and controlled anticoagulant activity. This biohybrid delivery system demonstrates a potentially scalable platform for the development of safer, easier to administer, and more effective antithrombotic nanotechnologies.


Assuntos
Heparina , Trombose , Humanos , Heparina/química , Fibrinolíticos/uso terapêutico , Trombose/tratamento farmacológico , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Anticoagulantes/química , Peptídeos
20.
Pest Manag Sci ; 78(11): 4480-4487, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36181415

RESUMO

BACKGROUND: The house mouse (Mus musculus) is a globally distributed rodent pest species against which anticoagulant rodenticides are widely used for the protection of human and animal health and the conservation of threatened wildlife. Anticoagulant-resistant house mice have been known for more than half a century. A house mouse strain was developed in the laboratory that was homozygous resistant for the single nucleotide polymorphism (SNP) Tyrosine139Cysteine (Y139C) and, subsequently, heterozygous resistant animals were produced from this strain by crossing with the homozygous susceptible strain. RESULTS: Using blood clotting response tests, resistance factors at the ED50 level in the homozygous resistant strain for the first-generation anticoagulants warfarin, chlorophacinone, diphacinone and coumatetralyl were in the range 31.5 to 628.0 for males (M) and 21.6 to 628.0 for females (F), thus indicating that Y139C house mice are substantially resistant to all these substances. Resistance factors at the ED50 level for the homozygous strain generated against the second-generation compounds were: brodifacoum (M, 1.7; F, 1.9), bromadiolone (M, 16.6; F, 21.0), difenacoum (M, 1.2; F, 2.7), difethialone (M, 1.5; F, 1.5), and flocoumafen (M, 0.9; F, 1.2). Equivalent values for the heterozygous strain were: brodifacoum (M, 1.6; F, 1.4), bromadiolone (M, 5.6; F, 6.5), difenacoum (M, 1.0; F, 1.3), difethialone (M, 1.1; F, 1.1), flocoumafen (M, 0.9; F, 1.1). CONCLUSION: Y139C SNP homozygous resistant mice are more resistant to anticoagulants than heterozygous resistant animals. All first-generation anticoagulants are highly resisted and, among the second-generation compounds, Y139C mice are resistant to bromadiolone and sometimes to difenacoum. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Assuntos
4-Hidroxicumarinas , Rodenticidas , 4-Hidroxicumarinas/farmacologia , Animais , Anticoagulantes/farmacologia , Coagulação Sanguínea , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Camundongos , Fatores R , Roedores , Rodenticidas/farmacologia , Varfarina
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