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1.
Nat Commun ; 15(1): 3977, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730234

RESUMO

Potent and selective inhibition of the structurally homologous proteases of coagulation poses challenges for drug development. Hematophagous organisms frequently accomplish this by fashioning peptide inhibitors combining exosite and active site binding motifs. Inspired by this biological strategy, we create several EXACT inhibitors targeting thrombin and factor Xa de novo by linking EXosite-binding aptamers with small molecule ACTive site inhibitors. The aptamer component within the EXACT inhibitor (1) synergizes with and enhances the potency of small-molecule active site inhibitors by many hundred-fold (2) can redirect an active site inhibitor's selectivity towards a different protease, and (3) enable efficient reversal of inhibition by an antidote that disrupts bivalent binding. One EXACT inhibitor, HD22-7A-DAB, demonstrates extraordinary anticoagulation activity, exhibiting great potential as a potent, rapid onset anticoagulant to support cardiovascular surgeries. Using this generalizable molecular engineering strategy, selective, potent, and rapidly reversible EXACT inhibitors can be created against many enzymes through simple oligonucleotide conjugation for numerous research and therapeutic applications.


Assuntos
Aptâmeros de Nucleotídeos , Domínio Catalítico , Hirudinas , Trombina , Humanos , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Trombina/antagonistas & inibidores , Trombina/metabolismo , Trombina/química , Hirudinas/química , Hirudinas/farmacologia , Anticoagulantes/farmacologia , Anticoagulantes/química , Fator Xa/metabolismo , Fator Xa/química , Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacologia , Animais , Sítios de Ligação , Coagulação Sanguínea/efeitos dos fármacos
2.
PeerJ ; 12: e17039, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38590700

RESUMO

Background: Acute pulmonary embolism (APE) is classified as a subset of diseases that are characterized by lung obstruction due to various types of emboli. Current clinical APE treatment using anticoagulants is frequently accompanied by high risk of bleeding complications. Recombinant hirudin (R-hirudin) has been found to have antithrombotic properties. However, the specific impact of R-hirudin on APE remains unknown. Methods: Sprague-Dawley (SD) rats were randomly assigned to five groups, with thrombi injections to establish APE models. Control and APE group rats were subcutaneously injected with equal amounts of dimethyl sulfoxide (DMSO). The APE+R-hirudin low-dose, middle-dose, and high-dose groups received subcutaneous injections of hirudin at doses of 0.25 mg/kg, 0.5 mg/kg, and 1.0 mg/kg, respectively. Each group was subdivided into time points of 2 h, 6 h, 1 d, and 4 d, with five animals per point. Subsequently, all rats were euthanized, and serum and lung tissues were collected. Following the assessment of right ventricular pressure (RVP) and mean pulmonary artery pressure (mPAP), blood gas analysis, enzyme-linked immunosorbnent assay (ELISA), pulmonary artery vascular testing, hematoxylin-eosin (HE) staining, Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, immunohistochemistry, and Western blot experiments were conducted. Results: R-hirudin treatment caused a significant reduction of mPAP, RVP, and Malondialdehyde (MDA) content, as well as H2O2 and myeloperoxidase (MPO) activity, while increasing pressure of oxygen (PaO2) and Superoxide Dismutase (SOD) activity. R-hirudin also decreased wall area ratio and wall thickness to diameter ratio in APE rat pulmonary arteries. Serum levels of endothelin-1 (ET-1) and thromboxaneB2 (TXB2) decreased, while prostaglandin (6-K-PGF1α) and NO levels increased. Moreover, R-hirudin ameliorated histopathological injuries and reduced apoptotic cells and Matrix metalloproteinase-9 (MMP9), vascular cell adhesion molecule-1 (VCAM-1), p-Extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P65/P65 expression in lung tissues. Conclusion: R-hirudin attenuated pulmonary hypertension and thrombosis in APE rats, suggesting its potential as a novel treatment strategy for APE.


Assuntos
Hominidae , Hipertensão Pulmonar , Embolia Pulmonar , Trombose , Ratos , Animais , Hipertensão Pulmonar/tratamento farmacológico , Ratos Sprague-Dawley , Hirudinas/farmacologia , Peróxido de Hidrogênio/uso terapêutico , Embolia Pulmonar/complicações , Trombose/tratamento farmacológico
3.
J Cardiothorac Surg ; 19(1): 242, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38632589

RESUMO

BACKGROUND: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome is a severe adverse drug reaction marked by delayed hypersensitivity reactions causing skin and systemic complications. DRESS diagnosis is challenging due to the variety of clinical presentations and symptom overlap with other conditions. The perioperative period in these patients requires precise pharmacological strategies to prevent complications associated with this syndrome. The treatment of DRESS induced by unfractionated heparin during cardiopulmonary bypass (CPB) surgery presents some challenges that must be considered when selecting an anticoagulant to avoid side effects. In this case, bivalirudin, a direct thrombin inhibitor, is indicated as an alternative to heparin in patients undergoing CPB. However, in contrast to heparin/protamine, there is no direct reversal agent for bivalirudin. CASE PRESENTATION: We report the case of an 11-year-old male diagnosed with native aortic valve endocarditis and thrombosis in his left lower extremity. During valvular replacement surgery, systemic unfractionated heparin was administered. Postoperatively, the patient developed fever, eosinophilia and pruritic rash. Warm shock and elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels followed, leading to the diagnosis of DRESS syndrome. Treatment with methylprednisolone resulted in complete resolution of symptoms. Seven years later, the patient was readmitted due to insufficient anticoagulation and a thrombus in the prosthetic aortic valve, presenting a recurrent DRESS episode due to the administration of unfractionated heparin, which was later replaced with low-molecular-weight heparin during hospitalization. Treatment with corticosteroids and antihistamines was initiated, resulting in the resolution of this episode. Ultimately, the patient required the Ross procedure. During this intervention the anticoagulation strategy was modified, unfractionated heparin was replaced with bivalirudin during the procedure and fondaparinux was administered during the postoperative period. This resulted in stable transaminases levels and no eosinophilia. CONCLUSION: The severity of DRESS Syndrome underscores the importance of early recognition, heightened monitoring, and a comprehensive approach tailored to each patient's needs. This particular case highlights the significance of this approach and may have a substantial clinical impact since it provides alternatives to heparin, such as bivalirudin and fondaparinux, in the anticoagulation strategy of CPB for patients who have a hypersensibility reaction to this medication; thus, enhancing clinical outcomes by minimizing risks linked to adverse drug reactions.


Assuntos
Anestésicos , Síndrome de Hipersensibilidade a Medicamentos , Eosinofilia , Masculino , Humanos , Criança , Heparina/uso terapêutico , Fondaparinux , Síndrome de Hipersensibilidade a Medicamentos/tratamento farmacológico , Anticoagulantes/uso terapêutico , Hirudinas/efeitos adversos , Eosinofilia/induzido quimicamente , Eosinofilia/tratamento farmacológico , Fragmentos de Peptídeos , Proteínas Recombinantes
4.
Chem Biol Drug Des ; 103(5): e14533, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38684373

RESUMO

Hirudin is one of the specific inhibitors of thrombin, which has been confirmed to have strong bioactivities, including inhibiting tumors. However, the function and mechanism of hirudin and protease-activated receptor 1 (PAR-1) in diffuse large B-cell lymphoma (DLBCL) have not been clear. Detecting the expression PAR-1 in DLBCL tissues and cells by RT-qPCR and IHC. Transfected sh-NC, sh-PAR-1, or pcDNA3.1-PAR-1 in DLBCL cells or processed DLBCL cells through added thrombin, Vorapaxar, Recombinant hirudin (RH), or Na2S2O4 and co-culture with EA.hy926. And built DLBCL mice observed tumor growth. Detecting the expression of related genes by RT-qPCR, Western blot, IHC, and immunofluorescence, measured the cellular hypoxia with Hypoxyprobe-1 Kit, and estimated the cell inflammatory factors, proliferation, migration, invasion, and apoptosis by ELISA, CCK-8, flow cytometry, wound-healing and Transwell. Co-immunoprecipitation and pull-down measurement were used to verify the relationship. PAR-1 was highly expressed in DLBCL tissues and cells, especially in SUDHL2. Na2S2O4 induced SUDHL2 hypoxia, and PAR-1 did not influence thrombin-activated hypoxia. PAR-1 could promote SUDHL2 proliferation, migration, and invasion, and it was unrelated to cellular hypoxia. PAR-1 promoted proliferation, migration, and angiogenesis of EA.hy926 or SUDHL2 through up-regulation vascular endothelial growth factor (VEGF). RH inhibited tumor growth, cell proliferation, and migration, promoted apoptosis of DLBCL, and inhibited angiogenesis by down-regulating PAR-1-VEGF. RH inhibits proliferation, migration, and angiogenesis of DLBCL cells by down-regulating PAR-1-VEGF.


Assuntos
Apoptose , Proliferação de Células , Hirudinas , Linfoma Difuso de Grandes Células B , Neovascularização Patológica , Receptor PAR-1 , Proteínas Recombinantes , Fator A de Crescimento do Endotélio Vascular , Humanos , Hirudinas/farmacologia , Receptor PAR-1/metabolismo , Receptor PAR-1/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Camundongos , Linhagem Celular Tumoral , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/metabolismo , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Angiogênese
5.
J Stomatol Oral Maxillofac Surg ; 125(3S): 101868, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38588856

RESUMO

BACKGROUND AND PURPOSE: Hirudin, a potent anticoagulant, is used in traditional Chinese medicine (TCM) to treat thrombotic conditions and prevent postoperative thrombosis. Coagulation-related vascular complications are a common cause of perforator flaps failure. This study explores hirudin's potential to enhance flap growth by mitigating coagulation-related issues. MATERIALS AND METHODS: Patients were divided into GroupⅠ(hirudin group) and GroupⅡ(control). Laboratory tests covered red blood cell count (RBC), hematocrit (HCT), platelet count (PLT), monocyte count (MONO), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and D-Dimer. Clinical parameters, including capillary refill time (CRT), flap swelling, and survival status, were evaluated. Animal experiments used Sprague-Dawley (SD) rats to establish random skin flaps. The experimental side received hirudin injection, while the control side received saline. Flaps were photographed to calculate survival rate, and CD31 immunohistochemical (IHC) analysis was performed to calculate microvessel density (MVD). RESULTS: The study, with 29 patients, found significant CRT differences between groups on postoperative days 2 and 6 (p = 0.027; p = 0.019), favoring GroupⅠ. Swelling severity varied significantly over time; GroupⅡhad more pronounced swelling. GroupⅠshowed superior flap growth with fewer complications, statistically significant (p = 0.033). Specific lab indicators (MONO, PT, and FIB) were significant at certain times. In animal experiments, the experimental side consistently had higher flap survival and slightly increased CD31 expression at various times, with higher MVD on days 2 and 6. CONCLUSIONS: Hirudin enhances flap survival through diverse mechanisms, supporting its role as a complementary approach in perforator flap surgeries.


Assuntos
Sobrevivência de Enxerto , Hirudinas , Retalho Perfurante , Ratos Sprague-Dawley , Animais , Ratos , Hirudinas/administração & dosagem , Hirudinas/farmacologia , Masculino , Retalho Perfurante/irrigação sanguínea , Humanos , Feminino , Pessoa de Meia-Idade , Sobrevivência de Enxerto/efeitos dos fármacos , Adulto
6.
Am J Cardiovasc Drugs ; 24(3): 385-398, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38683263

RESUMO

AIM: The efficacy and safety of bivalirudin when used concurrently with glycoprotein IIb/IIIa inhibitors (GPI) is uncertain. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of bivalirudin versus heparin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) and to explore the impact of differential use (greater and balanced) of GPI. METHODS: Online databases were queried from inception to March 2023 to identify eight randomized controlled trials (n = 22,483) for inclusion. The primary outcomes included all-cause mortality, major bleeding, major adverse cardiovascular events (MACE), and net adverse clinical events (NACE). Secondary efficacy endpoints included cardiac death, reinfarction, stent thrombosis (ST), and stroke. Data were pooled using a random-effects model to derive risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: When compared to heparin, bivalirudin was associated with a significant reduction in all-cause mortality (RR 0.83; 95% CI 0.72-0.97; P = 0.02), major bleeding (RR 0.73; 95% CI 0.57-0.93; P = 0.01), cardiac death (RR 0.79; 95% CI 0.66-0.94; P = 0.01), and NACE (RR 0.80; 95% CI 0.72-0.89; P < 0.0001). However, while the bivalirudin arm showed an increased likelihood of ST in the greater GPI subgroup (RR 1.70; 95% CI 1.13-2.56; P = 0.01), it was associated with a decreased likelihood of ST in the balanced GPI subgroup (RR 0.40; 95% CI 0.24-0.65; P = 0.0003). CONCLUSION: Overall, our findings suggest that bivalirudin may be a more efficacious intervention than heparin for reducing certain adverse events in patients with STEMI undergoing primary PCI.


Assuntos
Antitrombinas , Heparina , Hirudinas , Fragmentos de Peptídeos , Intervenção Coronária Percutânea , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Proteínas Recombinantes , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Hirudinas/efeitos adversos , Hirudinas/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Fragmentos de Peptídeos/uso terapêutico , Fragmentos de Peptídeos/efeitos adversos , Intervenção Coronária Percutânea/métodos , Intervenção Coronária Percutânea/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Heparina/efeitos adversos , Heparina/uso terapêutico , Heparina/administração & dosagem , Antitrombinas/uso terapêutico , Antitrombinas/efeitos adversos , Hemorragia/induzido quimicamente , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
J Stroke Cerebrovasc Dis ; 33(6): 107310, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38636321

RESUMO

OBJECTIVES: Heparin-induced thrombocytopenia is a known complication of heparin exposure with potentially life-threatening sequelae. Direct thrombin inhibitors can be substituted for heparin in patients with heparin-induced thrombocytopenia that require anticoagulation. However, the use of direct thrombin inhibitors as a substitute for heparin has not been widely reported in the neuroendovascular literature. MATERIALS AND METHODS: Here we report the first use of the direct thrombin inhibitor bivalirudin in a neuroendovascular procedure as a substitute for heparin in a patient with a ruptured pseudoaneurysm and heparin-induced thrombocytopenia, and review the literature on the use of bivalirudin and argatroban for such patients. RESULTS: Bivalirudin was safely and effectively used in the case reported, with no thrombotic or hemorrhagic complications. Our literature review revealed a paucity of studies on the use of heparin alternatives, including bivalirudin, in neuroendovascular procedures in patients with heparin-induced thrombocytopenia. CONCLUSIONS: Heparin-induced thrombocytopenia is an important iatrogenic disease process in patients undergoing neuroendovascular procedures, and developing protocols to diagnose and manage heparin-induced thrombocytopenia is important for healthcare systems. While further research needs to be done to establish the full range of anticoagulation options to substitute for heparin, our case indicates bivalirudin as a potential candidate.


Assuntos
Anticoagulantes , Antitrombinas , Heparina , Hirudinas , Fragmentos de Peptídeos , Proteínas Recombinantes , Trombocitopenia , Humanos , Masculino , Pessoa de Meia-Idade , Falso Aneurisma/cirurgia , Falso Aneurisma/tratamento farmacológico , Aneurisma Roto/cirurgia , Aneurisma Roto/diagnóstico por imagem , Anticoagulantes/efeitos adversos , Antitrombinas/efeitos adversos , Antitrombinas/uso terapêutico , Substituição de Medicamentos , Procedimentos Endovasculares/efeitos adversos , Heparina/efeitos adversos , Aneurisma Intracraniano/cirurgia , Aneurisma Intracraniano/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Fragmentos de Peptídeos/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombocitopenia/tratamento farmacológico , Resultado do Tratamento
9.
J Ethnopharmacol ; 330: 118257, 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-38677578

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Leeches exhibit robust anticoagulant activity, making them useful for treating cardiovascular diseases in traditional Chinese medicine. Whitmania pigra, the primary source species of leech-derived medicinal compounds in China, has been demonstrated to possess formidable anticoagulant properties. Hirudin-like peptides, recognized as potent thrombin inhibitors, are prevalent in hematophagous leeches. Considering that W. pigra is a nonhematophagic leech, the following question arises: does a hirudin variant exist in this species? AIM OF THE STUDY: In this study we identified the hirudin-encoding gene (WP_HV1) in the W. pigra genome. The goal of this study was to assess its anticoagulant activity and analyze the related mechanisms. MATERIALS AND METHODS: In this study, a hirudin-encoding gene, WP_HV1, was identified from the W. pigra genome, and its accurate coding sequence (CDS) was validated through cloning from cDNA extracted from fresh W. pigra specimens. The structure of WP_HV1 and the amino acids associated with its anticoagulant activity were determined by sequence and structural analysis and prediction of its binding energy to thrombin. E. coli was used for the expression of WP_HV1 and recombinant proteins with various structures and mutants. The anticoagulant activity of the synthesized recombinant proteins was then confirmed using thrombin time (TT). RESULTS: Validation of the WP_HV1 gene was accomplished, and three alternative splices were discovered. The TT of the blank sample exceeded that of the recombinant WP_HV1 sample by 1.74 times (0.05 mg/ml), indicating positive anticoagulant activity. The anticoagulant activity of WP_HV1 was found to be associated with its C-terminal tyrosine, along with the presence of 9 acidic amino acids on both the left and right sides. A significant reduction in the corresponding TT was observed for the mutated amino acids compared to those of the wild type, with decreases of 4.8, 6.6, and 3.9 s, respectively. In addition, the anticoagulant activity of WP_HV1 was enhanced and prolonged for 2.7 s when the lysine-67 residue was mutated to tryptophan. CONCLUSION: Only one hirudin-encoding variant was identified in W. pigra. The active amino acids associated with anticoagulation in WP_HV1 were resolved and validated, revealing a novel source for screening and developing new anticoagulant drugs.


Assuntos
Processamento Alternativo , Anticoagulantes , Hirudinas , Sanguessugas , Hirudinas/farmacologia , Hirudinas/genética , Animais , Sanguessugas/genética , Anticoagulantes/farmacologia , Sequência de Aminoácidos , Trombina/metabolismo , Clonagem Molecular , Proteínas Recombinantes/genética
10.
Molecules ; 29(5)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38474541

RESUMO

Chronic kidney disease (CKD) is a common public health concern. The global burden of CKD is increasing due to the high morbidity and mortality associated with it, indicating the shortcomings of therapeutic drugs at present. Renal fibrosis is the common pathology of CKD, which is characterized by glomerulosclerosis, renal tubular atrophy, and renal interstitial fibrosis. Natural hirudin is an active ingredient extracted from Hirudo medicinalis, which has been found to be the strongest natural specific inhibitor of thrombin. Evidence based on pharmacological data has shown that hirudin has important protective effects in CKD against diabetic nephrology, nephrotic syndrome, and renal interstitial fibrosis. The mechanisms of hirudin in treating CKD are mainly related to inhibiting the inflammatory response, preventing apoptosis of intrinsic renal cells, and inhibiting the interactions between thrombin and protease-activated receptors. In this review, we summarize the function and beneficial properties of hirudin for the treatment of CKD, and its underlying mechanisms.


Assuntos
Hirudinas , Insuficiência Renal Crônica , Humanos , Trombina , Insuficiência Renal Crônica/tratamento farmacológico , Rim , Fibrose
11.
Proc Natl Acad Sci U S A ; 121(11): e2314349121, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38442174

RESUMO

Thrombosis, induced by abnormal coagulation or fibrinolytic systems, is the most common pathology associated with many life-threatening cardio-cerebrovascular diseases. However, first-line anticoagulant drugs suffer from rapid drug elimination and risk of hemorrhagic complications. Here, we developed an in situ formed depot of elastin-like polypeptide (ELP)-hirudin fusion protein with a prodrug-like feature for long-term antithrombotic therapy. Highly secretory expression of the fusion protein was achieved with the assistance of the Ffu312 tag. Integration of hirudin, ELP, and responsive moiety can customize fusion proteins with properties of adjustable in vivo retention and controllable recovery of drug bioactivity. After subcutaneous injection, the fusion protein can form a reservoir through temperature-induced coacervation of ELP and slowly diffuse into the blood circulation. The biological activity of hirudin is shielded due to the N-terminal modification, while the activated key proteases upon thrombus occurrence trigger the cleavage of fusion protein together with the release of hirudin, which has antithrombotic activity to counteract thrombosis. We substantiated that the optimized fusion protein produced long-term antithrombotic effects without the risk of bleeding in multiple animal thrombosis models.


Assuntos
Polipeptídeos Semelhantes à Elastina , Trombose , Animais , Fibrinolíticos/farmacologia , Hirudinas/genética , Hirudinas/farmacologia , Anticoagulantes , Trombose/tratamento farmacológico , Trombose/prevenção & controle
13.
J Cardiothorac Vasc Anesth ; 38(6): 1328-1336, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38521630

RESUMO

OBJECTIVES: To evaluate the safety of cangrelor administered concurrently with heparin or bivalirudin in patients on mechanical circulatory support. DESIGN: A single-center, retrospective cohort study of adult patients consecutively admitted between January 2016 and October 2020. SETTING: A tertiary medical center. PARTICIPANTS: Adult patients admitted to the cardiovascular intensive care unit put on mechanical circulatory support for acute myocardial infarction (AMI) or non-AMI indications. Patients who received cangrelor underwent percutaneous coronary intervention with stenting during the index event or within the last year. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of major bleeding, defined by the Extracorporeal Life Support Organization criteria, in patients with mechanical circulatory support receiving cangrelor plus anticoagulation with heparin or bivalirudin with or without aspirin versus patients who did not receive cangrelor. Sixty-eight patients were included in the study. Twenty-nine patients received cangrelor, and 39 did not. Cangrelor was not associated with an increase in major bleeding; however, the CI was wide (adjusted hazard ratio 1.93, 95% CI 0.61-6.11; p = 0.262). CONCLUSIONS: Patients receiving cangrelor did not appear to be at higher risk of major bleeding compared to patients not receiving cangrelor. Larger trials should be conducted to better evaluate the safety of cangrelor in patients with mechanical circulatory support.


Assuntos
Monofosfato de Adenosina , Monofosfato de Adenosina/análogos & derivados , Anticoagulantes , Humanos , Feminino , Masculino , Estudos Retrospectivos , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/uso terapêutico , Monofosfato de Adenosina/efeitos adversos , Pessoa de Meia-Idade , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Idoso , Coração Auxiliar/efeitos adversos , Resultado do Tratamento , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/uso terapêutico , Hirudinas/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Heparina/administração & dosagem , Heparina/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Intervenção Coronária Percutânea/métodos , Infarto do Miocárdio/terapia , Inibidores da Agregação Plaquetária/administração & dosagem
15.
Pharmacotherapy ; 44(3): 283-289, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38304955

RESUMO

A growing body of evidence supports the use of bivalirudin as an alternative to unfractionated heparin (UFH) for the prevention of thrombotic events in patients on venovenous (VV) extracorporeal membrane oxygenation (ECMO). However, data in patients bridged to lung transplantation are limited. In this case series, we describe the outcomes of six patients who were transitioned from UFH to bivalirudin during their course of VV ECMO support as a bridge to lung transplantation. All six patients were on VV ECMO support until transplant, with a median duration of 73 days. Bivalirudin demonstrated a shorter time to first therapeutic activated thromboplastin time (aPTT) level. Additionally, time in therapeutic range was longer while patients were receiving bivalirudin compared to UFH (median 92.9% vs. 74.6%). However, major bleeding and thrombotic events occurred while patients were receiving either anticoagulant. Based on our experience, bivalirudin appears to be a viable option for anticoagulation in VV ECMO patients bridged to lung transplantation. Larger studies evaluating the optimal anticoagulation strategy in patients bridged to transplant are needed.


Assuntos
Transplante de Pulmão , Trombose , Adulto , Humanos , Heparina/efeitos adversos , Estudos Retrospectivos , Anticoagulantes/efeitos adversos , Hirudinas/efeitos adversos , Fragmentos de Peptídeos/uso terapêutico , Trombose/etiologia , Trombose/prevenção & controle , Proteínas Recombinantes/uso terapêutico
16.
Front Endocrinol (Lausanne) ; 15: 1296843, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38344666

RESUMO

Diabetic nephropathy (DN) is a major microvascular complication of diabetes and a common cause of chronic kidney disease. There is currently a lack of effective treatments for DN, and the prognosis for patients remains poor. Hirudin, one of the primary active components derived from leeches, demonstrates anti-coagulant, anti-fibrotic, anti-thrombotic, and anti-inflammatory properties, exhibiting significant protective effects on the kidneys. In recent years, there has been a surge of interest in studying the potential benefits of hirudin, especially in its role in the management of DN. This article delves into the mechanisms by which hirudin contributes to the treatment of DN and its clinical efficacy.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Sanguessugas , Animais , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Hirudinas , Rim , Medicina Tradicional Chinesa
18.
Biochem Biophys Res Commun ; 696: 149473, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38241814

RESUMO

The saliva of the medicinal leech contains various anticoagulants. Some of them, such as hirudin, are well known. However, it is reasonable to believe that not all anticoagulant proteins from medicinal leech saliva have been identified. We previously performed a comprehensive study of the transcriptome, genome, and proteome of leech salivary gland cells, which led to the discovery of several previously unknown hypothetical proteins that may have anticoagulant properties. Subsequently, we obtained a series of recombinant proteins and investigated their impact on coagulation in in vitro assays. We identified a previously undescribed protein that exhibited a high ability to suppress coagulation. The His-tagged recombinant protein was expressed in Escherichia coli and purified using metal chelate chromatography. To determine its activity, commonly used coagulation methods were used: activated partial thromboplastin time, prothrombin time, and thrombin inhibition clotting assay. Clotting and chromogenic assays for factor Xa inhibition were performed to evaluate anti-Xa activity. We used recombinant hirudin as a control anticoagulant protein in all experiments. The new protein showed significantly greater inhibition of coagulation than hirudin at the same molar concentrations in the activated partial thrombin time assay. However, hirudin demonstrated better results in the direct thrombin inhibition test, although the tested protein also exhibited the ability to inhibit thrombin. The chromogenic analysis of factor Xa inhibition revealed no activity, whereas the clotting test for factor Xa showed the opposite result. Thus, a new powerful anticoagulant protein has been discovered in the medicinal leech. This protein is homologous to antistatin, with 28 % identical amino acid residues. The recombinant protein was expressed in E. coli. This protein is capable of directly inhibiting thrombin, and based on indirect evidence, other proteases of the blood coagulation cascade have been identified.


Assuntos
Anticoagulantes , Hirudinas , Anticoagulantes/farmacologia , Hirudinas/farmacologia , Hirudinas/genética , Hirudinas/metabolismo , Trombina/metabolismo , Fator Xa , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas Recombinantes/metabolismo
19.
Eur Heart J Cardiovasc Pharmacother ; 10(3): 263-264, 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38285615
20.
Mol Biotechnol ; 66(5): 1062-1070, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38184808

RESUMO

To investigate the inhibitory effect of hirudin on the cell proliferation of human ovarian cancer A2780 cells by preventing thrombin and its underlying molecular mechanism. Cell Counting Kit-8 (CCK-8) method was used to detect the effect of different concentrations of hirudin and thrombin on the cell proliferation of A2780 cells. PAR-1 wild-type overexpression plasmid was constructed utilizing enzyme digestion identification, and it was transferred to A2780 cells. Sequencing and Western blot were used to detect the changes in PAR-1 protein expression. Western blot detection of PKCα protein phosphorylation in A2780 cells was performed. We also implemented quantitative PCR to detect the mRNA expression levels of epithelial-mesenchymal transition (EMT)-related genes, CDH2, Snail, and Vimentin, in A2780 cells. 1 µg/ml hirudin treatment maximally inhibited the promotion of A2780 cell proliferation by thrombin. Hirudin inhibited the binding of thrombin to the N-terminus of PAR-1, hindered PKCα protein phosphorylation in A2780 cells, and downregulated the mRNA expression levels of CDH2, Snail, and Vimentin. In conclusion, hirudin inhibits the cell proliferation of ovarian cancer A2780 cells, and the underlying mechanism may be through downregulating the transcription level of EMT genes, CDH2, Snail, and Vimentin. This study indicates that hirudin may have a therapeutic potential as an anti-cancer agent for ovarian cancer.


Assuntos
Proliferação de Células , Transição Epitelial-Mesenquimal , Hirudinas , Neoplasias Ovarianas , Humanos , Hirudinas/farmacologia , Hirudinas/genética , Feminino , Proliferação de Células/efeitos dos fármacos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C-alfa/genética , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Trombina/farmacologia , Trombina/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Vimentina/metabolismo , Vimentina/genética
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