RESUMEN
Managing antithrombotic therapy in patients undergoing complex and high-risk in indicated patients, including those treated with complex percutaneous coronary intervention (PCI) or presenting with cardiogenic shock (CS), is challenging. This review highlights the critical role of antithrombotic therapy, during and after PCI, to optimize the efficacy while minimizing risks. Unfractionated heparin remains the mainstay anticoagulant for complex PCI and CS, with bivalirudin as a potential safer alternative. Cangrelor offers consistent antiplatelet effects, especially when timely absorption of oral agents is uncertain.
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Fibrinolíticos , Intervención Coronaria Percutánea , Choque Cardiogénico , Humanos , Intervención Coronaria Percutánea/métodos , Fibrinolíticos/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Hirudinas/administración & dosificación , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Heparina/uso terapéutico , Heparina/administración & dosificación , Fragmentos de Péptidos , Proteínas RecombinantesRESUMEN
Glycosaminoglycans (GAGs) play a key role in a variety of biological processes in the extracellular matrix (ECM) via interactions with their protein targets. Due to their high flexibility, periodicity and electrostatics-driven interactions, GAG-containing complexes are very challenging to characterize both experimentally and in silico. In this study, we, for the first time, systematically analyzed the interactions of endostatin, a proteolytic fragment of collagen XVIII known to be anti-angiogenic and anti-tumoral, with heparin (HP) and representative heparan sulfate (HS) oligosaccharides of various lengths, sequences and sulfation patterns. We first used conventional molecular docking and a docking approach based on a repulsive scaling-replica exchange molecular dynamics technique, as well as unbiased molecular dynamic simulations, to obtain dynamically stable GAG binding poses. Then, the corresponding free energies of binding were calculated and the amino acid residues that contribute the most to GAG binding were identified. We also investigated the potential influence of Zn2+ on endostatin-HP complexes using computational approaches. These data provide new atomistic details of the molecular mechanism of HP's binding to endostatin, which will contribute to a better understanding of its interplay with proteoglycans at the cell surface and in the extracellular matrix.
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Endostatinas , Heparitina Sulfato , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Endostatinas/química , Endostatinas/metabolismo , Heparitina Sulfato/química , Heparitina Sulfato/metabolismo , Humanos , Heparina/química , Heparina/metabolismo , Colágeno Tipo XVIII/química , Colágeno Tipo XVIII/metabolismo , Sitios de Unión , Zinc/química , Zinc/metabolismo , Modelos Moleculares , Glicosaminoglicanos/química , Glicosaminoglicanos/metabolismo , TermodinámicaRESUMEN
BACKGROUND: The first purpose of this study was to determine whether a measurement of the level of direct oral anticoagulants (DOACs) was possible with heparin-calibrated chromogenic anti-factor Xa activity (AXA). The second purpose of this study was to evaluate whether the antidote treatment decision level (30 or 50 ng/mL of DOAC) can be determined by unfractionated heparin (UHF)/low molecular weight heparin (LMWH)-calibrated AXA. METHODS: AXA was measured by using two reagents and dedicated analyzers (Sysmex CS-5100 analyzer and STA R Max3). Four types of calibrators were used: 1) Stago DOAC (rivaroxaban, edoxaban, and apixaban)-specific calibrator, 2) Stago LMWH calibrator, 3) Sysmex UHF calibrator, and 4) Sysmex LMWH calibrator. Regression analysis was used between assays. Receiver operating characteristic (ROC) curves were performed, and the concordance rate was calculated. RESULTS: The correlation coefficients were in the range of 0.75 - 0.91 for rivaroxaban and 0.81 - 0.94 for apixaban. The correlation coefficient between edoxaban-calibrated AXA and Sysmex LMWH/Sysmex UHF calibrator-calibrated AXA was low (r = 0.47). Overall correlation between DOAC-calibrated AXA and Stago LMWH-calibrated AXA was linear, at only low concentration in all three DOACs. The concordance rate (89.3 - 100%) is good for de-termining the antidote management level by UFH/LMWH-calibrated AXA, compared with those of DOAC-calibrated AXA in rivaroxaban and apixaban. The concordance rate ranged from 63% to 67% between Sysmex UFH/ LMWH-calibrated AXA and edoxaban-calibrated AXA. CONCLUSIONS: The findings of our study suggest limitations in calculating accurate concentrations, when using UFH/LMWH-calibrated AXA to measure DOAC. This study demonstrates that UFH/LMWH-calibrated AXA may be useful in determining the presence of DOACs at the cutoff level for the antidote treatment in rivarovaban and apixaban. However, in edoxaban, UFH/LMWH-calibrated AXA could not accurately measure the presence of DOACs at the cutoff for antidote treatment.
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Inhibidores del Factor Xa , Heparina , Pirazoles , Piridinas , Piridonas , Rivaroxabán , Tiazoles , Piridonas/análisis , Humanos , Pirazoles/análisis , Rivaroxabán/sangre , Rivaroxabán/análisis , Inhibidores del Factor Xa/farmacología , Calibración , Heparina/análisis , Anticoagulantes/farmacología , Anticoagulantes/análisis , Curva ROC , Reproducibilidad de los Resultados , Pruebas de Coagulación Sanguínea/métodos , Pruebas de Coagulación Sanguínea/instrumentación , Pruebas de Coagulación Sanguínea/normas , Monitoreo de Drogas/métodos , Monitoreo de Drogas/instrumentaciónRESUMEN
Interest in citrate-based dialysate (Cit-D) is growing due to its benefits, including anticoagulation and dialysis efficacy. However, research on safety and efficiency of Cit-D in high-volume hemodiafiltration (HDF) via central concentrate delivery system (CCDS) is scarce. This study aimed to investigate the safety and efficacy of Cit-D when switching from acetate-based dialysate (Acet-D) in high-volume HDF via CCDS. This is a retrospective analysis of 28 patients who underwent post-dilution online HDF via CCDS, who switched from Acet-D to Cit-D. The study period was divided into 3 periods for analysis: 12 weeks using Acet-D (AD period), the first 12 weeks using Cit-D (CD-1 period), and the second 12 weeks using Cit-D (CD-2 period). We collected the laboratory, dialysis, and safety parameters in each period from electrical medical records. After switching from Acet-D to Cit-D, heparin dosage decreased by 17%, whereas the incidence of complications did not increase. Kt/VBUN and urea reduction ratio increased by 4.6% and 2.1%, respectively. Pre-dialysis beta2-microglobulin concentration decreased after using Cit-D. The corrected calcium levels decreased in the CD-1 period compared to the AD period, but in CD-2, they subsequently increased to levels similar to those observed during the AD period. Symptomatic hypocalcemia did not occur, and there was no significant difference in the incidence of hyperparathyroidism. Endotoxin levels and the bacterial culture of ultrapure dialysate were unremarkable throughout all periods. These results might suggest that Cit-D could potentially offer advantages over Acet-D, such as reducing the heparin dose and increasing dialysis efficiency, in patients undergoing high-volume HDF using CCDS.
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Acetatos , Ácido Cítrico , Soluciones para Diálisis , Hemodiafiltración , Humanos , Estudios Retrospectivos , Hemodiafiltración/métodos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Acetatos/administración & dosificación , Soluciones para Diálisis/administración & dosificación , Soluciones para Diálisis/química , Ácido Cítrico/administración & dosificación , Anticoagulantes/administración & dosificación , Fallo Renal Crónico/terapia , Heparina/administración & dosificaciónRESUMEN
OBJECTIVE: The study compared the impact of unfractionated heparin (UFH) administered via two routes (infusion and subcutaneous injection) on heparin-binding protein (HBP) and plasminogen activator inhibitor-1 (PAI-1) levels in critically ill sepsis patients. PATIENTS AND METHODS: Forty critically ill sepsis patients were randomly assigned to receive either a low-dose intravenous infusion of UFH (500 units/hour) or subcutaneous UFH (5,000 units/8 hours) for seven days. HBP and PAI-1 were measured at baseline and on days one, two, and seven. RESULTS: Intravenous administration of UFH showed a significant reduction in percentage change of HBP compared to subcutaneous administration on days one [(-35% vs. -13%, p = 0.03*) (*indicates a significant result *p < 0.05, relative to the subcutaneous group)] and seven (-62% vs. -39%, p = 0.02*). Also, the percentage change of PAI-1 was significantly reduced in the infusion group compared to the subcutaneous group on days one (-28% vs. -3%, p = 0.008*), two (-42% vs. -3%, p = 0.001*), and seven (-62% vs. 27%, p = 0.001*), respectively. Furthermore, a significant improvement in the 14-day survival was observed in the infusion group compared to the subcutaneous group (p = 0.008*). CONCLUSIONS: Intravenous infusion was the route of choice for UFH administration in critically ill septic patients, with a promising effect on HBP, PAI-1, and survival.
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Enfermedad Crítica , Heparina , Inhibidor 1 de Activador Plasminogénico , Sepsis , Humanos , Heparina/administración & dosificación , Infusiones Intravenosas , Sepsis/tratamiento farmacológico , Inyecciones Subcutáneas , Masculino , Femenino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/administración & dosificación , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proteínas Sanguíneas/metabolismo , Anciano , Péptidos Catiónicos Antimicrobianos/administración & dosificación , Anticoagulantes/administración & dosificaciónRESUMEN
Iatrogenic acute limb ischaemia (ALI) in neonates is a rare but severe event with potentially deleterious outcomes. In the neonatal intensive care unit, this risk is increased due to the high rate of catheterisation procedures. ALI management includes pharmacological and non-pharmacological interventions, but no commonly accepted clinical guidelines are available. In the present case, a peripheral catheter was erroneously placed in the left brachial artery of a term infant, causing blockage and ischaemia in the limb. The catheter was immediately removed, the affected limb was elevated and warm compresses were applied to the contralateral limb. The patient was treated with fresh frozen plasma, heparin, iloprost and topical nitroglycerin. Three nerve block procedures were also performed. At 6-8 days of age, significant improvement was observed. The patient was discharged at 17 days of age with near-complete resolution, whereas complete resolution was observed at postdischarge follow-up.
Asunto(s)
Enfermedad Iatrogénica , Isquemia , Humanos , Recién Nacido , Isquemia/etiología , Isquemia/terapia , Cateterismo Periférico/efectos adversos , Arteria Braquial/diagnóstico por imagen , Heparina/administración & dosificación , Heparina/uso terapéutico , Masculino , Nitroglicerina/administración & dosificación , Nitroglicerina/uso terapéutico , Femenino , Vasodilatadores/uso terapéutico , Vasodilatadores/administración & dosificación , Iloprost/administración & dosificación , Iloprost/uso terapéutico , Enfermedad Aguda , Bloqueo Nervioso/métodosRESUMEN
Lumboperitoneal shunt (LPS) has been an effective treatment of idiopathic normal pressure hydrocephalus (iNPH) but sometimes causes serious complications. Here we present the first reported case of cerebral venous thrombosis (CVT) after LPS. A 76-year-old man underwent LPS for iNPH and a week later developed weakness of the right arm and a generalized tonic-clonic seizure. Brain computed tomography and magnetic resonance imaging showed bilateral subdural hematoma (SDH) and left cortical vein thrombosis. Intravenous heparin was administered, followed by surgical evacuation of the SDH. The patient experienced gradual improvement and was subsequently discharged. It is conceivable that overdrainage of cerebrospinal fluid led to the development of both SDH and CVT. CVT is potentially fatal and should be recognized early as a possible complication after LPS to allow prompt treatment.
Asunto(s)
Hidrocéfalo Normotenso , Trombosis Intracraneal , Trombosis de la Vena , Humanos , Masculino , Anciano , Hidrocéfalo Normotenso/cirugía , Trombosis Intracraneal/etiología , Trombosis Intracraneal/diagnóstico por imagen , Trombosis de la Vena/etiología , Trombosis de la Vena/diagnóstico por imagen , Derivaciones del Líquido Cefalorraquídeo/efectos adversos , Hematoma Subdural/etiología , Hematoma Subdural/cirugía , Hematoma Subdural/diagnóstico por imagen , Imagen por Resonancia Magnética , Heparina/uso terapéutico , Tomografía Computarizada por Rayos XRESUMEN
Extracellular histones are crucial damage-associated molecular patterns involved in the development and progression of multiple critical and inflammatory diseases, such as sepsis, pancreatitis, trauma, acute liver failure, acute respiratory distress syndrome, vasculitis and arthritis. During the past decade, the physiopathologic mechanisms of histone-mediated hyperinflammation, endothelial dysfunction, coagulation activation, neuroimmune injury and organ dysfunction in diseases have been systematically elucidated. Emerging preclinical evidence further shows that anti-histone strategies with either their neutralizers (heparin, heparinoids, nature plasma proteins, small anion molecules and nanomedicines, etc.) or extracorporeal blood purification techniques can significantly alleviate histone-induced deleterious effects, and thus improve the outcomes of histone-related critical and inflammatory animal models. However, a systemic evaluation of the efficacy and safety of these histone-targeting therapeutic strategies is currently lacking. In this review, we first update our latest understanding of the underlying molecular mechanisms of histone-induced hyperinflammation, endothelial dysfunction, coagulopathy, and organ dysfunction. Then, we summarize the latest advances in histone-targeting therapy strategies with heparin, anti-histone antibodies, histone-binding proteins or molecules, and histone-affinity hemoadsorption in pre-clinical studies. Finally, challenges and future perspectives for improving the clinical translation of histone-targeting therapeutic strategies are also discussed to promote better management of patients with histone-related diseases.
Asunto(s)
Histonas , Inflamación , Humanos , Histonas/metabolismo , Animales , Inflamación/inmunología , Inflamación/terapia , Enfermedad Crítica , Heparina/uso terapéuticoRESUMEN
AIMS: Cancer-related thrombosis (CAT) is a common complication in cancer patients, significantly impacting their quality of life and survival prospects. Nattokinase (NK) has potent thrombolytic properties, however, its efficacy is limited by low oral bioavailability and the risk of severe allergic reactions with intravenous use. Heparin (HP) is a widely used anticoagulant in clinical settings. This study aimed to overcome the intravenous toxicity of NK and explore its effect on CAT in advanced tumors. MAIN METHODS: In this study, NK-HP electrostatic complexes were constructed, and their safety and thrombolytic efficacy were verified through guinea pig allergy tests, mouse tail vein tests, and both in vivo and in vitro thrombolysis experiments. Additionally, an S180 advanced tumor model was developed and combined with sialic acid-modified doxorubicin liposomes (DOX-SAL) to investigate the impact of NK-HP on CAT and its antitumor effects in advanced tumors. KEY FINDINGS: We observed that NK-HP can eliminate the intravenous injection toxicity of NK, has strong thrombolytic performance, and can prevent thrombosis formation. Intravenous injection of NK-HP can enhance the antitumor effect of DOX-SAL by reducing the fibrin content in advanced tumors and increasing the levels of the cross-linked protein degradation product D-dimer. SIGNIFICANCE: This study developed a method to eliminate the intravenous injection toxicity of NK, proposing a promising therapeutic strategy for CAT treatment, particularly for CAT in advanced tumors, and improving the efficacy of nano-formulations in anti-tumor therapy.
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Heparina , Neoplasias , Subtilisinas , Trombosis , Animales , Subtilisinas/administración & dosificación , Ratones , Trombosis/tratamiento farmacológico , Inyecciones Intravenosas , Heparina/administración & dosificación , Neoplasias/tratamiento farmacológico , Fibrinolíticos/administración & dosificación , Fibrinolíticos/farmacología , Electricidad Estática , Cobayas , Masculino , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Liposomas , HumanosRESUMEN
Aiming to improve the retrieval rate of retrievable vena cava filters (RVCF) and extend its dwelling time in vivo, a novel hydrogel coating loaded with 10 mg/mL heparin and 30 mg/mL cyclodextrin/paclitaxel (PTX) inclusion complex (IC) was prepared. The drug-release behavior in the phosphate buffer solution demonstrated both heparin and PTX could be sustainably released over approximately two weeks. Furthermore, it was shown that the hydrogel-coated RVCF (HRVCF) with 10 mg/mL heparin and 30 mg/mL PTX IC effectively extended the blood clotting time to above the detection limit and inhibited EA.hy926 and CCC-SMC-1 cells' proliferation in vitro compared to the commercially available bare RVCF. Both the HRVCF and the bare RVCF were implanted into the vena cava of sheep and retrieved at at 2nd and 4th week after implantation, revealing that the HRVCF had a significantly higher retrieval rate of 67 % than the bare RVCF (0 %) at 4th week. Comprehensive analyses, including histological, immunohistological, and immunofluorescent assessments of the explanted veins demonstrated the HRVCF exhibited anti-hyperplasia and anticoagulation properties in vivo, attributable to the hydrogel coating, thereby improving the retrieval rate in sheep. Consequently, the as-prepared HRVCF shows promising potential for clinical application to enhance the retrieval rates of RVCFs.
Asunto(s)
Ciclodextrinas , Heparina , Hidrogeles , Paclitaxel , Filtros de Vena Cava , Ciclodextrinas/química , Ciclodextrinas/farmacología , Paclitaxel/farmacología , Paclitaxel/química , Heparina/química , Heparina/farmacología , Animales , Hidrogeles/química , Hidrogeles/farmacología , Humanos , Ovinos , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Coagulación Sanguínea/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Liberación de FármacosRESUMEN
Oleanolic acid is an active ingredient from natural products with anti-breast cancer activity. However, the poor solubility in water and low bioavailability have limited its effectiveness in clinic. To improve the anticancer activity of oleanolic acid, we synthesized a novel oleanolic quaternary ammonium (QDT), which, driven by electrostatic interactions, was introduced into heparin and coated with chitosan to obtain a QDT/heparin/chitosan nanoaggregate (QDT/HEP/CS NAs). QDT/HEP/CS NAs showed the negative zeta potential (-35.01 ± 4.38 mV), suitable mean particle size (150.45 ± 0.68 nm) with strip shape, and high drug loading (36 %). The coated chitosan had strong anti-leakage characteristics toward QDT under physiological conditions. More importantly, upon sustained release in tumor cells, QDT could significantly decrease the mitochondrial membrane potential and induce apoptosis of breast cancer cells. Further in vivo antitumor study on 4 T1 tumor-bearing mice confirmed the enhanced anticancer efficacy of QDT/HEP/CS NAs via upregulation of caspase-3, caspase-9 and cytochrome C, which was attributed to the high accumulation in tumor via the enhanced permeability and retention effect. Moreover, QDT/HEP/CS NAs significantly enhanced the biosafety and biocompatibility of QDT in vitro and in vivo. Collectively, the development of QDT/HEP/CS NAs with high antitumor activity, favorable biodistribution and good biocompatibility provided a safe, facile and promising strategy to improve the anti-cancer effect of traditional Chinese medicine ingredients.
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Apoptosis , Neoplasias de la Mama , Quitosano , Heparina , Ácido Oleanólico , Quitosano/química , Quitosano/farmacología , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Humanos , Femenino , Ratones , Apoptosis/efectos de los fármacos , Heparina/química , Heparina/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Portadores de Fármacos/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Immunodetection of cardiac isoforms of troponin I (cTnI) and troponin T (cTnT) in blood samples is widely used for the diagnosis of acute myocardial infarction. The cardiac troponin complex (ITC-complex), comprising cTnI, cTnT, and troponin C (TnC), makes up a large portion of troponins released into the bloodstream after the necrosis of cardiomyocytes. However, the stability of the ITC-complex has not been fully investigated. This study aimed to investigate the stability of the ITC-complex in blood samples. A native ITC-complex was incubated in buffer solutions, serum, and citrate, heparin, or EDTA plasma at various temperatures. Western blotting and gel filtration were performed, and troponins were detected using specific monoclonal antibodies. The ITC-complex dissociated at 37 °C in buffers with or without anticoagulants, in citrate, heparin, and EDTA plasmas, and in serum, into a binary cTnI-TnC complex (IC-complex) and free cTnT. In plasma containing heparin and EDTA, the IC-complex further dissociated into free TnC and cTnI. No dissociation was found at 4 °C or at room temperature (RT) in all matrices within 24 h except for EDTA plasma. After incubation at 37 °C in EDTA plasma and serum, dissociation was accompanied by proteolytic degradation of both cTnI and cTnT. The presence of anti-troponin autoantibodies in the sample impeded dissociation of the ITC-complex. The ITC-complex dissociates in vitro to form the IC-complex and free cTnT at 37 °C but is mostly stable at 4 °C or RT. Further dissociation of the IC-complex occurs at 37 °C in plasmas containing heparin and EDTA.
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Anticoagulantes , Troponina I , Troponina T , Anticoagulantes/farmacología , Humanos , Troponina I/sangre , Troponina T/sangre , Troponina C/sangre , Ácido Edético/química , Ácido Edético/farmacología , Heparina , Ácido CítricoRESUMEN
To evaluate the safety and the potential antiviral treatment of inhaled enriched heparin in patients with COVID-19. The specific objectives were to investigate the anticoagulation profile, antiviral and anti-inflammatory effects, and respiratory evolution of inhaled enriched heparin. We conducted a randomized, triple-blind, placebo-controlled Phase I/II clinical trial in hospitalized adults with COVID-19 receiving inhalation of enriched heparin or saline (placebo) every 4 h for 7 days. Among the 27 patients who completed the study, no changes in blood coagulation parameters were observed, indicating the safety of inhaled enriched heparin. The group receiving enriched heparin showed a significant reduction in the need for supplemental oxygen and improvement in respiratory parameters, such as the PaO2/FiO2 ratio. Inhalation of enriched heparin is shown to be safe and has also demonstrated potential therapeutic benefits for patients with COVID-19. These promising results justify the continuation of the study to the next phase, Phase II/III, to further evaluate the therapeutic efficacy of inhaled enriched heparin in the treatment of COVID-19-associated viral pneumonia.Trial registration: ClinicalTrials.gov. 08/02/2021. Identifier: NCT04743011.
Asunto(s)
Anticoagulantes , Tratamiento Farmacológico de COVID-19 , COVID-19 , Heparina , Humanos , Heparina/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Administración por Inhalación , Anciano , COVID-19/virología , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Nebulizadores y Vaporizadores , SARS-CoV-2 , Adulto , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: There has been growing interest in exploring combined interventions to achieve a more effective heparin-free treatment approach. AIM: to evaluate combination of interventions compared to standard practice (intermittent flushes) to prevent clotting and consequently reduce premature interruptions of hemodialysis. METHODS: This open-label randomized controlled trial recruited chronic hemodialysis patients with contra-indication to systemic heparinization. Participants were randomized into one of five groups to receive different strategies of heparin-free hemodialysis treatment for up to three sessions. PRIMARY ENDPOINT: the successful completion of hemodialysis without clotting. SECONDARY OUTCOMES: the clotting of the air traps assessed by a semi-quantitative scale, online KT/V, and safety of the interventions. RESULTS: Forty participants were recruited and randomized between May and December 2020. Participants showed similar baseline biochemistry results and coagulation profiles. The highest success rates were observed in group 3 (heparin-coated dialyzers combined with intermittent flushes) (100%) and group 5 (hemodiafiltration with online predilution combined with heparin-coated dialyzers), with 91% vs. the control (intermittent flushes) (64%). Group 2 (heparin-coated dialyzers alone) had the poorest success rate, with 38% of the sessions being prematurely terminated due to clotting. KT/V and clotting scores were similar between groups. No adverse events related to the trial interventions were observed. CONCLUSIONS: The proposed combination of interventions may have had additive effects, leading to less frequent clotting and the premature termination of an HD/HDF session. Our study supports the feasibility of conducting a larger randomized controlled trial focusing on the efficacy of combined interventions for heparin-free HD in patients with a high risk of bleeding.
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Anticoagulantes , Hemorragia , Heparina , Diálisis Renal , Humanos , Femenino , Masculino , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Hemorragia/prevención & control , Persona de Mediana Edad , Anciano , Heparina/administración & dosificación , Heparina/uso terapéutico , Coagulación Sanguínea/efectos de los fármacosRESUMEN
Stability issues in membrane-free coacervates have been addressed with coating strategies, but these approaches often compromise the permeability of the coacervate. Here we report a facile approach to maintain both stability and permeability using tannic acid and then demonstrate the value of this approach in enzyme-triggered drug release. First, we develop size-tunable coacervates via self-assembly of heparin glycosaminoglycan with tyrosine and arginine-based peptides. A thrombin-recognition site within the peptide building block results in heparin release upon thrombin proteolysis. Notably, polyphenols are integrated within the nano-coacervates to improve stability in biofluids. Phenolic crosslinking at the liquid-liquid interface enables nano-coacervates to maintain exceptional structural integrity across various environments. We discover a pivotal polyphenol threshold for preserving enzymatic activity alongside enhanced stability. The disassembly rate of the nano-coacervates increases as a function of thrombin activity, thus preventing a coagulation cascade. This polyphenol-based approach not only improves stability but also opens the way for applications in biomedicine, protease sensing, and bio-responsive drug delivery.
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Sistemas de Liberación de Medicamentos , Polifenoles , Taninos , Trombina , Polifenoles/química , Trombina/metabolismo , Trombina/química , Humanos , Taninos/química , Heparina/química , Liberación de Fármacos , Péptidos/química , Péptidos/metabolismo , ProteolisisRESUMEN
Galectin-8 is a small soluble lectin with two carbohydrate recognition domains (CRDs). N- and C-terminal CRDs of Gal-8 differ in their specificity for glycan ligands. Here, we wanted to find out whether oligomerization of individual CRDs of galectin-8 affects its biological activity. Using green fluorescent protein polygons (GFPp) as an oligomerization scaffold, we generated intrinsically fluorescent CRDs with altered valency. We show that oligomers of C-CRD are characterized by significant cell surface affinity. Furthermore, the multivalency of the resulting variants has an impact on cellular activities such as cell signaling, heparin binding and proliferation. Our data indicates that tunable valence is a useful tool for modifying the biological activity of CRDs of galectins.
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Galectinas , Galectinas/metabolismo , Galectinas/química , Humanos , Ligandos , Unión Proteica , Ingeniería de Proteínas/métodos , Proteínas Fluorescentes Verdes/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/química , Multimerización de Proteína , Proliferación Celular , Heparina/química , Heparina/metabolismoRESUMEN
Neuropilin-1 acts as a coreceptor with vascular endothelial growth factor receptors to facilitate binding of its ligand, vascular endothelial growth factor. Neuropilin-1 also binds to heparan sulfate, but the functional significance of this interaction has not been established. A combinatorial library screening using heparin oligosaccharides followed by molecular dynamics simulations of a heparin tetradecasaccharide suggested a highly conserved binding site composed of amino acid residues extending across the b1 and b2 domains of murine neuropilin-1. Mutagenesis studies established the importance of arginine513 and lysine514 for binding of heparin to a recombinant form of Nrp1 composed of the a1, a2, b1, and b2 domains. Recombinant Nrp1 protein bearing R513A,K514A mutations showed a significant loss of heparin-binding, heparin-induced dimerization, and heparin-dependent thermal stabilization. Isothermal calorimetry experiments suggested a 1:2 complex of heparin tetradecasaccharide:Nrp1. To study the impact of altered heparin binding in vivo, a mutant allele of Nrp1 bearing the R513A,K514A mutations was created in mice (Nrp1D) and crossbred to Nrp1+/- mice to examine the impact of altered heparan sulfate binding. Analysis of tumor formation showed variable effects on tumor growth in Nrp1D/D mice, resulting in a frank reduction in tumor growth in Nrp1D/- mice. Expression of mutant Nrp1D protein was normal in tissues, suggesting that the reduction in tumor growth was due to the altered binding of heparin/heparan sulfate to neuropilin-1. These findings suggest that the interaction of neuropilin-1 with heparan sulfate modulates its stability and its role in tumor formation and growth.
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Heparitina Sulfato , Neuropilina-1 , Neuropilina-1/metabolismo , Neuropilina-1/genética , Neuropilina-1/química , Animales , Heparitina Sulfato/metabolismo , Ratones , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Unión Proteica , Sitios de Unión , Ratones Endogámicos C57BL , Heparina/metabolismo , Heparina/química , Simulación de Dinámica Molecular , MutaciónRESUMEN
In bone tissue engineering, biological scaffolds are designed with structural and functional properties that closely resemble the extracellular environment, aiming to establish a microenvironment conducive to osteogenesis. Macrophages hold significant potential for promoting osteogenesis and modulating the biological behavior of tumor cells. Multiple coculture experiments of macrophages and osteoblasts have demonstrated that macrophage polarization significantly impacts osteogenesis. Therefore, exploring bone biomaterials that can modulate macrophage polarization holds great clinical significance. In this study, heparin was modified with maleimide and was used as a raw material to form a hydrogel with 4-am-PEG-SH. The compound was used to polarize macrophages and promote osteogenesis after combining with interleukin 4 (IL-4) by taking advantage of the electronegativity of heparin. The results revealed overexpressed M2 macrophage-related phenotypic genes and cocultivation with MC3T3-E1 cells demonstrated the osteogenesis-promoting effect of the loaded IL-4 heparin hydrogel. Previous research reported that hydrogel loaded with IL-4 can be used as a biomaterial for osteogenesis promotion. Heparin materials used in this paper are derived from clinically anticoagulant drugs and feature a simple operation. The synthesized hydrogel effectively binds cytokines, regulates macrophages to induce osteogenesis and has many potential clinical applications.
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Diferenciación Celular , Heparina , Hidrogeles , Interleucina-4 , Macrófagos , Osteogénesis , Heparina/farmacología , Heparina/química , Animales , Interleucina-4/farmacología , Interleucina-4/metabolismo , Ratones , Osteogénesis/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Diferenciación Celular/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Células RAW 264.7RESUMEN
INTRODUCTION: Endovascular therapy has emerged as a prominent strategy for managing femoropopliteal peripheral artery disease, offering acceptable safety and efficacy compared with open surgical bypass. Both paclitaxel-eluting stents and heparin-bonded covered stents have exhibited enhanced clinical outcomes compared with bare metal stents. However, there is currently a lack of level I evidence comparing the safety and efficacy of paclitaxel-eluting stents and heparin-bonded covered stents. Therefore, the primary objective of this study is to systematically evaluate the efficacy and safety outcomes of these two types of stents. METHODS AND ANALYSIS: The ELITE trial is a prospective, multicentre, parallel, randomised controlled trial. A total of 450 patients will be recruited. The primary endpoints of the study include primary patency at 1 year post-index procedure. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the Ethics Committee of West China Hospital of Sichuan University (approval number: 2023-1186). The results will be submitted to a major clinical journal for peer review and publication. TRIAL REGISTRATION: ELITE trial was registered on 27 September 2023 in the Chinese Clinical Trials Registry (ChiCTR2300076236).
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Stents Liberadores de Fármacos , Arteria Femoral , Heparina , Enfermedad Arterial Periférica , Arteria Poplítea , Humanos , Heparina/administración & dosificación , Heparina/uso terapéutico , Enfermedad Arterial Periférica/terapia , Enfermedad Arterial Periférica/cirugía , Arteria Poplítea/cirugía , Estudios Prospectivos , Arteria Femoral/cirugía , China , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Resultado del Tratamiento , Procedimientos Endovasculares/métodos , Masculino , Femenino , Stents , Grado de Desobstrucción VascularRESUMEN
BACKGROUND: Medication-related osteonecrosis of the Jaw (MRONJ) is a rare but severe side effect in patients treated with medications such as Bisphosphonates (BPs). Its pathophysiological mechanism needs to be more precise. Establishing preventive measures and treatment standards is necessary. This study aimed to develop a composite hydrogel scaffold constituted by methacrylated gelatin (GelMA), methacrylated heparin (HepMA) and PRF, and investigate its potential application value in the prevention of MRONJ. METHODS: GelMA, HepMA, and PRF were prepared using specific ratios for hydrogel scaffolds. Through mechanical properties and biocompatibility analysis, the release rate of growth factors and the ability to promote bone differentiation in vitro were evaluated. To explore the healing-enhancing effects of hydrogels in vivo, the composite hydrogel scaffold was implanted to the MRONJ rat model. Micro-computed tomography (Micro-CT) and histological examination were conducted to evaluate the bone morphology and tissue regeneration. RESULTS: The Hep/GelMA-PRF hydrogel improved the degradation rate and swelling rate. It was also used to control the release rate of growth factors effectively. In vitro, the Hep/GelMA-PRF hydrogel was biocompatible and capable of reversing the inhibitory effect of zoledronic acid (ZOL) on the osteogenic differentiation of MC3T3-E1s. In vivo, the micro-CT analysis and histological evaluation demonstrated that the Hep/GelMA-PRF group exhibited the best tissue reconstruction. Moreover, compared to the ZOL group, the expression of osteogenesis proteins, including osteocalcin (OCN), type collagen I (Col I), and bone morphogenetic protein-2 (BMP-2) in the Hep/GelMA-PRF group were all significantly upregulated (P < 0.05). CONCLUSIONS: The Hep/GelMA-PRF hydrogel scaffold could effectively control the release rate of growth factors, induce osteogenic differentiation, reduce inflammation, and keep a stable microenvironment for tissue repair. It has potential application value in the prevention of MRONJ.