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1.
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
2.
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
Trombose , Animais , Fibrinolíticos/farmacologia , Hirudinas/genética , Hirudinas/farmacologia , Anticoagulantes , Trombose/tratamento farmacológico , Trombose/prevenção & controle
4.
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
5.
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
6.
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
8.
Mol Cell Biochem ; 479(1): 63-72, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36988778

RESUMO

Severe hemorrhage shock and resuscitation (HSR) has been reported to induce myocardial ischemia-reperfusion injury (MIRI), resulting in a poor prognosis. Hirudin, an effective thrombin inhibitor, can offer protection against MIRI. This study aimed to determine if hirudin administration ameliorates HSR-induced MIRI and the underlying mechanism. A rat model of HSR was established by bleeding rats to a mean arterial blood pressure of 30-35 mmHg for 45 min and then resuscitating them with all the shed blood through the left femoral vein. After HSR, 1 mg/kg of hirudin was administrated immediately. At 24 h after HSR, the cardiac injury was assessed using serum CK-MB, cTnT, hematoxylin-eosin (HE) staining, echocardiography, M1-polarized macrophages, and pyroptosis-associated factors, including cleaved caspase-1, Gasdermin D (GSDMD) N-terminal, IL-1ß, and IL-18 were measured by immunofluorescence and western blot assays. Nigericin, a unique agonist, was utilized to evaluate the responsibilities of NLRP3 signaling. Under the HSR condition, rats exhibited a significant increase in myocardial injury score, an elevation of serum cTnT, CK-MB levels, an aggrandization of M1-polarized macrophages, an upregulation of pyroptosis-associated factors, including cleaved caspase-1, GSDMD N-terminal, IL-1ß, and IL-18, but a significant decrease in left ventricular ejection fraction (EF%) and a reduction of left ventricular fractional shortening (FS%), while hirudin administration partially restored the changes. However, the NLRP3 agonist nigericin reversed the cardioprotective effects of hirudin. We determined the cardioprotective effects of hirudin against HSR-induced MIRI. The mechanism may involve the inhibition of NLRP3-induced pyroptosis.


Assuntos
Traumatismo por Reperfusão Miocárdica , Choque Hemorrágico , Ratos , Animais , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-18 , Hirudinas/farmacologia , Choque Hemorrágico/metabolismo , Volume Sistólico , Nigericina/farmacologia , Função Ventricular Esquerda , Caspase 1/metabolismo , Transdução de Sinais
9.
Proteins ; 92(3): 329-342, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37860993

RESUMO

Thrombin is one of the key enzymes of the blood coagulation system and a promising target for the development of anticoagulants. One of the most specific natural thrombin inhibitors is hirudin, contained in the salivary glands of medicinal leeches. The medicinal use of recombinant hirudin is limited because of the lack of sulfation on Tyr63, resulting in a 10-fold decrease in activity compared to native (sulfated) hirudin. In the present work, a set of hirudin derivatives was tested for affinity to thrombin: phospho-Tyr63, Tyr63(carboxymethyl)Phe, and Tyr63Glu mutants, which mimic Tyr63 sulfation and Gln65Glu mutant and lysine-succinylated hirudin, which enhance the overall negative charge of hirudin, as well as sulfo-hirudin and desulfo-hirudin as references. Using steered molecular dynamics simulations with subsequent umbrella sampling, phospho-hirudin was shown to exhibit the highest affinity to thrombin among all hirudin analogs, including native sulfo-hirudin; succinylated hirudin was also prospective. Phospho-hirudin exhibited the highest antithrombotic activity in in vitro assay in human plasma. Taking into account the modern methods for obtaining phospho-hirudin and succinylated hirudin, they are prospective as anticoagulants in clinical practice.


Assuntos
Fibrinolíticos , Hirudinas , Humanos , Hirudinas/genética , Hirudinas/farmacologia , Hirudinas/metabolismo , Fibrinolíticos/farmacologia , Trombina , Fosforilação , Estudos Prospectivos , Anticoagulantes , Proteínas Recombinantes/genética , Tirosina/metabolismo
10.
Chembiochem ; 25(3): e202300744, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38055188

RESUMO

Hirudins, natural sulfo(glyco)proteins, are clinical anticoagulants that directly inhibit thrombin, a key coagulation factor. Their potent thrombin inhibition primarily results from antagonistic interactions with both the catalytic and non-catalytic sites of thrombin. Hirudins often feature sulfate moieties on Tyr residues in their anionic C-terminus region, enabling strong interactions with thrombin exosite-I and effectively blocking its engagement with fibrinogen. Although sulfotyrosines have been identified in various hirudin variants, the precise relationship between sulfotyrosine and the number of negatively charged amino acids within the anionic-rich C-terminus peptide domain for the binding of thrombin has remained elusive. By using Fmoc-SPPS, hirudin dodecapeptides homologous to the C-terminus of hirudin variants from various leech species were successfully synthesized, and the effect of sulfotyrosine and the number of negatively charged amino acids on hirudin-thrombin interactions was investigated. Our findings did not reveal any synergistic effect between an increasing number of sulfotyrosines or negatively charged amino acids and their inhibitory activity on thrombin or fibrinolysis in the assays, despite a higher binding level toward thrombin in the sulfated dodecapeptide Hnip_Hirudin was observed in SPR analysis.


Assuntos
Hirudinas , Trombina , Tirosina/análogos & derivados , Hirudinas/farmacologia , Hirudinas/química , Hirudinas/metabolismo , Aminoácidos , Peptídeos/farmacologia , Sítios de Ligação
11.
ASAIO J ; 70(3): e31-e37, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38029748

RESUMO

The use of bivalirudin as the primary anticoagulant for children supported on extracorporeal membrane oxygenation (ECMO) is growing. Ideal management of bivalirudin dosing during therapeutic plasma exchange (TPE) on ECMO is unknown. We performed a single-center retrospective study of ECMO patients anticoagulated with bivalirudin who underwent TPE from January 2019 to December 2021. Therapeutic plasma exchange sessions were analyzed individually by bivalirudin dosing strategy (no change [NC] versus increased dose [dose change {DC} bivalirudin group]) and replacement fluid (all fresh-frozen plasma [FFP] versus all albumin or FFP and albumin [FFP/Albumin]). Primary outcomes included bleeding, coagulopathy, and circuit thrombosis within 24 hours of TPE. Secondary outcomes included change in bivalirudin dose and coagulation parameters following TPE. There were 60 unique TPE sessions. Bivalirudin dosing or replacement fluid strategies were not associated with bleeding, coagulopathy, or thrombosis post-TPE. All albumin or fresh frozen plasma and albumin combinations (FFP/Albumin) group had longer post-TPE thromboelastography (TEG) reaction time, clot time, and more acute angle. The FFP/Albumin group had increased post-TPE international normalization ratio (INR) and partial thrombin time (PTT). Therapeutic plasma exchange for children on ECMO and bivalirudin anticoagulation is feasible; however, optimal dosing during TPE requires further investigation. Replacement fluid with FFP/Albumin is associated with more coagulopathic laboratory parameters. Patients may benefit from all FFP fluid replacement strategy. Further investigation is needed to prove generalizability.


Assuntos
Oxigenação por Membrana Extracorpórea , Hirudinas , Trombose , Criança , Humanos , Troca Plasmática/efeitos adversos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Estudos Retrospectivos , Fragmentos de Peptídeos/uso terapêutico , Anticoagulantes/efeitos adversos , Hemorragia , Trombose/etiologia , Trombose/prevenção & controle , Trombose/tratamento farmacológico , Albuminas , Proteínas Recombinantes/efeitos adversos
13.
Am J Physiol Lung Cell Mol Physiol ; 326(3): L213-L225, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38113296

RESUMO

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.


Assuntos
Antitrombinas , Arginina/análogos & derivados , Heparina , Ácidos Pipecólicos , Sulfonamidas , Humanos , Animais , Camundongos , Heparina/farmacologia , Heparina/uso terapêutico , Antitrombinas/farmacologia , Antitrombinas/uso terapêutico , Anticoagulantes/uso terapêutico , Pneumonectomia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Hirudinas/farmacologia , Fibrinolíticos , Pulmão/metabolismo , Fragmentos de Peptídeos/farmacologia , Proteínas Recombinantes/farmacologia , Trombina/farmacologia , Trombina/metabolismo
14.
Expert Rev Cardiovasc Ther ; 21(12): 901-911, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37919937

RESUMO

INTRODUCTION: Bivalirudin, a bivalent direct thrombin inhibitor, has been developed to reduce bleeding without any trade-off in thrombotic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). AREAS COVERED: Despite showing a superior safety profile compared with unfractionated heparin (UFH), bivalirudin is not considered the anticoagulant of choice in ACS patients undergoing PCI, mainly because of an increased rate of acute stent thrombosis (ST) shown by several randomized controlled trials (RCTs), in addition to limited availability in certain countries and increased costs. However, RCTs on bivalirudin have been characterized by several confounding factors hindering the interpretation of its safety and efficacy compared with UFH among the spectrum of ACS patients. Furthermore, a significant body of evidence has demonstrated that the risk of acute ST can be mitigated by a full-dose infusion regimen following PCI, without compromising the favorable safety profile compared to UFH. EXPERT OPINION: In light of the increased understanding of the prognostic relevance of bleeding events and the excellent safety profile of bivalirudin, recent trial evidence may allow for this anticoagulant agent to reemerge and have a more prominent role in the management of ACS patients undergoing PCI.


Assuntos
Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Humanos , Síndrome Coronariana Aguda/tratamento farmacológico , Resultado do Tratamento , Hirudinas/efeitos adversos , Heparina/efeitos adversos , Antitrombinas/efeitos adversos , Anticoagulantes/efeitos adversos , Fragmentos de Peptídeos/efeitos adversos , Hemorragia/induzido quimicamente , Proteínas Recombinantes/efeitos adversos
15.
Protein Sci ; 32(12): e4825, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37924304

RESUMO

Hirudin from Hirudo medicinalis is a bivalent α-Thrombin (αT) inhibitor, targeting the enzyme active site and exosite-I, and is currently used in anticoagulant therapy along with its simplified analogue hirulog. Haemadin, a small protein (57 amino acids) isolated from the land-living leech Haemadipsa sylvestris, selectively inhibits αT with a potency identical to that of recombinant hirudin (KI = 0.2 pM), with which it shares a common disulfide topology and overall fold. At variance with hirudin, haemadin targets exosite-II and therefore (besides the free protease) it also blocks thrombomodulin-bound αT without inhibiting the active intermediate meizothrombin, thus offering potential advantages over hirudin. Here, we produced in reasonably high yields and pharmaceutical purity (>98%) wild-type haemadin and the oxidation resistant Met5 → nor-Leucine analogue, both inhibiting αT with a KI of 0.2 pM. Thereafter, we used site-directed mutagenesis, spectroscopic, ligand-displacement, and Hydrogen/Deuterium Exchange-Mass Spectrometry techniques to map the αT regions relevant for the interaction with full-length haemadin and with the synthetic N- and C-terminal peptides Haem(1-10) and Haem(45-57). Haem(1-10) competitively binds to/inhibits αT active site (KI = 1.9 µM) and its potency was enhanced by 10-fold after Phe3 → ß-Naphthylalanine exchange. Conversely to full-length haemadin, haem(45-57) displays intrinsic affinity for exosite-I (KD = 1.6 µM). Hence, we synthesized a peptide in which the sequences 1-9 and 45-57 were joined together through a 3-Glycine spacer to yield haemanorm, a highly potent (KI = 0.8 nM) inhibitor targeting αT active site and exosite-I. Haemanorm can be regarded as a novel class of hirulog-like αT inhibitors with potential pharmacological applications.


Assuntos
Hirudinas , Trombina , Hirudinas/genética , Hirudinas/farmacologia , Hirudinas/química , Trombina/química , Trombina/metabolismo , Sequência de Aminoácidos , Peptídeos , Heme
16.
Braz J Med Biol Res ; 56: e13013, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37970924

RESUMO

Although bivalirudin has been recently made available for purchase in China, large-scale analyses on the safety profile of bivalirudin among Chinese patients is lacking. Thus, this study aimed to compare the safety profile of bivalirudin and heparin as anticoagulants in Chinese ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI). A total of 1063 STEMI patients undergoing PCI and receiving bivalirudin (n=424, bivalirudin group) or heparin (n=639, heparin group) as anticoagulants were retrospectively enrolled. The net adverse clinical events (NACEs) within 30 days after PCI were recorded, including major adverse cardiac and cerebral events (MACCEs) and bleeding events (bleeding academic research consortium (BARC) grades 2-5 (BARC 2-5)). The incidences of NACEs (10.1 vs 15.6%) (P=0.010), BARC 2-5 bleeding events (5.2 vs 10.3%) (P=0.003), and BARC grades 3-5 (BARC 3-5) bleeding events (2.1 vs 5.5%) (P=0.007) were lower in the bivalirudin group compared to the heparin group, whereas general MACCEs incidence (8.9 vs 6.4%) (P=0.131) and each category of MACCEs (all P>0.05) did not differ between two groups. Furthermore, the multivariate logistic analyses showed that bivalirudin (vs heparin) was independently correlated with lower risk of NACEs (OR=0.508, P=0.002), BARC 2-5 bleeding events (OR=0.403, P=0.001), and BARC 3-5 bleeding events (OR=0.452, P=0.042); other independent risk factors for NACEs, MACCEs, or BARC bleeding events included history of diabetes mellitus, emergency operation, multiple lesional vessels, stent length >33.0 mm, and higher CRUSADE score (all P<0.05). Thus, bivalirudin presented a better safety profile than heparin among Chinese STEMI patients undergoing PCI.


Assuntos
Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Heparina/efeitos adversos , Estudos Retrospectivos , Antitrombinas/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Intervenção Coronária Percutânea/efeitos adversos , População do Leste Asiático , Resultado do Tratamento , Hirudinas/efeitos adversos , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Fragmentos de Peptídeos/efeitos adversos , Fibrinolíticos , Proteínas Recombinantes/efeitos adversos
17.
Genes (Basel) ; 14(11)2023 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-38003011

RESUMO

Leeches are well-known annelids due to their obligate blood-feeding habits. Some leech species secrete various biologically active substances which have important medical and pharmaceutical value in antithrombotic treatments. In this study, we provided a high-quality genome of the Asian buffalo leech (Hirudinaria manillensis), based on which we performed a systematic identification of potential antithrombotic genes and their corresponding proteins. Combining automatic and manual prediction, we identified 21 antithrombotic gene families including fourteen coagulation inhibitors, three platelet aggregation inhibitors, three fibrinolysis enhancers, and one tissue penetration enhancer. A total of 72 antithrombotic genes, including two pseudogenes, were identified, including most of their corresponding proteins forming three or more disulfide bonds. Three protein families (LDTI, antistasin, and granulin) had internal tandem repeats containing 6, 10, and 12 conserved cysteines, respectively. We also measured the anticoagulant activities of the five identified hirudins (hirudin_Hman1 ~ hirudin_Hman5). The results showed that three (hirudin_Hman1, hirudin_Hman2, and hirudin_Hman5), but not the remaining two, exhibited anticoagulant activities. Our study provides the most comprehensive collection of antithrombotic biomacromolecules from a leech to date. These results will greatly facilitate the research and application of leech derivatives for medical and pharmaceutical purposes in the treatment of thrombotic diseases.


Assuntos
Hirudinas , Sanguessugas , Animais , Sequência de Aminoácidos , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Fibrinolíticos/farmacologia , Fibrinolíticos/metabolismo , Hirudinas/metabolismo , Sanguessugas/genética , Sanguessugas/química , Sanguessugas/metabolismo , Preparações Farmacêuticas/metabolismo
18.
Coron Artery Dis ; 34(8): 562-579, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37865864

RESUMO

BACKGROUND: The use of bivalirudin-based anticoagulation over heparin-based anticoagulation for coronary percutaneous intervention has been debated for a long time. Multiple trials have shown promising benefits of bivalirudin over heparin therapy with the most recent addition being the BRIGHT-4 trial. We performed a meta-analysis to assess evidence from these trials, focusing on the coronary intervention of the STEMI population. METHODS: This meta-analysis was performed based on PRISMA guidelines after registering in PROSPERO (CRD42023394701). Databases were searched for relevant articles published before January 2023. Pertinent data from the included studies were extracted and analyzed using RevMan v5.4. RESULTS: Out of 2375 studies evaluated, 13 randomized control trials with 24 360 acute ST-elevation myocardial infarction patients were included for analysis. The bivalirudin-based anticoagulation reduced the net clinical events (OR 0.75, CI 0.61-0.92), major adverse cardiac or cerebral events (OR 0.85, CI 0.74-0.98), any bleeding (OR 0.61, CI 0.45-0.83), major bleeding (OR 0.54, CI 0.39-0.75), all-cause mortality (OR 0.79, CI 0.67-0.92) and cardiac mortality (OR 0.78, CI 0.65-0.93) significantly without increasing the risk of any stent thrombosis (OR 0.92, 95% CI 0.52-1.61), definite stent thrombosis (OR 1.17, 95% CI 0.62-2.22) and acute stent thrombosis (OR 2.06, 95% CI 0.69-6.09) significantly at 30 days. CONCLUSION: Based on this meta-analysis, bivalirudin plus a post-PCI high-dose infusion-based anticoagulation during STEMI PCI has significant benefits over heparin therapy for cardiovascular outcomes without a significant increase in the risk of thrombotic outcomes.


Assuntos
Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Trombose , Humanos , Heparina/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Antitrombinas/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Hirudinas/efeitos adversos , Anticoagulantes/efeitos adversos , Fragmentos de Peptídeos/efeitos adversos , Trombose/etiologia , Trombose/prevenção & controle , Proteínas Recombinantes/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
J Appl Lab Med ; 8(6): 1074-1083, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37811688

RESUMO

BACKGROUND: Direct thrombin inhibitors (DTIs) are usually monitored with the activated partial thromboplastin time (aPTT) or activated clotting time (ACT). Both are complex assays with multiple enzymatic steps, and performance may be influenced by physiologic and pathologic factors unrelated to the DTI. Simpler systems, such as clot-based dilute thrombin time (dTT) and chromogenic anti-factor IIa assays, have been developed for monitoring DTIs, but there is limited data on their performance in clinical settings. METHODS: Medical records of patients who received bivalirudin between March 2020 and April 2022 at a single institution were reviewed for demographic data and adverse outcomes. Plasma samples drawn for aPTT testing were analyzed with chromogenic anti-IIa and dTT bivalirudin assays. Results were compared to bivalirudin dosing. RESULTS: Results of aPTT assays from 32 patients were compared with the chromogenic (n = 136) and dTT (n = 120) bivalirudin assays. Correlations between the aPTT and the chromogenic and dTT assays were poor (Spearman coefficients 0.55 and 0.62, respectively). There was a stronger correlation when results of the chromogenic and dTT assays were compared to each other (Spearman coefficient 0.92). When assay results were compared to bivalirudin dose, there were stronger correlations with the chromogenic and dTT assays than with the aPTT (Spearman coefficients 0.51, 0.63 and 0.22, respectively). CONCLUSIONS: There was considerable variation between results of specific bivalirudin assays and the aPTT. While bivalirudin assay results correlated better with administered drug dose, suggesting improving reliability, more studies are needed to determine if there is correlation between testing and clinical outcomes.


Assuntos
Hirudinas , Trombose , Humanos , Reprodutibilidade dos Testes , Hirudinas/farmacologia , Coagulação Sanguínea , Antitrombinas/farmacologia
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