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1.
Vasc Endovascular Surg ; 53(7): 602-605, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31272299

RESUMO

INTRODUCTION: Carotid angioplasty and stenting (CAS) represents an effective procedure for treating carotid artery disease. The acute in-stent thrombosis is an extremely rare complication of CAS especially when it occurs postprocedurally during the first 24 hours. Improper antiplatelet therapy or poor response to antiplatelet medications is known to be associated with a higher risk of in-stent thrombosis during early postprocedural period following a successful intervention. MATERIAL AND METHODS: A patient who experienced acute carotid in-stent thrombosis in early postprocedural period is described. He had been taking dual antiplatelet therapy for 2 weeks before undergoing a successful CAS. Moreover, pharmacogenetics studies showed the patient to be a clopidogrel ultrarapid metabolizer, which theoretically confers hyperresponsivity to medication. Alongside the report itself, a brief literature review of relevant sources pertinent to the case has been conducted. RESULTS: According to the available literature, this is the first case report describing an ultrarapid clopidogrel metabolizer who underwent an uneventful CAS but experienced acute carotid in-stent thrombosis in early postprocedural period. A rescue procedure included an endovascular intervention consisting of thrombectomy and local alteplase application, followed by postprocedural administration of intravenous eptifibatide. At discharge, patient's dual antiplatelet therapy included ticagrelor instead of clopidogrel. CONCLUSION: Acute carotid in-stent thrombosis is a highly unexpected complication of CAS and can occur despite ultrarapid clopidogrel metabolism trait.


Assuntos
Angioplastia com Balão/instrumentação , Estenose das Carótidas/terapia , Clopidogrel/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Inibidores da Agregação de Plaquetas/metabolismo , Stents , Trombose/etiologia , Doença Aguda , Administração Intravenosa , Angiografia Digital , Angioplastia com Balão/efeitos adversos , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/fisiopatologia , Clopidogrel/administração & dosagem , Angiografia por Tomografia Computadorizada , Citocromo P-450 CYP2C19/genética , Substituição de Medicamentos , Eptifibatida/administração & dosagem , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Fenótipo , Inibidores da Agregação de Plaquetas/administração & dosagem , Fatores de Risco , Trombectomia , Trombose/diagnóstico por imagem , Trombose/terapia , Ticagrelor/administração & dosagem , Resultado do Tratamento
2.
Am J Cardiol ; 124(3): 373-380, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31146891

RESUMO

The role of glycoprotein IIb/IIIa inhibitors (GPI) in primary percutaneous coronary intervention (PPCI) remains uncertain. Previous analyses compare PPCI outcomes with clopidogrel plus GPI, versus without GPI. This does not reflect modern contemporary PPCI practice with ticagrelor or prasugrel. Nor does it answer the important question faced daily by PPCI operators: should GPI be used routinely or selectively? We aim to determine whether a strategy of routine use of GPI in contemporary PPCI practice is superior to selective GPI use. A total of 110,327 consecutive PPCIs performed in England were prospectively recorded in the British Cardiovascular Intervention Society Database (2009 to 2015). The cohort was divided into routine and selective GPI usage groups based on the PPCI operator's strategy, defined as GPI used in >75% and <25% PPCIs, respectively. Overall, GPI use declined from 73.1% to 43.3% of PPCIs. Routine compared with selective GPI usage was associated with lower all-cause 1-year mortality: 9.7% versus 11.0%, p < 0.001. There was a consistent survival benefit for routine GPI usage as compared with selective GPI usage: univariable analysis (hazard ratio = 0.88 [95% confidence interval 0.83 to 0.93], p < 0.001), multivariable analysis (hazard ratio = 0.82 [0.77 to 0.88], p < 0.001). For survival, there was no interaction between GPI usage and the type of P2Y12-inhibitor used. In conclusion, a strategy of routine GPI usage in patients who underwent PPCI was associated with lower all-cause mortality as compared with selective GPI usage. This benefit was maintained despite 44.3% of patients receiving prasugrel or ticagrelor.


Assuntos
Uso de Medicamentos/estatística & dados numéricos , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Abciximab/uso terapêutico , Clopidogrel/uso terapêutico , Terapia Combinada , Uso de Medicamentos/tendências , Eptifibatida/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cloridrato de Prasugrel/uso terapêutico , Ticagrelor/uso terapêutico , Reino Unido
3.
Inflammation ; 42(5): 1767-1776, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31175488

RESUMO

In human sepsis, hemolysis is an independent predictor of mortality, but the mechanisms evoking hemolysis have not been fully elucidated. Therefore, we tested the hypotheses that (1) lipopolysaccharide (LPS)-induced hemolysis is dependent on thrombin generation or platelet aggregation and (2) red cell membranes are weakened by LPS. Anesthetized male Wistar rats were subjected to LPS or vehicle for 240 min. The effects of hemostasis inhibition on LPS-induced hemolysis were investigated by use of the thrombin inhibitor argatroban or the platelet function inhibitor eptifibatide. Free hemoglobin concentration, red cell membrane stiffness and red cell morphological changes were determined by spectrophotometry, atomic force microscopy, and light microscopy. Efficacy of argatroban and eptifibatide was assessed by rotational thrombelastometry and impedance aggregometry, respectively. LPS markedly increased free hemoglobin concentration (20.8 µmol/l ± 3.6 vs. 3.5 ± 0.3, n = 6, p < 0.0001) and schistocytes, reduced red cell membrane stiffness, and induced disseminated intravascular coagulation. Inhibition of thrombin formation with argatroban abolished the increase in free hemoglobin concentration, schistocyte formation, and disseminated intravascular coagulation in LPS-treated animals. Eptifibatide had no inhibitory effect. The LPS evoked decrease of red cell stiffness that was not affected by argatroban or eptifibatide. LPS causes hemolysis, schistocyte formation, and red cell membrane weakening in rats. The thrombin inhibitor argatroban but not the platelet inhibitor eptifibatide abolished hemolysis and schistocyte formation. Thus, LPS-induced hemolysis depends on disseminated intravascular coagulation, possibly enhanced by red cell membrane weakening. Clinical studies are necessary to investigate whether thrombin antagonists can decrease hemolysis and mortality in sepsis.


Assuntos
Hemólise/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Trombina/antagonistas & inibidores , Animais , Coagulação Intravascular Disseminada/fisiopatologia , Eptifibatida/farmacologia , Membrana Eritrocítica/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Humanos , Lipopolissacarídeos/efeitos adversos , Masculino , Ácidos Pipecólicos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Ratos , Ratos Wistar , Trombina/biossíntese
4.
J Chromatogr Sci ; 57(6): 541-551, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31004428

RESUMO

Eptifibatide (EPT) is a cyclic heptapeptide derived from a protein found in the venom of the south-eastern pygmy rattle snake used as an antiplatelet drug. In this study, a newly developed HPLC method demonstrating no interference from the different degradation products of EPT has been optimized and validated. The method was based on HPLC separation of eptifibatide from its degradation products using reversed phase C18 column at ambient temperature with mobile phase consisting of acetonitrile: 50 mM sodium dihydrogen orthophosphate dihydrate, pH was adjusted to 2.2 with orthophosphoric acid (25:75 v/v). Quantitation was achieved with UV detection at 220 nm based on peak area. The proposed method was validated according to the ICH guidelines and applied to evaluate the stability of EPT under different stress conditions including temperature, oxidation and hydrolysis over wide pH range (2-10). Moreover, kinetic study of EPT oxidation and its hydrolysis at pH 10 was demonstrated. The proposed method was successfully applied to quantify EPT in bulk powder and in pharmaceutical formulation with a runtime shorter than all the reported methods.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Eptifibatida/análise , Eptifibatida/química , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Cinética , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes
5.
World Neurosurg ; 127: e149-e154, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30862588

RESUMO

BACKGROUND: Wide-necked intracranial aneurysms present unique treatment challenges in the setting of subarachnoid hemorrhage. New generations of endoluminal devices (stents) have expanded our ability to treat complex aneurysms. The PulseRider Aneurysm Neck Reconstruction Device (PulseRider [Cerenovus, Irvine, California, USA]) is new to the U.S. market after receiving Food and Drug Administration approval in June 2017. Official recommendation for use of the PulseRider is with dual antiplatelet therapy (DAPT). Its design has been hypothesized to carry a lower risk of thromboembolic complications in the circumstance that DAPT needs to be discontinued. METHODS: Between March and June 2018, we treated 4 cases of ruptured wide-necked basilar tip aneurysms at the University of Colorado Hospital, Aurora, Colorado, with PulseRider-assisted coil embolization. Imaging and chart reviews were performed retrospectively on each of these patients. RESULTS: All 4 aneurysms were successfully treated with PulseRider-assisted coil embolization. There were no periprocedural hemorrhages and no postprocedural reruptures. Two patients developed nonocclusive thrombi in the posterior cerebral arteries at the time of coiling, which was resolved with intra-arterial glycoprotein IIb/IIIa receptor antagonists. Two patients developed external ventricular drain-associated hemorrhages, only one of which developed after the administration of DAPT. All patients were eventually discharged to home. CONCLUSIONS: The PulseRider device represents a novel design for stent-assisted coil embolization. We report a small but promising series of its successful use in the acute treatment of wide-necked, ruptured basilar artery aneurysms. Additional experience is needed to determine if this device has a place in our armamentarium for treatment of ruptured aneurysms.


Assuntos
Aneurisma Roto/terapia , Embolização Terapêutica/instrumentação , Aneurisma Intracraniano/terapia , Abciximab/uso terapêutico , Adulto , Idoso , Aneurisma Roto/complicações , Aneurisma Roto/diagnóstico por imagem , Bloqueadores dos Canais de Cálcio/uso terapêutico , Angiografia Cerebral , Terapia Combinada , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/métodos , Eptifibatida/uso terapêutico , Desenho de Equipamento , Feminino , Humanos , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/diagnóstico por imagem , Trombose Intracraniana/tratamento farmacológico , Trombose Intracraniana/etiologia , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Artéria Cerebral Posterior , Stents , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/etiologia , Hemorragia Subaracnóidea/terapia , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/etiologia , Verapamil/uso terapêutico
6.
Luminescence ; 34(1): 64-69, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30537239

RESUMO

A spectrofluorimetric method for the determination of eptifibatide is presented based on its native fluorescence. The type of solvent and the wavelength of maximum excitation and emission were carefully selected to optimize the experimental conditions. Under the specified experimental conditions, the linearities obtained between the emission intensity and the corresponding concentrations of eptifibatide were in the range 0.1-2.5 µg/ml for the calibration curve constructed for direct determination of eptifibatide in dosage form and 0.05-2.2 µg/ml for the calibration curve constructed in spiked human plasma with a good correlation coefficient (r > 0.99). The lower limit of quantification for the calibration curve constructed in human plasma was 0.05 µg/ml. Recovery results for eptifibatide in spiked plasma samples and in dosage form, represented as mean ± % RSD, were 95.17 ± 1.94 and 100.29 ± 1.33 respectively. The suggested procedures were validated according to the International Conference on Harmonization (ICH) guidelines for the direct determination of eptifibatide in its pure form and dosage form and United States Food and Drug Administration (US FDA) Guidance for Industry, Bioanalytical Method Validation for the assay of eptifibatide in human plasma.


Assuntos
Eptifibatida/análise , Espectrometria de Fluorescência/métodos , Calibragem , Estabilidade de Medicamentos , Eptifibatida/sangue , Humanos , Limite de Detecção , Inibidores da Agregação de Plaquetas/análise , Inibidores da Agregação de Plaquetas/sangue , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Solventes/química , Temperatura
7.
Am J Cardiol ; 123(1): 44-49, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30539747

RESUMO

Potent platelet inhibition is one of the most important medical interventions to prevent ischemic complications during and after percutaneous coronary intervention (PCI). Practice has evolved with the introduction of potent oral P2Y12 inhibitors that provide quick, effective platelet inhibition, and the need for routine glycoprotein IIb/IIIa inhibitors (GPIs) has decreased. Additionally, a shorter duration of GPI infusion has been shown to be safe with adequate oral antiplatelet loading, but clinical outcome data are limited to eptifibatide. This single-center, retrospective cohort study analyzed in-hospital outcomes for patients who received adjunctive GPI therapy for PCI before and after an institution-wide switch to high-dose bolus tirofiban with shortened infusion from short-duration eptifibatide. The primary end point was a composite in-hospital outcome of major and minor bleeding and cardiovascular events (death, myocardial infarction, coronary artery bypass grafting, ischemic stroke, and target vessel revascularization). Secondary end points included bleeding and cardiovascular event types. A total of 357 and 446 patients received eptifibatide and tirofiban, respectively, from February 1, 2014 through September 30, 2017. Thirty five eptifibatide and 46 tirofiban patients experienced an in-hospital composite event (9.8% vs 10.3%, p = 0.81). There was no difference found between in-hospital bleeding (6.4% vs 5.4%, p = 0.52) or cardiovascular events (5.6% vs 6.5%, p = 0.60) with the use of eptifibatide or tirofiban, respectively. Multivariable analysis showed that patients with transradial access or an indication of unstable angina were less likely to experience an in-hospital composite event (OR 0.30 and 0.19, respectively, p <0.001 for both). In conclusion, the use of high-dose bolus tirofiban with shortened infusion versus short-duration eptifibatide was not associated with an increase of in-hospital bleeding or cardiovascular events.


Assuntos
Hemorragia/induzido quimicamente , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/administração & dosagem , Tirofibana/administração & dosagem , Idoso , Eptifibatida/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
8.
Circ Cardiovasc Interv ; 11(6): e006084, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29895599

RESUMO

BACKGROUND: Monitoring anticoagulation with activated clotting time (ACT) has been proposed to reduce ischemic or bleeding events. However, the value of using ACT to improve outcomes is uncertain. This study sought to determine the relationship between ACT and outcomes during percutaneous coronary intervention in patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) treated by unfractionated heparin with GPIs (glycoprotein IIb/IIIa inhibitors). METHODS AND RESULTS: From the randomized TAO trial (Treatment of Acute Coronary Syndromes With Otamixaban), we analyzed the value of ACT to predict ischemic and bleeding outcomes in the 3275 patients receiving unfractionated heparin plus eptifibatide. Ischemic and safety outcomes were analyzed according to ACT to determine the best threshold. Median peak ACT was 225 s. There was no correlation (r=-0.02; P=0.24) between the unfractionated heparin dose received and the ACT value before percutaneous coronary intervention. There was no evidence of a nonlinear association between ACT and either ischemic or bleeding events (P=0.66; P=0.07). No threshold was found to predict ischemic complications. Conversely, increased bleeding was observed with ACT >230 s with an optimal threshold of ACTs ≥250 s (4.53% versus 6.17%; odds ratio, 1.46; 95% confidence interval, 1.04-2.06; P=0.028). This optimal threshold varied according to access site: ≥250 s (6.86% versus 10.18%; odds ratio, 1.57; 95% confidence interval, 1.00-2.45; P=0.047) by femoral approach and ≥290 s (2.86% versus 5.43%; odds ratio, 2.24; 95% confidence interval, 1.05-4.44; P=0.027) by radial approach. CONCLUSIONS: In the TAO trial, peak procedural ACT ≥250 s was associated with increased bleeding risk in non-ST-segment-elevation acute coronary syndrome patients treated with unfractionated heparin plus GPIs. This threshold was increased to 290 s when performing radial approach. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01076764.


Assuntos
Síndrome Coronariana Aguda/terapia , Anticoagulantes/efeitos adversos , Coagulação Sanguínea/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Eptifibatida/efeitos adversos , Hemorragia/induzido quimicamente , Heparina/efeitos adversos , Infarto do Miocárdio sem Supradesnível do Segmento ST/terapia , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/efeitos adversos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Tempo de Coagulação do Sangue Total , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Idoso , Anticoagulantes/administração & dosagem , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/efeitos adversos , Cálculos da Dosagem de Medicamento , Eptifibatida/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Heparina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio sem Supradesnível do Segmento ST/sangue , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação de Plaquetas/administração & dosagem , Valor Preditivo dos Testes , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
9.
Perfusion ; 33(8): 699-703, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29874954

RESUMO

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been used as a bridge to cardiac recovery in patients following a major cardiac event. There is a lack of literature surrounding prolonged use of eptifibatide and optimal dosing during ECMO. This case report describes our experience with extended durations and standard dosing of eptifibatide in the setting of ECMO. CASE: A 40-year-old male with a history of Marfan's syndrome, aortic root and ascending aortic aneurysm status post a modified Bentall with a St. Jude mechanical aortic valve conduit and hemi-Cabrol with a Dacron graft to the left main coronary artery presented with exertional chest pain and was found to have an anastomotic narrowing to the left main which occluded while awaiting surgical revision. A rescue percutaneous coronary intervention at the anastomotic site was performed. Due to hemodynamic instability, he was placed on femoral VA-ECMO. The patient was started on anticoagulation for the ECMO circuit and eptifibatide to maintain stent patency. The patient experienced several bleeding episodes for which he received supportive care, endoscopic intervention and left gastric artery embolization. Eptifibatide was maintained at standard dosing and the heparin infusion was withheld. A coronary angiogram revealed no thrombus within the Cabrol graft a patent stent previously placed at the site of the distal graft-coronary anastomosis. The patient was decannulated from ECMO and underwent coronary artery bypass grafting and division of the hemi-Cabrol graft. CONCLUSION: While eptifibatide was effective in maintaining stent patency, our patient experienced several bleeding episodes during ECMO. Thus, the risks and benefits of concurrent antiplatelet and anticoagulant therapy must be appropriately weighed in this patient population. Additionally, as the need for dual antiplatelet therapy due to coronary stent implantation is increasing, further studies are needed to validate optimal dosing of eptifibatide in patients at a high risk of bleeding during ECMO.


Assuntos
Stents Farmacológicos , Eptifibatida/administração & dosagem , Oxigenação por Membrana Extracorpórea , Síndrome de Marfan/terapia , Adulto , Humanos , Masculino , Síndrome de Marfan/diagnóstico por imagem , Síndrome de Marfan/fisiopatologia
10.
Curr Opin Pharmacol ; 41: 27-33, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29679803

RESUMO

The health benefits of soy consumption have long been recognized. An important potential benefit is the linkage of soy consumption with reduced cancer risk. One emerging factor that may confer the anticancer effects of soy is the peptide lunasin. Lunasin has both chemopreventive and therapeutic activities against a variety of carcinogens and cancer types. A novel feature of lunasin is that it contains multiple functional domains that can modulate gene expression through effects on histone acetylation and integrin signaling. Recent studies suggest that lunasin effects on integrin signaling in cancer stem cells reduce expression of stemness factors with a concomitant reduction in metastatic potential. Here, we highlight recent studies of the potential use of lunasin as an anticancer agent and its mode of action.


Assuntos
Anticarcinógenos/farmacologia , Histonas/metabolismo , Proteínas de Soja/farmacologia , Acetilação/efeitos dos fármacos , Animais , Eptifibatida/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Camundongos
11.
Am J Cardiol ; 121(7): 796-804, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29397104

RESUMO

Although routine aspiration thrombectomy (AT) is not recommended by the current American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guideline, for selected cases, a class IIb indication is given because of lack of data. We studied the impact of selective AT on mortality in patients with ST-segment elevation myocardial infarction using a prospective registry. We analyzed data of 1,255 patients, of whom 535 underwent AT based on operator's decision. Separate propensity score matching procedures were performed including all patients and only those with initial TIMI (Thrombolysis In Myocardial Infarction) 0 to 1 flow, indicating the highest thrombus burden. Primary outcome measure was time to all-cause death at 1 year. Both studies were sufficiently powered to detect the hazard ratio (HR) of 0.52 seen in the TAPAS (Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study) trial. In the study with open inclusion criteria, 1-year mortality rates were 15.5% and 14.5% in the AT and conventional percutaneous coronary intervention arm, respectively (p = 0.77). The unadjusted HR was 1.05 (95% CI 0.73 to 1.51), p = 0.80, whereas the adjusted HR was 0.97 (95% CI 0.66 to 1.41), p = 0.87. In patients with initial TIMI 0 to 1 flow, mortality rate at 1 year was 15.6% in the AT and 16.7% in the standard percutaneous coronary intervention group (p = 0.76). The unadjusted and adjusted HRs were similar: 0.91 (95% CI 0.62 to 1.34), p = 0.65 and 0.93 (95% CI 0.62 to 1.37), p = 0.70, respectively. In conclusion, selective AT based on operator's discretion offers no mortality benefit of the magnitude detected in the TAPAS trial, even for patients with initial TIMI 0 to 1 flow grade.


Assuntos
Trombose Coronária/cirurgia , Mortalidade , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Trombectomia , Idoso , Eptifibatida/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Pontuação de Propensão , Modelos de Riscos Proporcionais , Sistema de Registros
13.
J Pharm Biomed Anal ; 151: 260-265, 2018 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-29358126

RESUMO

Eptifibatide is a therapeutic cyclic peptide with poor collision-induced dissociation (CID) efficiency for multiple reaction monitoring (MRM), which limits the development of a traditional liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioassay with MRM. In this study, a method combining differential mobility spectrometry (DMS) with liquid chromatography-multiple ion monitoring (LC-DMS-MIM) was developed for the quantitation of eptifibatide in rat plasma. After solid phase extraction (SPE) of 100 µL plasma on an Oasis® HLB cartridge, the analyte and I.S. (octreotide) were analyzed using a SCIEX QTRAP 6500 operated in the positive ion mode and preceded by a DMS device. The lower limit of quantitation (LLOQ) for eptifibatide was 0.5 ng/mL using only 100 µL plasma. The method was linear in the concentration range 0.5-300 ng/mL with good precision and accuracy. Compared to regulated quantitative LC-MS/MS bioanalysis of eptifibatide, the LC-DMS-MIM method effectively overcomes the sensitivity challenge in the LC-MRM method and reduces the high background noise and matrix interference in LC-MIM method without DMS. The method was successfully applied to a pharmacokinetic study involving intravenous injection of eptifibatide to Wistar rats.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Peptídeos/farmacocinética , Inibidores da Agregação de Plaquetas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Cromatografia Líquida de Alta Pressão/instrumentação , Eptifibatida , Feminino , Limite de Detecção , Masculino , Peptídeos/sangue , Inibidores da Agregação de Plaquetas/sangue , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Extração em Fase Sólida/instrumentação , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/instrumentação
14.
Neurosurgery ; 82(3): 268-277, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28472526

RESUMO

Thromboembolic complications remain a major risk of endovascular neurosurgery during the treatment of intracranial aneurysms, despite the use of therapeutic heparinization and oral antiplatelet therapy when indicated. Glycoprotein (GP) IIb/IIIa inhibitors target a nonredundant pathway of platelet aggregation following adhesion and activation. Initially established and implemented in the cardiovascular arena, this drug class has provided a new tool in the neurovascular armamentarium as well. Numerous case reports, case series, and retrospective reviews have evaluated the safety and efficacy of abciximab, eptifibatide, and tirofiban in the treatment of acute thromboembolic complications during the endovascular treatment of intracranial aneurysms. The use of this drug class has also been found to be beneficial as a prophylactic agent, providing ischemia protection during the placement of intracranial stents, flow diverters, and thrombogenic coils in the setting of subarachnoid hemorrhage and during elective aneurysmal embolization. While the current published literature clearly establishes efficacy and safety of GP IIb/IIIa inhibitors in the prevention of thromboembolic complications, there does not yet exist an established protocol for their administration in endovascular neurosurgery. This review provides a comprehensive evaluation of the current published literature pertaining to the use of all available GP IIb/IIIa inhibitors for thromboembolic complications, providing recommendations for dosing and administration of abciximab, eptifibatide, and tirofiban based on previously published rates of efficacy and intracranial hemorrhage.


Assuntos
Embolização Terapêutica/métodos , Procedimentos Endovasculares/métodos , Aneurisma Intracraniano/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Tromboembolia/tratamento farmacológico , Abciximab/farmacologia , Abciximab/uso terapêutico , Animais , Embolização Terapêutica/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Eptifibatida/farmacologia , Eptifibatida/uso terapêutico , Humanos , Aneurisma Intracraniano/metabolismo , Inibidores da Agregação de Plaquetas/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Estudos Retrospectivos , Tromboembolia/metabolismo , Tirofibana/farmacologia , Tirofibana/uso terapêutico , Resultado do Tratamento
15.
Platelets ; 29(3): 265-269, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28406726

RESUMO

Mechanisms of platelet activation are triggered by thrombin, adenosine diphosphate (ADP), epinephrine, thromboxane A2, and other soluble agonists which induce signaling via heterotrimeric Gαq, Gαi, and Gα12/13 proteins. We have undertaken a study addressing the contribution of these G proteins to platelet activation and clot formation in the presence of eptifibatide, thus excluding outside-in signaling provided by integrin αIIbß3-fibrinogen engagement. Selective and combined activation of the G proteins was achieved by using combinations of platelet agonists and inhibitors. Platelet activation in platelet-rich plasma was evaluated by P-selectin expression using flow cytometry. Contribution of platelets to whole blood clotting was assessed by rotation thromboelastometry (ROTEM). Selective signaling of Gαq or Gαi but not Gα12/13 promoted P-selectin expression. Further enhancement of P-selectin expression was achieved by ADP-induced combined signaling of Gαq and Gαi, and to more extent by U46619 at high concentration (1.5 µM) induced combined signaling of Gαq and Gα12/13 while maximal P-selectin expression was achieved by thrombin receptor-activating peptide (TRAP)-induced combined signaling of Gαq, Gαi, and Gα12/13. In ROTEM, selective activation of Gαq, Gαi, or Gα12/13 failed to affect blood clotting. Combined signaling of Gαq and Gαi or Gαq and Gα12/13 or all three G proteins shortened the clotting time and stimulated clot strength. Pretreatment of platelets with acetylsalicylic acid did not change the effect of ADP but inhibited the effect of TRAP. Signaling of Gαq and Gα12/13 triggered by U46619 also stimulated clot formation. Combined signaling of either Gαq and Gαi or Gαq and Gα12/13 is sufficient to stimulate maximal platelet activation and enhanced clot formation in platelets treated with inhibitor of integrin αIIbß3. It could be suggested that outside-in signaling is not necessarily required to fulfill these platelet functions.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Trombose/etiologia , Trombose/metabolismo , Adulto , Biomarcadores , Eptifibatida , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/farmacologia , Testes de Função Plaquetária/métodos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Adulto Jovem
16.
J Thromb Haemost ; 15(11): 2230-2244, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28815933

RESUMO

Essentials FcγRIIa-mediated thrombocytopenia is associated with drug-dependent antibodies (DDAbs). We investigated the correlation between αIIb ß3 binding epitopes and induction of DDAbs. An FcγRIIa-transgenic mouse model was used to evaluate thrombocytopenia among anti-thrombotics. An antithrombotic with binding motif toward αIIb ß-propeller domain has less bleeding tendency. SUMMARY: Background Thrombocytopenia, a common side effect of Arg-Gly-Asp-mimetic antiplatelet drugs, is associated with drug-dependent antibodies (DDAbs) that recognize conformation-altered integrin αIIb ß3 . Objective To explore the correlation between αIIb ß3 binding epitopes and induction of DDAb binding to conformation-altered αIIb ß3 , we examined whether two purified disintegrins, TMV-2 and TMV-7, with distinct binding motifs have different effects on induction of αIIb ß3 conformational change and platelet aggregation in the presence of AP2, an IgG1 inhibitory mAb raised against αIIb ß3 . Methods We investigated the possible mechanisms of intrinsic platelet activation of TMV-2 and TMV-7 in the presence of AP2 by examining the signal cascade, tail bleeding time and immune thrombocytopenia in Fc receptor γ-chain IIa (FcγRIIa) transgenic mice. Results TMV-7 has a binding motif that recognizes the αIIb ß-propeller domain of αIIb ß3 , unlike that of TMV-2. TMV-7 neither primed the platelets to bind ligand, nor caused a conformational change of αIIb ß3 as identified with the ligand-induced binding site mAb AP5. In contrast to eptifibatide and TMV-2, cotreatment of TMV-7 with AP2 did not induce FcγRIIa-mediated platelet aggregation and the downstream activation cascade. Both TMV-2 and TMV-7 efficaciously prevented occlusive thrombosis in vivo. Notably, both eptifibatide and TMV-2 caused severe thrombocytopenia mediated by FcγRIIa, prolonged tail bleeding time in vivo, and repressed human whole blood coagulation indexes, whereas TMV-7 did not impair hemostatic capacity. Conclusions TMV-7 shows antiplatelet and antithrombotic activities resulting from a mechanism different from that of all other tested αIIb ß3 antagonists, and may offer advantages as a therapeutic agent with a better safety profile.


Assuntos
Anticorpos/sangue , Plaquetas/efeitos dos fármacos , Fibrinolíticos/farmacologia , Peptídeos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Receptores de IgG/metabolismo , Trombocitopenia/induzido quimicamente , Trombose/prevenção & controle , Animais , Anticorpos Monoclonais/farmacologia , Sítios de Ligação , Plaquetas/metabolismo , Modelos Animais de Doenças , Eptifibatida , Fibrinolíticos/imunologia , Fibrinolíticos/toxicidade , Predisposição Genética para Doença , Humanos , Motivo de Ativação do Imunorreceptor Baseado em Tirosina , Masculino , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Peptídeos/imunologia , Peptídeos/toxicidade , Fenótipo , Fosfolipase C gama/sangue , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/imunologia , Inibidores da Agregação de Plaquetas/toxicidade , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Conformação Proteica , Receptores de IgG/genética , Relação Estrutura-Atividade , Quinase Syk/sangue , Trombocitopenia/sangue , Trombocitopenia/imunologia , Trombose/sangue , Trombose/genética
17.
J Am Heart Assoc ; 6(6)2017 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-28611098

RESUMO

BACKGROUND: In patients with non-ST-segment elevation acute coronary syndromes, inhibition of platelet aggregation (IPA) with a potent P2Y12 inhibitor, ticagrelor, was inferior to tirofiban infusion at 2 hours, indicating that glycoprotein IIb/IIIa inhibitors are still needed. Ticagrelor and eptifibatide bolus only may maximally inhibit platelet aggregation and decrease bleeding, but IPA with ticagrelor and eptifibatide bolus versus 2-hour infusion is unknown. METHODS AND RESULTS: A total of 70 P2Y12-naïve patients, with high-risk non-ST-segment elevation acute coronary syndromes, were randomized to ticagrelor and eptifibatide bolus (group 1) versus ticagrelor and eptifibatide bolus with 2-hour infusion (group 2). Levels of IPA with ADP, thrombin receptor-activating peptide, collagen, and high on-treatment platelet reactivity were measured by light transmission aggregometry at baseline and at 2, 6, and 24 hours after percutaneous coronary intervention in both groups. The primary end point, IPA with ADP 20 µmol/L at 2 hours, was 99.59±0.43% in group 1 versus 99.88±1.0% in group 2 (P<0.001 for noninferiority). High on-treatment platelet reactivity with ADP was zero at 2, 6, and 24 hours in both groups. IPA levels with ADP, thrombin receptor-activating peptide, and collagen were significantly higher at 2 and 6 hours than at 24 hours in both groups. Periprocedural myocardial infarction was not significantly different between the groups. Hemoglobin level was significantly less at 24 hours versus baseline in group 2 (13.35±1.8 versus 12.38±1.8 g/dL, respectively; P<0.01). CONCLUSIONS: Ticagrelor and eptifibatide bolus maximally inhibited platelet aggregation at 2 hours, which was associated with no significant hemoglobin drop after percutaneous coronary intervention. This obviates the need for eptifibatide 2-hour infusion and might decrease bleeding complications. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01919723.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Adenosina/análogos & derivados , Peptídeos/administração & dosagem , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/cirurgia , Adenosina/administração & dosagem , Cateterismo Cardíaco , Angiografia Coronária , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletrocardiografia , Eptifibatida , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/administração & dosagem , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Método Simples-Cego , Ticagrelor , Fatores de Tempo , Resultado do Tratamento
18.
Mymensingh Med J ; 26(2): 300-305, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28588165

RESUMO

The purpose of this study was to assess the immediate and short term outcome of single bolus dose of eptifibatide in elective percutaneous coronary intervention (PCI). We enrolled 146 patients who underwent elective PCI from May 2013 to May 2014 in University Cardiac Centre, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Among 146 patients, seventy four patients received single bolus dose of eptifibatide (10 mg intra coronary single bolus dose) just after crossing the lesion were selected as case. The other 72 patients, who did not receive eptifibatide, were selected as control. All patients of both the groups were treated with aspirin, clopidogrel before and after the procedure and all received a single bolus dose of Clopidogrel (300mg) before the procedure. All patient received weight adjusted doses of heparin during and after the procedure. The outcome measures were 24-hours and 30-day morbidity (complications or adverse events) and mortality. The patients of eptifibatide group experienced significantly lower incidence of QMI lesions and complete absence of NQMI lesion in 24 hours of PCI as compared to 5.6% and 6.9% of the lesions respectively in their control counterparts (p=0.027 and p=0.025 respectively). However, the incidence of bleeding and target vessel revascularization (TVR) were no different between the groups (p=0.255 and p=0.117). There was no incidence of TVR at all in the eptifibatide group as opposed to 5.6% in the control group in 30 days following stenting (p=0.017). Single bolus dose of eptifibatite reduces the Major adverse cardiac events as immediate and short term outcome in elective percutaneous coronary intervention.


Assuntos
Angioplastia Coronária com Balão , Eptifibatida , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas , Bangladesh , Eptifibatida/uso terapêutico , Humanos , Peptídeos , Inibidores da Agregação de Plaquetas/uso terapêutico , Resultado do Tratamento
19.
Artif Organs ; 41(12): 1092-1098, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28621461

RESUMO

Pump thrombosis and hemolysis in patients with left ventricular assist devices (LVADs) are associated with significant morbidity and mortality. Intensification of anticoagulation has been suggested as potential therapy, with mixed results. The aim of this study is to assess the safety and efficacy of adding eptifibatide with or without an anticoagulation agent in managing patients with LVAD presenting with hemolysis and suspected pump thrombosis. This retrospective single center study included all patients who presented with their first episode of suspected pump thrombosis and were treated with eptifibatide with or without an anticoagulant between March 1, 2011 and July 30, 2015. A total of 27 patients (23 HeartMate II, 4 HeartWare) were identified. The average age was 55 years (range 19-75) and time from implant to event averaged 513 days (range 35-1760). The average lactate dehydrogenase on presentation was 1111 and 63% of patients had power elevations. The average international normalized ratio (INR) on admission was 2.4, with INR of ≥2 in 21/27 patients. All patients received eptifibatide: 10 received eptifibatide only, 9 received eptifibatide and argatroban, and 8 received eptifibatide and heparin. Warfarin was continued in 25/27 patients. Overall, 21 patients (77.8%) were successfully treated medically, 5 (18.5%) underwent pump exchange, and 1 (3.7%) died. There were no differences in outcomes or complications between the three treatment groups. Despite initial success, 12/21 patients developed repeat episodes of hemolysis at 1 year. The 1-year survival in the patients treated medically was 90% and surgically was 60%. Our experience indicates that medical therapy for hemolysis and suspected LVAD thrombosis with warfarin and eptifibatide alone or in combination with argatroban or heparin appears safe and may be effective, although the episodes of recurrent hemolysis after medical management remain high.


Assuntos
Coração Auxiliar/efeitos adversos , Heparina/uso terapêutico , Peptídeos/uso terapêutico , Ácidos Pipecólicos/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Trombose/tratamento farmacológico , Varfarina/uso terapêutico , Adulto , Idoso , Anticoagulantes/uso terapêutico , Eptifibatida , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/terapia , Hemólise/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Trombose/etiologia , Adulto Jovem
20.
J Interv Cardiol ; 30(4): 291-300, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28543770

RESUMO

OBJECTIVES: We sought to evaluate the patterns of use and outcomes associated with eptifibatide and abciximab administration among dialysis patients who underwent percutaneous coronary intervention (PCI). BACKGROUND: Contraindicated medications are frequently administered to dialysis patients undergoing PCI often resulting in adverse outcomes. Eptifibatide is a glycoprotein IIb/IIIa inhibitor that is often used during PCI and is contraindicated in dialysis. METHODS: We included dialysis patients who underwent PCI from January 2010 to September 2015 at 47 hospitals in Michigan. We compared outcomes between patients who received eptifibatide compared with abciximab. Both groups required concurrent treatment with unfractionated heparin only. In-hospital outcomes included repeat PCI, bleeding, major bleeding, need for transfusion, and death. Optimal full matching was used to adjust for non-random drug administration. RESULTS: Of 177 963 patients who underwent PCI, 4303 (2.4%) were on dialysis. Among those, 384 (8.9%) received eptifibatide and 100 (2.3%) received abciximab. Prior to matching, patients who received eptifibatide had higher pre-procedural hemoglobin levels (11.3 g/dL vs. 10.7 g/dL; P < 0.001) and less frequently had a history of myocardial infarction (36.5% vs. 52.0%; P = 0.005). After matching, there were no significant differences in in-hospital outcomes between eptifibatide and abciximab including transfusion (aOR: 1.15; 95%CI: 0.55-2.40; P = 0.70), bleeding (1.47; 0.64-3.40; P = 0.36), major bleeding (4.68; 0.42-52.3; P = 0.21), repeat PCI (0.38; 0.03-4.23; P = 0.43), and death (1.53; 0.2-9.05; P = 0.64). CONCLUSIONS: Despite being contraindicated in dialysis, eptifibatide was used approximately 3.5 times more frequently than abciximab among dialysis patients undergoing PCI but was associated with similar in-hospital outcomes.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Peptídeos/uso terapêutico , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/uso terapêutico , Complicações Pós-Operatórias/epidemiologia , Diálise Renal , Abciximab , Idoso , Planos de Seguro Blue Cross Blue Shield , Contraindicações de Medicamentos , Eptifibatida , Feminino , Heparina/uso terapêutico , Humanos , Masculino , Michigan , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Estudos Retrospectivos , Resultado do Tratamento
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