Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.176
Filtrar
1.
Int J Pharm ; 595: 120243, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33484923

RESUMO

Cardiovascular diseases constitute a number of conditions which are the leading cause of death globally. To combat these diseases and improve the quality and duration of life, several cardiac implants have been developed, including stents, vascular grafts and valvular prostheses. The implantation of these vascular prosthesis has associated risks such as infection or blood clot formation. In order to overcome these limitations medicated vascular prosthesis have been previously used. The present paper describes a 3D printing method to develop medicated vascular prosthesis using fused deposition modelling (FDM) technology. For this purpose, rifampicin (RIF) was selected as a model molecule as it can be used to prevent vascular graft prosthesis infection. Thermoplastic polyurethane (TPU) and RIF were combined using hot melt extrusion (HME) to obtain filaments containing RIF concentrations ranging between 0 and 1% (w/w). These materials are capable of providing RIF release for periods ranging between 30 and 80 days. Moreover, TPU-based materials containing RIF were capable of inhibiting the growth of Staphylococcus aureus. This behaviour was observed even for TPU-based materials containing RIF concentrations of 0.1% (w/w). TPU containing 1% (w/w) of RIF showed antimicrobial properties even after 30 days of RIF release. Alternatively, these methods were used to prepare dipyridamole containing TPU filaments. Finally, using a dual extrusion 3D printer vascular grafts containing both drugs were prepared.


Assuntos
Antibacterianos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Poliuretanos/química , Rifampina/farmacocinética , Tecnologia Farmacêutica/métodos , Células Sanguíneas/efeitos dos fármacos , Prótese Vascular/efeitos adversos , Preparações de Ação Retardada/química , Dipiridamol/farmacocinética , Liberação Controlada de Fármacos , Desenho de Equipamento/métodos , Células Endoteliais da Veia Umbilical Humana , Humanos , Inibidores da Agregação de Plaquetas/farmacocinética , Poliuretanos/uso terapêutico , Impressão Tridimensional , Infecções Estafilocócicas/etiologia , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Trombose/etiologia , Trombose/prevenção & controle
2.
Medicine (Baltimore) ; 99(50): e23695, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327360

RESUMO

BACKGROUND: Randomized trials and observation studies have revealed conflicting results regarding the interaction between clopidogrel and proton pump inhibitors (PPIs). The aim of our study was to provide laboratory evidence regarding whether PPIs blunt the antiplatelet reactivity of clopidogrel. METHODS: We included records of Asian patients who received clopidogrel treatment for cardiovascular or cerebrovascular events and the VerifyNow P2Y12 assay for platelet reactivity monitoring. The responsiveness of antiplatelet effect to clopidogrel was analyzed according to 3 criteria:Results: Patients treated without PPIs did not differ significantly from those concomitantly treated with PPIs in terms of levels of PI (25.7% ± 24.3% vs 23.0 ± 25.3%, P = .4315), PRU (187.3 ± 74.0 vs 197.4 ±â€Š77.3, P = .3373), or responsiveness to antiplatelet (adjusted absolute risk, 3.5%; 95% confidence interval, - 10.7 to 17.7%; P = .6297). Patients treated with lansoprazole, esomeprazole, pantoprazole, and rabeprazole exhibited no significant differences in PRU or PI levels compared with those treated without PPIs. By contrast, patients treated with dexlansoprazole exhibited a significantly decreased level of PI (25.7% ±â€Š24.3% vs 14.0% ±â€Š21.6%, P = .0297) and responsiveness to clopidogrel under the criterion PI > 20% (adjusted absolute risk: 10.5%; 95% confidence interval: 2.6% to 43.6%; P = .0274). CONCLUSION: No robust interaction between clopidogrel and PPIs was found, but caution should be exercised in the concomitant use of dexlansoprazole and clopidogrel in Asians.


Assuntos
Clopidogrel/farmacocinética , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Bomba de Prótons/farmacologia , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Comorbidade , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Fatores Sexuais
4.
Chem Biol Interact ; 330: 109228, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32827518

RESUMO

This study aimed at exploring the potential mechanism of decreased in vivo exposure of the antiplatelet agent, ticagrelor and its active metabolite, AR-C124910XX, mediated by tea polyphenols, which was first revealed by our previous study, as well as predicting the in vivo drug-drug interaction (DDI) potential utilizing an in vitro to in vivo extrapolation (IVIVE) approach. The bidirectional transport and uptake kinetics of ticagrelor were determined using Caco-2 cells. Inhibition potency of major components of tea polyphenols, epigallocatechin gallate (EGCG) and epigallocatechin (EGC) were obtained from Caco-2 cells, human intestinal and hepatic microsomes (HIMs and HLMs) in vitro. A mean efflux ratio of 2.28 ± 0.38 and active uptake behavior of ticagrelor were observed in Caco-2 cell studies. Further investigation showed that the IC50 values of EGCG and EGC on the uptake of ticagrelor were 42.0 ± 5.1 µM (95% CI 31.9-54.8 µM) and 161 ± 13 µM (95% CI 136-191 µM), respectively. EGCG and EGC also displayed moderate to weak reversible inhibition on the formation of AR-C124910XX and the inactive metabolite, AR-C133913XX in HIMs and HLMs, while no clinically significant time-dependent inhibition was observed for either compound. IVIVE indicated a significant inhibition effect of EGCG on the uptake process of ticagrelor, while no potential DDI risk was found based on microsomal data. A 45% decrease in ticagrelor in vivo exposure was mechanistically predicted by incorporating intestinal and hepatic metabolism as well as intestinal absorption. This dual inhibition of tea polyphenols on ticagrelor revealed the underlying potential of transporter-enzyme interplay, in which the altered uptake process was more critical.


Assuntos
Modelos Teóricos , Polifenóis/farmacologia , Chá/química , Ticagrelor/antagonistas & inibidores , Adenosina/análogos & derivados , Adenosina/metabolismo , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Catequina/análogos & derivados , Catequina/farmacologia , Linhagem Celular Tumoral , Interações Medicamentosas , Humanos , Absorção Intestinal/efeitos dos fármacos , Cinética , Microssomos Hepáticos/metabolismo , Inibidores da Agregação de Plaquetas/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Ticagrelor/metabolismo , Ticagrelor/farmacocinética
5.
J Stroke Cerebrovasc Dis ; 29(8): 104901, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32439350

RESUMO

OBJECTIVE: Polymorphisms in the CYP2C9 gene may be associated with adverse vascular events following endovascular procedures independent of antiplatelet therapy. We aimed to investigate the impact of CYP2C9 loss-of-function polymorphisms on adverse vascular events following neurointervention. PATIENTS AND METHODS: Consecutive patients undergoing neurointervention were prospectively recruited between 2010 and 2016. Patients were genotyped for the CYP2C9*2 and *3 loss-of-function polymorphisms. On the basis of possible genetic influence on antiplatelet response, ex vivo clopidogrel response was measured using the VerifyNow® P2Y12 Assay. The primary endpoint was the 90-day incidence of adverse vascular events including ischemic stroke. RESULTS: A total of 229 patients were included. The median age was 57 years (IQR: 49-64), and 158 (69.00%) were female. Eighty-one (35.37%) patients carried at least one CYP2C9 loss-of-function (LOF) allele. After adjustment for stroke risk factors, the 90-day incidence of ischemic stroke was significantly lower in the LOF group compared to the wild type group (1.23% vs 10.14%; ORadj = 0.16, 95% CI: 0.03-0.91; p = 0.04). CONCLUSIONS: Our results suggest protection against ischemic stroke in carriers of CYP2C9*2 or *3 polymorphisms undergoing neurointervention. Our findings warrant further studies to investigate the mechanisms by which CYP2C9 may influence the risk of ischemic stroke.


Assuntos
Isquemia Encefálica/genética , Isquemia Encefálica/prevenção & controle , Transtornos Cerebrovasculares/terapia , Citocromo P-450 CYP2C9/genética , Procedimentos Endovasculares/efeitos adversos , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/prevenção & controle , Idoso , Isquemia Encefálica/diagnóstico , Clopidogrel/farmacocinética , Citocromo P-450 CYP2C9/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inibidores da Agregação de Plaquetas/farmacocinética , Estudos Prospectivos , Fatores de Proteção , Queensland , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Fatores de Tempo , Resultado do Tratamento , Vitória
6.
J Stroke Cerebrovasc Dis ; 29(7): 104877, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32414579

RESUMO

OBJECTIVES: To assess the prevalence of high on-clopidogrel platelet reactivity (HCPR) in patients with ischaemic stroke or transient ischaemic attack (IS/TIA), their outcome and genetic basis of on-treatment response variability in IS/TIA patients. METHODS: We conducted a comprehensive search of PubMed and EMBASE from their inceptions to March 9, 2019. Studies that reported absolute numbers/percentages of HCRP at any time point after IS/TIA onset evaluated with any type of platelet function tests, clinical outcomes and genotyping data were included. RESULTS: Among 21 studies of 4312 IS/TIA patients treated with clopidogrel, the pooled prevalence of HCPR was 28% (95%CI: 24-32%; high heterogeneity: I2 = 88.2%, p < 0.001). Heterogeneity degree diminished across groups defined by the HCPR testing method. Clopidogrel non-responder IS/TIA patients had poorer outcome compared to responders (RR = 2.09, 95%CI: 1.61-2.70; p = 0.036; low heterogeneity across studies: I2 = 27.4%, p = 0.210). IS/TIA carriers of CYP2C19*2 or CYP2C19*3 loss of function alleles had a higher risk of HCPR compared to wild type (RR = 1.69, 95%CI: 1.47-1.95; p < 0.001; I2 = 0.01%, p = 0.475). CONCLUSIONS: This systematic review shows a high prevalence of clopidogrel resistance in IS/TIA and poor outcome in these patients. CYP2C19 polymorphisms may potentially influence clopidogrel resistance.


Assuntos
Plaquetas/efeitos dos fármacos , Clopidogrel/uso terapêutico , Resistência a Medicamentos , Ataque Isquêmico Transitório/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Plaquetas/metabolismo , Clopidogrel/efeitos adversos , Clopidogrel/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Resistência a Medicamentos/genética , Humanos , Ataque Isquêmico Transitório/sangue , Ataque Isquêmico Transitório/diagnóstico , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Polimorfismo Genético , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Resultado do Tratamento
7.
AAPS PharmSciTech ; 21(4): 118, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32318890

RESUMO

Pentoxifylline (PTX), an anti-hemorrhage drug used in the treatment of intermittent claudication, is extensively metabolized by the liver resulting in a reduction of the therapeutic levels within a short duration of time. Self-nano-emulsifying drug delivery system (SNEDDS) is well reported to enhance the bio-absorption of drugs by forming nano-sized globules upon contact with the biological fluids after oral administration. The present study aimed to formulate, characterize, and improve the oral bioavailability of PTX using SNEDDS. The formulated SNEDDS consisted of palm oil, Capmul® MCM, and Tween® 80 as oil, surfactant, and co-surfactant, respectively. The mixture design module under the umbrella of the design of experiments was used for the optimization of SNEDDS. The dynamic light-scattering technique was used to confirm the formation of nanoemulsion based on the globule size, in addition to the turbidity measurements. In vivo bioavailability studies were carried out on male Wistar rats. The pharmacokinetic parameters upon oral administration were calculated using the GastroPlus software. The optimized SNEDDS had a mean globule size of 165 nm with minimal turbidity in an aqueous medium. Bioavailability of PTX increased 1.5-folds (AUC = 1013.30 ng h/mL) as SNEDDS than the pure drug with an AUC of 673.10 ng h/mL. In conclusion, SNEDDS was seen to enhance the bioavailability of PTX and can be explored to effectively control the incidents of intermittent claudication.


Assuntos
Caprilatos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Emulsificantes/farmacocinética , Glicerídeos/farmacocinética , Nanopartículas/metabolismo , Óleo de Palmeira/farmacocinética , Pentoxifilina/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Caprilatos/administração & dosagem , Liberação Controlada de Fármacos , Emulsificantes/administração & dosagem , Glicerídeos/administração & dosagem , Masculino , Nanopartículas/administração & dosagem , Óleo de Palmeira/administração & dosagem , Tamanho da Partícula , Pentoxifilina/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/farmacocinética , Ratos , Ratos Wistar
8.
J Food Sci ; 85(4): 1285-1291, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32157685

RESUMO

Green tea is widely consumed as a beverage and/or dietary supplement worldwide, resulting in the difficulty to avoid the comedication with ticagrelor for acute coronary syndrome (ACS) patients receiving antiplatelet therapy. This study was designed to investigate the effect of the most abundant content in green tea, tea polyphenols on the oral and intravenous pharmacokinetics of ticagrelor in rats and its in vitro metabolism. Rats were orally treated with either saline or tea polyphenol extracts (TPEs) dissolved in saline once daily for 6 consecutive days. On day 6, after the last dose of saline or TPE, ticagrelor was given to the rats orally or intravenously. Plasma samples were collected for pharmacokinetic analysis. Human liver and intestinal microsomes were then used to investigate the inhibition by TPE, as well as its major constituents on the metabolism of ticagrelor to its two metabolites, AR-C124910XX and AR-C133913XX. Apparent kinetic constants and inhibition potency (IC50 ) for each metabolic pathway of each compound were estimated. Oral study indicated that exposure of ticagrelor and AR-C124910XX was significantly decreased after TPE administration, while no significant differences were observed in pharmacokinetic parameters after intravenous administration of ticagrelor. TPE effectively inhibited the metabolism of ticagrelor in vitro, with epigallocatechin-3-gallate as the major constituent responsible for the observed inhibitory effects in human liver microsomes and intestinal microsomes (IC50 = 4.23 ± 0.18 µM). Caution should be taken for ACS patients receiving ticagrelor therapy with daily drinking of green tea. PRACTICAL APPLICATION: Potential interactions between tea polyphenols and ticagrelor were revealed for the first time. Results can provide suggestions for clinicians to optimize the dosing of ticagrelor while they are in the face of ACS patients receiving ticagrelor therapy, who also take green tea or its related products in their daily life.


Assuntos
Microssomos Hepáticos/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Polifenóis/farmacocinética , Chá/química , Ticagrelor/farmacocinética , Adenosina/análogos & derivados , Administração Intravenosa , Administração Oral , Animais , Catequina/análogos & derivados , Masculino , Microssomos Hepáticos/metabolismo , Inibidores da Agregação de Plaquetas/administração & dosagem , Polifenóis/administração & dosagem , Polifenóis/química , Ratos , Ticagrelor/administração & dosagem , Ticagrelor/metabolismo
9.
JACC Cardiovasc Interv ; 13(5): 606-617, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32139218

RESUMO

OBJECTIVES: The aim of this study was to develop a risk score integrating cytochrome P450 2C19 loss-of-function genotypes with clinical risk factors influencing clopidogrel response that would allow the identification with more precision of subjects at risk for high platelet reactivity (HPR) and adverse clinical outcomes. BACKGROUND: Clopidogrel is the most broadly used platelet P2Y12 inhibitor. However, a considerable number of patients achieve inadequate platelet inhibition, with persistent HPR, an established marker of increased thrombotic risk, underscoring the need for tools to help identify these subjects. Although carriers of loss-of-function alleles of the cytochrome P450 2C19 enzyme have reduced clopidogrel metabolism leading to increased rates of HPR and thrombotic complications, this explains only a fraction of the pharmacodynamic response to clopidogrel, and a number of clinical factors have also been shown to have contributing roles. METHODS: Three prospective and independent studies were used to: 1) develop a risk score integrating genetic and clinical factors to identify patients with HPR while on clopidogrel; 2) investigate the external validity of the risk score; and 3) define clinical outcomes associated with the risk score in a cohort of patients with myocardial infarction treated with clopidogrel. RESULTS: A risk score ABCD-GENE (Age, Body Mass Index, Chronic Kidney Disease, Diabetes Mellitus, and Genotyping) was developed incorporating 5 independent predictors of HPR: 4 clinical (age >75 years, body mass index >30 kg/m2, chronic kidney disease [glomerular filtration rate <60 ml/min], and diabetes mellitus) and 1 genetic (cytochrome P450 2C19 loss-of-function alleles). The C-statistics for the score as an integer variable were 0.71 (95% confidence interval [CI]: 0.68 to 0.75) and 0.64 (95% CI: 0.60 to 0.67) in the pharmacodynamic derivation and validation cohorts, respectively. A cutoff score ≥10 was associated with the best sensitivity and specificity to identify HPR status. The C-statistics for the score were 0.67 (95% CI: 0.64 to 0.71) for all-cause death and 0.66 (95% CI: 0.63 to 0.69) for the composite of all-cause death, stroke, or myocardial infarction at 1 year. Using multiple models for adjustment, the ABCD-GENE score consistently and independently correlated with all-cause death, as well as with the composite of all-cause death, stroke, or myocardial infarction, both as a continuous variable and by using the cutoff of ≥10. The score did not predict bleeding. CONCLUSIONS: The ABCD-GENE score is a simple tool to identify patients with HPR on clopidogrel and who are at increased risk for adverse ischemic events, including mortality, following an acute myocardial infarction. In patients with a high ABCD-GENE score, long-term oral P2Y12 inhibitors other than clopidogrel should be considered.


Assuntos
Regras de Decisão Clínica , Clopidogrel/uso terapêutico , Trombose Coronária/prevenção & controle , Resistência a Medicamentos , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Fatores Etários , Idoso , Índice de Massa Corporal , Clopidogrel/efeitos adversos , Clopidogrel/farmacocinética , Trombose Coronária/diagnóstico por imagem , Trombose Coronária/etiologia , Trombose Coronária/mortalidade , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Bases de Dados Factuais , Diabetes Mellitus/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Obesidade/complicações , Obesidade/diagnóstico , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Valor Preditivo dos Testes , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
10.
JACC Cardiovasc Interv ; 13(5): 621-630, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32139220

RESUMO

OBJECTIVES: The aim of this study was to evaluate prospectively the clinical impact of routine transmission of CYP2C19 genotype in the management of acute ST-segment elevation myocardial infarction with primary percutaneous coronary intervention. BACKGROUND: Response to clopidogrel differs widely among patients, notably because of CYP2C19 genetic polymorphisms. METHODS: CYP2C19 genotype (6 alleles) was determined centrally and communicated within 4.1 ± 1.9 days of primary percutaneous coronary intervention in 1,445 patients with ST-segment elevation myocardial infarction recruited at 57 centers in France. CYP2C19 metabolic status was predicted from genotype and served to adjust thienopyridine treatment. The primary endpoint was differences in 12-month outcomes (death, myocardial infarction, and stent thrombosis) between patients with the wild-type genotype or gain-of-function allele (class 1, n = 1,118) and those with loss-of-function (LOF) alleles (class 2, n = 272) who received optimized thienopyridine treatment. RESULTS: Detection of LOF alleles resulted in adjustment of P2Y12 inhibition in 85% of patients, with significantly higher use of prasugrel or double-dose clopidogrel. The primary endpoint did not differ between class 1 and class 2 patients (3.31% vs. 3.04%, respectively; p = 0.82). In contrast, carriers of LOF alleles without treatment adjustment had significantly worse outcomes (15.6%; p < 0.05). Bleeding rates were not different between groups. CONCLUSIONS: In a real-world setting, a complete CYPC2C19 genotype can be mostly determined in <7 days using analysis of saliva deoxyribonucleic acid collected during the in-hospital phase among patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Genotype information led to stronger platelet inhibition treatment in the vast majority of LOF allele carriers and to similar clinical outcomes as in patients carrying the wild-type genotype or gain-of-function allele. (Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment [GIANT]; NCT01134380).


Assuntos
Clopidogrel/administração & dosagem , Trombose Coronária/prevenção & controle , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/administração & dosagem , Polimorfismo Genético , Cloridrato de Prasugrel/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Idoso , Tomada de Decisão Clínica , Clopidogrel/efeitos adversos , Clopidogrel/farmacocinética , Trombose Coronária/etiologia , Trombose Coronária/mortalidade , Citocromo P-450 CYP2C19/metabolismo , Resistência a Medicamentos , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Cloridrato de Prasugrel/efeitos adversos , Cloridrato de Prasugrel/farmacocinética , Medicina de Precisão , Estudos Prospectivos , Recidiva , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Fatores de Tempo , Resultado do Tratamento
12.
J Cardiovasc Pharmacol Ther ; 25(3): 201-211, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32027168

RESUMO

BACKGROUND AND OBJECTIVES: Clopidogrel is widely used after the percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and requires activation by cytochrome P450 (CYP), primarily CYP2C19. Patients with CYP2C19 loss-of-function alleles are at increased risk of major adverse cardiovascular events, while more expensive novel antiplatelet agents (ticagrelor and prasugrel) are unaffected by the CYP2C19 mutations. This systematic review aims to answer the question about whether overall evidence supports the genotype-guided selection of antiplatelet therapy as a cost-effective strategy in post-PCI ACS. METHODS: A systematic literature search of PubMed, EMBASE, EconLit, and PharmGKB was done to identify all the economic evaluations related to genotype-guided therapy compared to the universal use of antiplatelets in ACS patients. Quality of Health Economic Studies tool was used for quality assessment. RESULTS: The search identified 13 articles, where genotype-guided treatment was compared to universal clopidogrel, ticagrelor, and/or prasugrel. Six studies showed that genotype-guided therapy was cost-effective compared to universal clopidogrel, while 5 studies showed that it was dominant. One study specified that genotype-guided with ticagrelor is cost-effective only in both CYP2C19 intermediate and poor metabolizers. Genotype-guided therapy was dominant when compared to universal prasugrel, ticagrelor, or both in 5, 1, and 3 studies, respectively. Only 2 studies reported that universal ticagrelor was cost-effective compared to genotype-guided treatment. All the included articles had good quality. CONCLUSION: Based on current economic evaluations in the literature, implementing CYP2C19 genotype-guided therapy is a cost-effective approach in guiding the selection of medication in patients with ACS undergoing PCI.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/economia , Citocromo P-450 CYP2C19/genética , Custos de Medicamentos , Testes Farmacogenômicos/economia , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/economia , Inibidores da Agregação de Plaquetas/uso terapêutico , Medicina de Precisão/economia , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Tomada de Decisão Clínica , Clopidogrel/economia , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/metabolismo , Humanos , Seleção de Pacientes , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Cloridrato de Prasugrel/economia , Cloridrato de Prasugrel/uso terapêutico , Valor Preditivo dos Testes , Ticagrelor/economia , Ticagrelor/uso terapêutico , Resultado do Tratamento
13.
Eur J Clin Pharmacol ; 76(3): 419-430, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31897532

RESUMO

PURPOSE: Impaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin. METHODS: The study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n = 25) or rosuvastatin (n = 25) for at least 6 months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay. RESULTS: There were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P < 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P < 0.01). CONCLUSION: The CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.


Assuntos
Atorvastatina/uso terapêutico , Clopidogrel/farmacocinética , Clopidogrel/uso terapêutico , Sistema Enzimático do Citocromo P-450/genética , Polimorfismo Genético/genética , Rosuvastatina Cálcica/uso terapêutico , Alelos , Anticolesterolemiantes/uso terapêutico , Plaquetas/efeitos dos fármacos , Feminino , Genótipo , Humanos , Isoenzimas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Agregação de Plaquetas/uso terapêutico
14.
Eur J Clin Pharmacol ; 76(2): 257-265, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31773191

RESUMO

PURPOSE: Use of oral antiplatelets (OAPs) is essential for preventing thrombotic events in patients with acute coronary syndrome (ACS). Effects of clopidogrel, prasugrel, and ticagrelor may be enhanced due to pharmacodynamic interactions, but as CYP substrates, they are prone to pharmacokinetic interactions too. The aim was to study polypharmacy in ACS patients following hospital discharge. METHODS: This observational drug utilization study linked patient-level data from nationwide registers. The study population consisted of adult ACS patients discharged from Finnish hospitals in 2009-2013. Logistic regression was used to model the probability of drug-drug interactions with odd ratios for predefined predictors such as age, gender, and ACS type. RESULTS: In the cohort of 54,416 ACS patients, 91% of those treated with OAP received clopidogrel. Of clopidogrel-treated patients, 12% purchased warfarin at least once while on clopidogrel treatment. Old age, male sex, ST-elevation myocardial infarction as index event, and a history of previous ACS events were associated with an increased risk of warfarin-OAP interaction (p < 0.001 for all). Ibuprofen, and serotonergic drugs tramadol, citalopram, and escitalopram were the next most common drugs causing pharmacodynamic interactions. In general, concomitant use of drugs known to cause pharmacokinetic interactions was rare, but both esomeprazole and omeprazole were prescribed in more than 6% of clopidogrel-treated patients. CONCLUSIONS: Warfarin and ibuprofen were the most commonly used concomitant medications causing pharmacodynamic interactions and potentially increasing the risk of bleeding in OAP-treated patients. Esomeprazole and omeprazole were used in clopidogrel-treated patients although there are alternatives available for gastric protection.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Inibidores da Agregação de Plaquetas/administração & dosagem , Polimedicação , Administração Oral , Adulto , Idoso , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Clopidogrel/farmacocinética , Estudos de Coortes , Interações Medicamentosas , Feminino , Finlândia , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Cloridrato de Prasugrel/administração & dosagem , Cloridrato de Prasugrel/efeitos adversos , Cloridrato de Prasugrel/farmacocinética , Estudos Retrospectivos , Ticagrelor/administração & dosagem , Ticagrelor/efeitos adversos , Ticagrelor/farmacocinética
16.
Platelets ; 31(3): 329-336, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31037994

RESUMO

Although acid suppressants are needed to attenuate gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI), pharmacodynamic interaction between clopidogrel and proton pump inhibitor (PPI) can increase the risk of high platelet reactivity (HPR). We sought to evaluate serial changes of platelet measures and influence of rabeprazole on platelet measures. After 600-mg clopidogrel loading for elective PCI, clopidogrel-sensitive patients were recruited and randomly assigned to add rabeprazole of daily 20 mg (n = 40) or famotidine of daily 40 mg (n = 40). Platelet measures were performed with light transmittance aggregometry and VASP-P assay. Primary endpoint was 5 µM ADP-induced platelet aggregation (PA) at 30-day follow-up. HPR was defined as 5 µM ADP-induced PA > 46%. Baseline platelet measures did not differ significantly between the groups. The 30-day level of 5 µM ADP-induced PA was similar between the famotidine vs. rabeprazole group (30.0 ± 16.4% vs. 30.2 ± 13.9%, P= .956). In addition, other platelet measures were comparable between the groups. At 30-day follow-up, the incidence of HPR was similar between the famotidine and rabeprazole groups (20.5% vs. 15.4%; P= .555). In conclusion, adjunctive use of rabeprazole showed the similar antiplatelet effect even in clopidogrel-sensitive patients compared with adjunctive famotidine, which may support the similar effect of rabeprazole and famotidine on the antiplatelet effect of dual antiplatelet therapy with clopidogrel plus aspirin.


Assuntos
Clopidogrel/farmacocinética , Famotidina/farmacologia , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Bomba de Prótons/farmacologia , Rabeprazol/farmacologia , Idoso , Clopidogrel/efeitos adversos , Interações Medicamentosas , Famotidina/administração & dosagem , Famotidina/efeitos adversos , Feminino , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/tratamento farmacológico , Hemorragia Gastrointestinal/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/efeitos adversos , Testes de Função Plaquetária , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Rabeprazol/administração & dosagem , Rabeprazol/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
J Pharm Biomed Anal ; 179: 112955, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31866139

RESUMO

Vicagrel is a promising novel antiplatelet drug. However, the quantification of vicagrel in plasma is currently unavailable since it is liable to be hydrolyzed in plasma by esterases. In this study, an optimized strategy was developed and validated to stabilize vicagrel, 2-oxo-clopidogrel (thiolactone metabolite), and H4 (active thiol metabolite) before quantification of the analytes, such as addition of citric acid (for plasma acidification) and NaF (a non-specific esterase inhibitor) to inhibit esterase activity, immediate addition of a thiol-alkylating reagent MPB into blood samples to derivatize H4 for the formation of stable H4 derivative (i.e., MP-H4), use of the anticoagulant K2EDTA to minimize the conversion of 2-oxo-clopidogrel to H-endo, and keeping the analytes at 4 °C or on wet ice to minimize degradation of the analytes when processed and analyzed. The stability was measured as percent of each analyte remained in plasma samples after their storage for 4 h at 4 °C or in blood samples after 1 h at 4 °C. The results indicated that stability of vicagrel was increased significantly in stabilized plasma or blood samples compared with non-stabilized controls for rats and humans, respectively, and that the stability of 2-oxo-clopidogrel was increased to a certain extent. In contrast, MP-H4 formed was stable in plasma immediately after thorough mixture of MPB with blood. We conclude that the above strategy is useful for improving the stability of vicagrel, 2-oxo-clopidogrel, and H4 in rat or human plasma, and that vicagrel and its two major metabolites can be quantified accurately and simultaneously.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fenilacetatos/análise , Inibidores da Agregação de Plaquetas/análise , Espectrometria de Massas em Tandem/métodos , Tiofenos/análise , Animais , Feminino , Humanos , Masculino , Fenilacetatos/farmacocinética , Inibidores da Agregação de Plaquetas/farmacocinética , Ratos , Ratos Sprague-Dawley , Manejo de Espécimes , Temperatura , Tiofenos/farmacocinética , Fatores de Tempo
18.
Semin Thromb Hemost ; 46(1): 50-61, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31830766

RESUMO

Platelet transfusions aim to improve primary hemostasis and to prevent or treat bleeding in patients with reduced platelet numbers and/or platelet function. In this review, the authors address the role of platelet transfusions with a focus on perioperative medicine. They summarize different causes of thrombocytopenia in perioperative patients, describe general characteristics and potential adverse effects of different platelet concentrates, describe principles of perioperative platelet transfusion strategies, and highlight specific perioperative scenarios, for example, in patients undergoing antiplatelet therapy. The evidence for any transfusion threshold in perioperative patients based on platelet numbers is low. The evidence supporting prophylactic platelet transfusions in the perioperative setting is very low, and all recommended thresholds for preintervention platelet transfusions are based on weak evidence or expert opinion. Besides the platelet count, platelet function, additional risk factors for bleeding, and the pharmacokinetic properties of concomitant antiplatelet drugs are important criteria for the decision to transfuse or not to transfuse platelets. The few available prospective trials give at least a signal that a liberal platelet transfusion strategy might be associated with poorer outcomes compared with a restrictive platelet transfusion strategy in critically ill patients. Given the unknown risks for adverse outcomes, a therapeutic transfusion strategy during surgery (eventually guided by point of care testing in cardiac surgery, major liver surgery, and major trauma) may be most appropriate for interventions, in which intraoperative bleeding can be controlled until platelets are available, and during the postsurgery period.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Tomada de Decisão Clínica , Assistência Perioperatória , Inibidores da Agregação de Plaquetas , Transfusão de Plaquetas , Procedimentos Cirúrgicos Operatórios , Humanos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Agregação de Plaquetas/uso terapêutico , Contagem de Plaquetas
19.
Artigo em Inglês | MEDLINE | ID: mdl-31855569

RESUMO

Background The high prevalence of thrombotic abnormalities has become a major concern in the health sector. This is triggered by uncontrolled platelet aggregation, which causes complications and death. The problem becomes more complicated because of the undesirable side effects of the drugs currently in use, some of which have reportedly become resistant. This study aims to evaluate the potency of o-hydroxycinnamic acid derivatives (OCA1a-22a) and their pharmacokinetic properties and toxicity for them to be developed as new antiplatelet candidates. Methods In silico analysis of pharmacokinetics was carried out using pKCSM. Molecular docking of the compounds OCA 1a-22a was performed using the Molegro Virtual Docker. In silico evaluation of the potency of biological activity was done by measuring the bonding energy of each tested compound to the target receptor i.e. COX-1 and P2Y12, as the Moldock score (MDS). Results pKCSM analyses showed that more than 90% of OCA 1a-22a are absorbed through the intestine and distributed in plasma. Most tested compounds are not hepatotoxic, and none is mutagenic. An evaluation of the COX-1 receptor showed that OCA 2a-22a have lower binding energy compared to aspirin, which is the COX-1 inhibitor used today. So, it can be predicted that OCA 2-22a have stronger activity. Interactions with P2Y12 show lower MDS than aspirin, but slightly higher than ibuprofen, which is the standard ligand. Conclusions ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile prediction shows that OCA 1a-22a have the potential to be developed as oral preparations. OCA 1a-22a have strong potential to interact with COX-1 and P2Y12 receptors, so they are prospective anti-platelet candidates.


Assuntos
Ácidos Cumáricos/farmacologia , Ácidos Cumáricos/farmacocinética , Ciclo-Oxigenase 1/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Simulação de Acoplamento Molecular , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Agregação de Plaquetas/farmacologia
20.
Value Health ; 22(11): 1231-1239, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31708059

RESUMO

BACKGROUND: For patients undergoing percutaneous coronary intervention, gene-drug associations exist relevant to first-line treatment options-antiplatelet agent, clopidogrel, and pain medication, tramadol. Knowledge of genotype information may allow for avoidance of adverse drug events during critical clinical windows. OBJECTIVE: This evaluation estimated cost-effectiveness associated with a multi-gene panel pre-emptively testing two genes providing CYP2C19 genotype-guided strategy for antiplatelet therapy, with CYP2D6 genotype-guided pain management, compared to single gene test for CYP2C19 with random assignment for pain treatment, and to no testing (empiric clopidogrel with random assignment for pain treatment). METHODS: Decision analysis modeling was used to project costs from a payer perspective and patient quality-adjusted life years (QALYs) from the three strategies. The model captured composite risks of major adverse cardiovascular events and pain therapy-related adverse drug events and associated utility estimates. We conducted sensitivity analyses to assess influential input parameters. RESULTS: Over 15 months, multi-gene testing was least costly and yielded more QALYs compared to both single gene and no testing; total incremental costs were $1646 lower with incremental gains of 0.04 QALYs for multi-gene compared with single gene and $11 368 lower with 0.17 QALY gains compared to no test. Base case analyses revealed multi gene was dominant compared to both single gene and no test, as it demonstrated cost savings with increased QALYs. CONCLUSIONS: For these patients, a multi-gene-guided strategy yields a favorable incremental cost-effectiveness ratio compared to the other two treatment strategies. Pre-emptively ascertaining additional gene-drug pair information can inform clinical and economic decision-making at the point of care.


Assuntos
Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Testes Genéticos/economia , Testes Genéticos/métodos , Intervenção Coronária Percutânea/métodos , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacocinética , Clopidogrel/efeitos adversos , Clopidogrel/farmacocinética , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Humanos , Modelos Econômicos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Anos de Vida Ajustados por Qualidade de Vida , Tramadol/efeitos adversos , Tramadol/farmacocinética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...