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1.
J Invasive Cardiol ; 31(9): 265-271, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31478892

RESUMO

OBJECTIVE: In this secondary analysis of the PACIFY randomized trial, we assessed whether dose and timing of fentanyl have implications for the pharmacokinetics and pharmacodynamics of ticagrelor loading during percutaneous coronary intervention (PCI). METHODS: Among 212 patients undergoing clinically indicated coronary angiography, a total of 70 required PCI and received 180 mg oral ticagrelor. Of these, thirty-two patients received no fentanyl and 38 received fentanyl (with variability in the timing of administration and cumulative dose among those randomized to fentanyl, given that both were provided at the interventional cardiologist's discretion). A time-weighted cumulative fentanyl exposure variable was calculated based on total dose of fentanyl and proximity in time of fentanyl administrations to the ticagrelor load. Patients were stratified based on receiving above or below the median time-weighted cumulative dose. Outcomes included ticagrelor concentrations by mass spectrometry (24-hour area under the curve) and platelet function measured using both VerifyNow platelet reactivity units (PRU) and light-transmission aggregometry (LTA). RESULTS: Unadjusted ticagrelor 24-hour area under the curve was significantly lower across the categories of increasing fentanyl exposure (P=.02). In adjusted regression models, this difference only remained when comparing the no-fentanyl group with the time-weighted cumulative dose above the median group (P=.04). Similarly, with the no-fentanyl group as the reference, adjusted models testing 2-hour PRU and LTA values demonstrated significant differences (with less platelet inhibition for both tests) only among those with time-weighted cumulative fentanyl exposures above the median value (5.1 µg/min). CONCLUSIONS: We have previously shown that fentanyl slows absorption of oral ticagrelor, attenuating its effect on platelet inhibition. We now demonstrate this mechanism appears to be dose- and time-dependent.


Assuntos
Doença da Artéria Coronariana/terapia , Fentanila/administração & dosagem , Intervenção Coronária Percutânea/métodos , Ticagrelor/farmacocinética , Administração Oral , Idoso , Anestésicos Intravenosos/administração & dosagem , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/cirurgia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/cirurgia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/farmacocinética , Testes de Função Plaquetária , Ticagrelor/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
2.
Interv Cardiol Clin ; 8(4): 321-340, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31445718

RESUMO

Several platelet P2Y12 inhibiting agents, both oral and intravenous, are available for clinical use. The oral P2Y12 inhibitors comprise clopidogrel, prasugrel, and ticagrelor. Cangrelor is the only intravenous P2Y12 inhibitor. Numerous pharmacodynamic studies have been performed to assess the impact of P2Y12 inhibitor switching on platelet reactivity profiles and to define the optimal strategy if switching is needed, with the goal of minimizing the risk of having inadequate platelet inhibition due to potential drug-drug interactions occurring during the drug overlap phase. This article provides an overview of pharmacodynamic studies assessing switching between P2Y12 inhibitors and recommendations on switching modalities based on these findings.


Assuntos
Isquemia Miocárdica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/farmacocinética , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Substituição de Medicamentos , Humanos , Isquemia Miocárdica/metabolismo
3.
Am J Vet Res ; 80(7): 702-708, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31246127

RESUMO

OBJECTIVE: To determine the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl metabolite (M-I) after IV administration of increasing doses of PTX to sheep. ANIMALS: 6 healthy adult Merino sheep. PROCEDURES: Each sheep received 10-, 20-, and 40-mg/kg doses of PTX, IV, with a 15-day washout period between doses. Blood samples were collected before and at predetermined times after administration of each dose to determine plasma PTX and M-I concentrations by high-performance liquid chromatography. Pharmacokinetic parameters for PTX and M-I were estimated by noncompartmental analysis. RESULTS: No adverse effects were observed after administration of the 10- and 20-mg/kg doses. Following administration of the 40-mg/kg dose, all sheep developed tachycardia and hypersalivation and appeared agitated for approximately 4 hours. Plasma PTX concentrations considered therapeutic in other species were achieved in all sheep after administration of all 3 doses. Pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner. For PTX, the mean area under the concentration-time curve (AUC), elimination half-life, and volume of distribution increased with dose and ranged from 15.67 to 94.66 h·µg/mL, 0.68 to 0.91 hours, and 0.55 to 0.66 L/kg, respectively, whereas clearance decreased with dose and ranged from 0.42 to 0.64 L/h/kg. The mean ratio of the AUC for M-I to AUC for PTX ranged from 0.38 to 0.46. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner in healthy sheep. Further studies are warranted to determine the therapeutic threshold and optimal dosage for PTX in sheep.


Assuntos
Pentoxifilina/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Ovinos/metabolismo , Administração Intravenosa/veterinária , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/veterinária , Estudos Cross-Over , Relação Dose-Resposta a Droga , Meia-Vida , Pentoxifilina/farmacocinética , Inibidores da Agregação de Plaquetas/farmacocinética , Distribuição Aleatória
4.
Clin Drug Investig ; 39(8): 765-773, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31140114

RESUMO

BACKGROUND AND OBJECTIVE: Ticagrelor is a P2Y12 receptor inhibitor approved as an antiplatelet drug for patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor is also being investigated for the reduction of vaso-occlusive crises in pediatric patients with sickle cell disease. A pediatric formulation suitable for this age range was developed; the development strategy is described. Primary objectives were determining the relative bioavailability of ticagrelor pediatric tablets and granules for oral suspension to the adult immediate-release tablet, and the pediatric tablets taken whole and dispersed/suspended in water to the granules for oral suspension. Bioequivalence between the pediatric tablet taken whole or suspended in water was also assessed. Secondary objectives were comparing the formulations' safety and tolerability. METHODS: We conducted a randomized, four-period, cross-over, single-dose study. Pharmacokinetic parameters were assessed for ticagrelor and its active metabolite AR-C124910XX. Bioequivalence was concluded if the 90% confidence intervals of the maximum plasma concentration and area under the plasma concentration-time curve ratios were contained completely within the 80.00-125.00% limits for ticagrelor/AR-C124910XX. RESULTS: Forty-four healthy adults (95% white; 57% male) were included. Similar bioavailability of ticagrelor (and AR-C124910XX) was demonstrated for all comparisons tested. Ticagrelor pediatric tablets taken whole were bioequivalent to pediatric tablets suspended in water. The plasma concentration-time profiles for ticagrelor and AR-C124910XX were similar, showing rapid ticagrelor absorption and AR-C124910XX formation. All formulations were well tolerated. CONCLUSION: Similar bioavailability of a new pediatric dispersible tablet formulation of ticagrelor for use across a wide age range of pediatric patients was demonstrated compared with other oral ticagrelor formulations. CLINICALTRIALS. GOV IDENTIFIER: NCT03126695. EUDRACT: 2017-000371-93.


Assuntos
Inibidores da Agregação de Plaquetas/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Comprimidos , Ticagrelor/farmacocinética , Adenosina/análogos & derivados , Adolescente , Disponibilidade Biológica , Criança , Estudos Cross-Over , Feminino , Humanos , Masculino , Inibidores da Agregação de Plaquetas/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Equivalência Terapêutica , Ticagrelor/administração & dosagem
5.
Am J Obstet Gynecol ; 221(3): 255.e1-255.e9, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31051121

RESUMO

BACKGROUND: The benefit of aspirin in preventing preeclampsia is well established; however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing, and preparation of aspirin. OBJECTIVE: We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid, in pregnant women and nonpregnant women, and to examine the effect of dose (100 mg vs 150 mg), preparation (enteric coated vs non-enteric-coated), and chronotherapy of aspirin (morning vs evening) between the 2 groups. MATERIALS AND METHODS: Twelve high-risk pregnant women and 3 nonpregnant women were enrolled in this study. Pregnant women were in 1 of 4 groups (100 mg enteric coated, 100 mg non-enteric-coated, 150 mg non-enteric-coated morning dosing, and 150 mg non-enteric-coated evening dosing), whereas nonpregnant women undertook each of the 4 dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (before ingestion) and at 1, 2, 4, 6, 12, and 24 hours after ingestion of aspirin. Plasma obtained was analyzed for salicylic acid levels by means of liquid chromatography-mass spectrometry. Pharmacokinetic values of area under the curve from time point 0 to 24 hours point of maximum concentration, time of maximum concentration, volume of distribution, clearance, and elimination half-life were analyzed for statistical significance with SPSS v25 software. RESULTS: Pregnant women had a 40% ± 4% reduction in area under the curve from time point 0 to 24 hours (P < .01) and 29% ± 3% reduction in point of maximum concentration (P < .01) with a 44% ± 8% increase in clearance (P < .01) in comparison to that in nonpregnant women when 100 mg aspirin was administered. The reduction in the area under the curve from time point 0 to 24 hours, however, was minimized with the use of 150 mg aspirin in pregnant women, with which the area under the curve from time point 0 to 24 hours was closer to that achieved with the use of 100 mg aspirin in nonpregnant women. There was a 4-hour delay (P < .01) in the time of maximum concentration, a 47% ± 3% reduction in point of maximum concentration (P < .01) and a 48% ± 1% increase in volume of distribution (P < .01) with the use of 100 mg enteric-coated aspirin compared to non-enteric-coated aspirin, with no difference in the overall area under the curve. There was no difference in the pharmacokinetics of aspirin between morning and evening dosing. CONCLUSION: There is a reduction in the total drug metabolite concentration of aspirin in pregnancy, and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy, with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric-coated and non-enteric-coated aspirin and between morning and evening dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings.


Assuntos
Aspirina/farmacocinética , Cronoterapia Farmacológica , Inibidores da Agregação de Plaquetas/farmacocinética , Gravidez/fisiologia , Adulto , Área Sob a Curva , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Feminino , Humanos , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/uso terapêutico , Pré-Eclâmpsia/prevenção & controle , Comprimidos com Revestimento Entérico
6.
Colloids Surf B Biointerfaces ; 180: 127-140, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31035056

RESUMO

Resveratrol (RES), also known as 3,5,4'-trihydroxystilbene, is a polyphenolic phytoalexin that has been widely researched in the past decade due to its recognized numerous biological activities. Despite the potential benefits of RES, its effective use is limited due to its poor solubility, photosensitivity and rapid metabolism, which strongly undermine RES bioavailability and bioactivity. Thereby, recently, nanotechnology appeared as a potential strategy to circumvent RES physicochemical and pharmacokinetics constrains. However, only few studies have addressed the crucial in vivo suitability of the developed delivery systems to improve RES efficacy. Facing this scenario, in the present review, it is intended to present and discuss the in vivo resveratrol bioavailability and bioactivity, following its encapsulation or conjugation in nanotechnology-based carriers, contemplating their pharmacokinetics effectiveness.


Assuntos
Antineoplásicos/farmacocinética , Antioxidantes/farmacocinética , Cardiotônicos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Fármacos Neuroprotetores/farmacocinética , Inibidores da Agregação de Plaquetas/farmacocinética , Resveratrol/farmacocinética , Animais , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Disponibilidade Biológica , Cardiotônicos/farmacologia , Composição de Medicamentos/métodos , Humanos , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanotecnologia/métodos , Fármacos Neuroprotetores/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Polímeros/síntese química , Resveratrol/farmacologia , Solubilidade
7.
Am J Vet Res ; 80(5): 505-512, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31034271

RESUMO

OBJECTIVE: To determine pharmacokinetics and pharmacodynamics after oral administration of a single dose of clopidogrel to horses. ANIMALS: 6 healthy adult horses. PROCEDURES: Blood samples were collected before and at various times up to 24 hours after oral administration of clopidogrel (2 mg/kg). Reactivity of platelets from each blood sample was determined by optical aggregometry and phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Concentrations of clopidogrel and the clopidogrel active metabolite derivative (CAMD) were measured in each blood sample by use of liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were determined with a noncompartmental model. RESULTS: Compared with results for preadministration samples, platelet aggregation in response to 12.5µM ADP decreased significantly within 4 hours after clopidogrel administration for 5 of 6 horses. After 24 hours, platelet aggregation was identical to that measured before administration. Platelet aggregation in response to 25µM ADP was identical between samples obtained before and after administration. Phosphorylation of VASP in response to ADP (20µM) and prostaglandin E1 (3.3µM) was also unchanged by administration of clopidogrel. Time to maximum concentration of clopidogrel and CAMD was 0.54 and 0.71 hours, respectively, and calculated terminal-phase half-life of clopidogrel and CAMD was 1.81 and 0.97 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Clopidogrel or CAMD caused competitive inhibition of ADP-induced platelet aggregation during the first 24 hours after clopidogrel administration. Because CAMD was rapidly eliminated from horses, clopidogrel administration may be needed more frequently than in other species in which clopidogrel causes irreversible platelet inhibition. (Am J Vet Res 2019;80:505-512).


Assuntos
Plaquetas/efeitos dos fármacos , Clopidogrel/farmacocinética , Cavalos/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Difosfato de Adenosina/farmacologia , Administração Oral , Animais , Área Sob a Curva , Plaquetas/metabolismo , Moléculas de Adesão Celular/metabolismo , Clopidogrel/administração & dosagem , Feminino , Masculino , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/administração & dosagem
8.
Arterioscler Thromb Vasc Biol ; 39(5): 956-964, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31017822

RESUMO

Objective- ACT017 is a novel, first in class, therapeutic antibody to platelet GPVI (glycoprotein VI) with potent and selective antiplatelet effects. This first-in-human, randomized, placebo-controlled phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT017 in healthy subjects. Approach and Results- Six cohorts of 8 healthy male and female subjects each received ascending single doses of ACT017 (n=6) or placebo (n=2) as a 6-hour intravenous infusion, with » of the total dose administered within 15 minutes and the rest of the dose (¾ of the total dose) administered within 5 hours and 45 minutes. The 6 investigated doses ranged from 62.5 to 2000 mg. All doses of ACT017 were well tolerated, and no serious adverse events occurred during the study. None of the subjects reported an infusion site reaction. Template bleeding time was not affected in a clinically significant manner by any of the ACT017 doses. Plasma concentrations, determined by liquid chromatography-tandem mass spectrometry, increased linearly with the dose received as were the established pharmacokinetics values. There was no change in the platelet count, platelet GPVI expression assessed by flow cytometry, or plasma levels of soluble GPVI assessed by ELISA. In contrast, administration of ACT017 inhibited collagen-induced platelet aggregation measured by light transmission aggregometry on platelet-rich plasma, and the extent and duration of the effect were dose-dependent. Conclusions- The novel antiplatelet agent ACT017 has consistent pharmacokinetic/pharmacodynamic properties and favorable safety and tolerability profiles warranting further clinical development.


Assuntos
Tolerância a Medicamentos , Segurança do Paciente , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/farmacocinética , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável
10.
J Ethnopharmacol ; 235: 100-110, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30710735

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Dual antiplatelet therapy (DAPT) with aspirin (ASA) and clopidogrel (CLP) has been consistently shown clinical effectiveness in patients with coronary artery disease. According to the literature, four traditional Chinese medicine (TCM) herbs effective for prevention cardiovascular diseases, namely Radix Salvia Miltiorrhiza (Red sage root, Danshen), Radix Pueraria Lobata (Kudzu root, Gegen), Radix Angelica Sinensis (Angelica root, Danggui), and Rhizoma Ligusticum chuanxiong (Szehuan lovage rhizome, Chuanxiong), are of high potential to be co-administered during DAPT. Since all these herbs are blood vitalizing medicines and can promote blood circulation and eliminate blood stasis, it was hypothesized that they may potentially alter the clinical outcomes of DAPT with clopidogrel and aspirin. AIM OF STUDY: The current study is proposed aiming to preliminarily evaluate the impact of these four commonly used Chinese medicinal herbs on the pharmacokinetics and pharmacodynamics of the combination therapy with clopidogrel and aspirin and its relevant outcomes and mechanisms. MATERIALS AND METHODS: In order to mimic the standard dosing regimen for DAPT in human, various Sprague-Dawley rats treatment groups were received a bolus oral dose of DAPT on day 1 followed by DAPT for consecutive 13 days in absence and presence of orally co-administered four TCM herbs (Danshen, Gegen, Danggui and Chuanxiong) at their low and high doses. On day 14, serial blood samples were collected after dosing to obtain the plasma concentrations of ASA, CLP and their corresponding metabolites by LC/MS/MS. At the end of last blood sampling point of each rat, about 4.5 ml of whole blood were collected to estimate the prothrombin time from each treatment groups. After all the blood sampling, the rats were sacrificed followed by collecting their livers for evaluations of enzyme activities and expressions in the related liver microsome preparations and stomach tissues for evaluations of their potential ulcer index. In addition, gene expression and protein levels of related biomarkers (COX-1, COX-2, P2Y12) in rat livers were measured by RT-PCR and Western blot, respectively, and compared among different treatment groups. RESULTS: Co-administration of Gegen and Danggui significantly altered the pharmacokinetics of ASA and CLP in DAPT with increased systemic exposure of ASA and CLP respectively. Although minimal impact on aspirin esterase activity for all co-administered herbs, significant inhibition on rCyp2c11 and carboxylesterase activities were observed for DAPT with Danshen, Gegen and Danggui co-treatment. In addition, significantly longer PT were found in all DAPT treatment groups. However, a trend of decrease in PT of DAPT in presence of Gegen, Danggui and Chuanxiong was noticed. Nevertheless, all the treatments did not cause detectable changes in COX and P2Y12 mRNA and protein expressions. CONCLUSION: Among the four studied TCMs, it was demonstrated that co-administration of Gegen and Danggui could lead to altered pharmacokinetics of DAPT with significant inhibition on rCyp2c11 and carboxylesterase activities. Although Gegen, Danggui and Chuanxiong might potentially offset the anticoagulant activity of DAPT, the overall pharmacodynamics outcome was not considered to be harmful due to lack of risk in bleeding, which warrant further verification for its clinical impact.


Assuntos
Aspirina/administração & dosagem , Clopidogrel/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Inibidores da Agregação de Plaquetas/administração & dosagem , Animais , Aspirina/farmacocinética , Aspirina/farmacologia , Biomarcadores/metabolismo , Western Blotting , Cromatografia Líquida , Clopidogrel/farmacocinética , Clopidogrel/farmacologia , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Agregação de Plaquetas/farmacologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas em Tandem
11.
Arterioscler Thromb Vasc Biol ; 39(4): 647-652, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30760018

RESUMO

Current guidelines recommend dual antiplatelet therapy-a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin-for patients undergoing percutaneous coronary intervention. Although clopidogrel is the most commonly prescribed P2Y12 inhibitor, it is associated with an increased risk of major adverse cardiovascular events in patients carrying loss-of-function CYP2C19 alleles. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Nevertheless, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial because of the lack of large randomized controlled trials evaluating this strategy. Emerging results from registry studies and small clinical trials of CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention offer new insight and contribute to a growing evidence base that supports the clinical utility of a genotyping strategy to personalize antiplatelet therapy selection.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Síndrome Coronariana Aguda/genética , Alelos , Biotransformação/genética , Ensaios Clínicos como Assunto , Clopidogrel/farmacocinética , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/sangue , Citocromo P-450 CYP2C19/metabolismo , Genótipo , Humanos , Mutação com Perda de Função , Metanálise como Assunto , Seleção de Pacientes , Inibidores da Agregação de Plaquetas/uso terapêutico , Guias de Prática Clínica como Assunto , Medicina de Precisão , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Risco
12.
Crit Care Nurs Clin North Am ; 31(1): 15-30, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30736932

RESUMO

This update presents evidence for new antiplatelet therapies including modified P2Y12 inhibitors and a new class of thromboxane antagonists. Discussed are emerging data on established antihyperlipidemic medications that support an additional antiplatelet effect. Current information about the effectiveness of several bleeding reversal agents is discussed, and the concept of personalized antiplatelet therapy, wherein selection of an antiplatelet therapy is based on genetic factors or laboratory testing that predict response to therapy and risk of adverse effects. Finally, future drug targets are introduced and drug interactions that can be leveraged to design more effective and safe antiplatelet therapies are described.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Comportamento de Redução do Risco , Enfermagem de Cuidados Críticos , Humanos , Inibidores da Agregação de Plaquetas/farmacocinética
13.
Drug Dev Ind Pharm ; 45(6): 959-967, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30767579

RESUMO

In this work, aspirin (ASP) sustained granules were prepared using micro-crystal coating and hot-melt granulation, respectively. In the process of micro-crystal coating, PVP was used to form the isolation layer and then coated with either Eudragit RS/RL30D or ethyl cellulose (EC) as sustained-release layers to prepare sustained granules (the granules from this method were denoted m-cG). And in the process of hot-melt granulation, the granules were obtained with stearyl alcohol as a binder and EC as matrix material to prepare sustained granules (the granules were denoted h-mG). The in vitro release of ASP sustained-release granules was investigated by dissolution apparatus and the stability of the granules was studied. Since both methods effectively prevented the hydrolysis of ASP, the sustained granules by micro-crystal coating and hot-melt granulation were stable. However, there was a clear difference in the in vitro release of h-mG and m-cG. The h-mG was completely released in 4 h, while the m-cG with EC as sustained-release layer released 80% in 24 h and the m-cG with the Eudragit RS/RL 30 D as sustained-release layer released completely in 5 h. The results showed that micro-crystal coating was more suitable for the preparation of ASP sustained granules, and the granules with EC as sustained layer could achieve a better sustained-release effect.


Assuntos
Aspirina/farmacocinética , Composição de Medicamentos/métodos , Excipientes/química , Inibidores da Agregação de Plaquetas/farmacocinética , Aspirina/administração & dosagem , Aspirina/química , Celulose/análogos & derivados , Celulose/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/química , Solubilidade , Acidente Vascular Cerebral/prevenção & controle
14.
Arch Cardiovasc Dis ; 112(3): 199-216, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30621917

RESUMO

The French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Haemostasis and Thrombosis (GFHT), in collaboration with the French Society for Anaesthesia and Intensive Care (SFAR), drafted up-to-date proposals on the management of antiplatelet therapy for non-elective invasive procedures or bleeding complications. The proposals were discussed and validated by a vote; all proposals could be assigned with a high strength. Management of oral antiplatelet agents in emergency settings requires knowledge of their pharmacokinetic and pharmacodynamic parameters, evaluation of the degree of alteration of haemostatic competence and the associated bleeding risk. Platelet function testing may be considered. When antiplatelet agent-induced bleeding risk may worsen the prognosis, measures should be taken to neutralize antiplatelet therapy, by considering not only the efficacy of available means (which can be limited for prasugrel and even more for ticagrelor), but also the risks that these means expose the patient to. The measures include platelet transfusion at the appropriate dose and haemostatic agents (tranexamic acid; recombinant activated factor VII for ticagrelor). When possible, postponing non-elective invasive procedures at least for a few hours until the elimination of the active compound (which could compromise the effect of transfused platelets) or, if possible, for a few days (reduction of the effect of antiplatelet agents) should be considered.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Assistência Perioperatória/métodos , Inibidores da Agregação de Plaquetas/administração & dosagem , Hemorragia Pós-Operatória/prevenção & controle , Administração Oral , Consenso , Esquema de Medicação , Monitoramento de Medicamentos/normas , Humanos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Testes de Função Plaquetária/normas , Transfusão de Plaquetas , Hemorragia Pós-Operatória/sangue , Hemorragia Pós-Operatória/induzido quimicamente , Medição de Risco , Fatores de Risco , Sociedades Médicas/normas , Resultado do Tratamento
15.
Presse Med ; 48(1 Pt 1): 34-45, 2019 Jan.
Artigo em Francês | MEDLINE | ID: mdl-30665790

RESUMO

Indications for aspirin during pregnancy are a matter of debate and there is a recent trend to an extended prescription and an overuse of aspirin in pregnancy. Aspirin is efficient in secondary prevention of preeclampsia essentially in patients with a personal history of preeclampsia. The effect of aspirin on platelet aggregation and on the TXA2/PGI2 balance is dose-dependent. The optimum dosage, from 75mg/day to 150mg/day, needs to be determined. Fetal safety data at 150mg/day are still limited. The efficacy of aspirin seems to be subject to a chronobiological effect. It is recommended to prescribe an evening or bedtime intake. Aspirin, in primary prevention of preeclampsia, given to high-risk patients identified in the first trimester by screening tests, seems to reduce the occurrence of early-onset preeclampsia. Nevertheless, there are insufficient data for the implementation of such screening procedures in practice.


Assuntos
Aspirina/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Pré-Eclâmpsia/prevenção & controle , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Aspirina/farmacocinética , Fenômenos Cronobiológicos , Contraindicações de Medicamentos , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/efeitos adversos , Inibidores de Ciclo-Oxigenase/farmacocinética , Inibidores de Ciclo-Oxigenase/uso terapêutico , Uso de Medicamentos , Diagnóstico Precoce , Feminino , Doenças Fetais/induzido quimicamente , França/epidemiologia , Humanos , Programas de Rastreamento , Metanálise como Assunto , Placenta/metabolismo , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/epidemiologia , Gravidez , Complicações na Gravidez/induzido quimicamente , Primeiro Trimestre da Gravidez , Prevenção Primária , Antagonistas de Prostaglandina/administração & dosagem , Antagonistas de Prostaglandina/efeitos adversos , Antagonistas de Prostaglandina/farmacocinética , Antagonistas de Prostaglandina/uso terapêutico , Fatores de Risco , Prevenção Secundária
16.
J Am Heart Assoc ; 8(2): e010152, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30636504

RESUMO

Background Morphine administration is a strong predictor of delayed onset of action of orally administered ticagrelor in patients with ST-segment-elevation myocardial infarction, likely because of impaired gastrointestinal motility. The aim of this study was to evaluate whether the peripheral opioid antagonist methylnaltrexone could improve pharmacodynamics and pharmacokinetics of orally administered ticagrelor in patients with ST-segment-elevation myocardial infarction receiving morphine. Methods and Results The MOVEMENT (Methylnaltrexone to Improve Platelet Inhibition of Ticagrelor in Morphine-Treated Patients With ST-Segment Elevation Myocardial Infarction) trial was a multicenter, prospective, randomized, controlled trial in patients with ST-segment-elevation myocardial infarction treated with morphine and ticagrelor. Upon arrival to the catheterization laboratory, patients were randomized to a blinded intravenous injection of either methylnaltrexone (8 or 12 mg according to weight) or 0.9% sodium chloride. The proportion of patients with high on-treatment platelet reactivity and plasma concentrations of ticagrelor and AR -C124910XX were assessed at baseline (arrival in the catheterization laboratory) and 1 and 2 hours later. A total of 82 patients received either methylnaltrexone (n=43) or placebo (n=39). Median (interquartile range) time from ticagrelor administration to randomization was 41 (31-50) versus 45.5 (37-60) minutes ( P=0.16). Intravenous methylnaltrexone administration did not significantly affect prevalence of high on-treatment platelet reactivity at 2 hours after inclusion, the primary end point, when compared with placebo (54% versus 51%, P=0.84). Plasma concentrations of ticagrelor and its active metabolite, the prespecified secondary end points, did not differ significantly between the groups over time. There was no significant difference in patient self-estimated pain between the groups. Conclusions Methylnaltrexone did not significantly improve platelet reactivity or plasma concentrations of orally administered ticagrelor in patients with ST-segment-elevation myocardial infarction receiving morphine. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02942550.


Assuntos
Plaquetas/metabolismo , Morfina/uso terapêutico , Naloxona/análogos & derivados , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Ticagrelor/farmacocinética , Administração Oral , Idoso , Analgésicos Opioides/uso terapêutico , Plaquetas/efeitos dos fármacos , Cateterismo Cardíaco , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Naloxona/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/farmacocinética , Testes de Função Plaquetária , Estudos Prospectivos , Compostos de Amônio Quaternário/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Método Simples-Cego , Ticagrelor/administração & dosagem , Resultado do Tratamento
17.
Int J Pharm ; 558: 284-290, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30641181

RESUMO

Commercially available cilostazol (CIL) tablet releases drug immediately and is given twice a day as an antiplatelet and vasodilatory agent. However, clinical usefulness of immediate release (IR) preparation is limited due to its extremely poor water solubility and the difficulty in sustaining the blood concentration, resulting in unwanted side effects such as headaches, pyknocardia and heavy-headed symptoms. To achieve once a day dosage form with enhanced solubility and controlled release, double controlled release CIL matrix tablets (DCRT) were designed by modulating a sol-gel process of binary polymeric blends of a pH-independent hydroxylpropylmethylcellulose (HPMC) and a pH-dependent polymer (carbomer) assisted with anionic surfactant (sodium lauryl sulfate, SLS). The release profiles of the DCRT were varied according to the ratio of the two polymers. This DCRT enhanced dissolution rate of CIL in a controlled manner due to the sol-gel and erosion process of HPMC, and SLS-driven modulation of charged carbomer via neutralization and micellar interaction. The near-infrared (NIR) chemical imaging and gravimetric behaviors of DCRT clearly showed dynamic modulation of CIL during the swelling and hydration process. Furthermore, the plasma concentration of CIL in DCRT was highly improved and sustained in beagle dogs in a controlled manner.


Assuntos
Cilostazol/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Vasodilatadores/administração & dosagem , Animais , Disponibilidade Biológica , Cilostazol/química , Cilostazol/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Cães , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacocinética , Polímeros/administração & dosagem , Polímeros/química , Polímeros/farmacocinética , Dodecilsulfato de Sódio/administração & dosagem , Dodecilsulfato de Sódio/química , Dodecilsulfato de Sódio/farmacocinética , Solubilidade , Tensoativos/administração & dosagem , Tensoativos/química , Tensoativos/farmacocinética , Vasodilatadores/química , Vasodilatadores/farmacocinética
18.
Vascul Pharmacol ; 115: 1-12, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30685502

RESUMO

Platelet P2Y12 receptors play a key role in platelet activation and thrombus formation. Accordingly, P2Y12 receptor antagonists are the cornerstone of secondary prevention of atherothrombotic events in patients undergoing percutaneous coronary intervention (PCI). The availability of different oral P2Y12 antagonists (clopidogrel, prasugrel, ticagrelor) along with the introduction of the first intravenous P2Y12 antagonist cangrelor offer an opportunity to individualize antiplatelet therapy according to the changing clinical setting. The recent International Expert Consensus provided the first recommendations on switching between the P2Y12 antagonists. While the consensus greatly helps to guide switching between P2Y12 antagonists, a number of controversial clinical scenarios remain where the evidence regarding the optimal switch strategy is scarce. In such clinical scenarios, understanding of the (i) pharmacological properties of P2Y12 antagonists, (ii) recent evidence from pharmacodynamics studies, clinical trials and registries, and (iii) factors affecting the efficacy and safety of the P2Y12 antagonists, all summarized below, are crucial to choose the optimal switch strategy.


Assuntos
Doença das Coronárias/terapia , Substituição de Medicamentos , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Animais , Tomada de Decisão Clínica , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , Técnicas de Apoio para a Decisão , Árvores de Decisões , Esquema de Medicação , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Guias de Prática Clínica como Assunto , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Fatores de Risco , Resultado do Tratamento
19.
Int J Cardiol ; 275: 95-100, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30509374

RESUMO

BACKGROUND: The optimal antithrombotic strategy after interventional left atrial appendage closure (LAAC) is controversial. Dual antiplatelet therapy with aspirin and clopidogrel is the most frequently used regiment. However, pharmacodynamic response to antiplatelet medication differs significantly between individuals. Therefore, we aimed to analyse pharmacodynamic response to aspirin and clopidogrel after LAAC. METHODS: In this study, we included 129 patients undergoing interventional LAAC. Primary end point was pharmacodynamic response to antiplatelet medication. Platelet reactivity was measured by light transmittance aggregometry and vasodilator stimulated protein phosphorylation assay. Secondary endpoints were TIMI bleeding events and MACCE during hospital course and one-year follow-up. RESULTS: Insufficient pharmacodynamic response (high on-treatment platelet reactivity - HTPR) to clopidogrel occurred in 67 patients (52%); HTPR to aspirin in 15 patients (12%); low on-treatment platelet reactivity - LTPR - to clopidogrel in 13 patients (10%). No occluder thrombosis or stroke occurred during one year follow-up. Pharmacodynamic response to antiplatelet medication was not associated with MACCE. However, the incidence of TIMI minor bleeding was increased in patients with LTPR to clopidogrel. CONCLUSIONS: Impaired clopidogrel antiplatelet effects were very frequent in patients after LAAC. No stroke or occluder thrombosis occurred. Patients with LTPR to clopidogrel showed more minor bleeding events. Therefore, this hypothesis generating pilot study raises the question if clopidogrel early after LAAC is needed. This question should be addressed in large scale trials.


Assuntos
Aspirina/farmacocinética , Apêndice Atrial/efeitos dos fármacos , Fibrilação Atrial/terapia , Clopidogrel/farmacocinética , Agregação Plaquetária/efeitos dos fármacos , Dispositivo para Oclusão Septal , Acidente Vascular Cerebral/prevenção & controle , Idoso , Aspirina/administração & dosagem , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/cirurgia , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Clopidogrel/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Ecocardiografia Transesofagiana , Feminino , Seguimentos , Humanos , Masculino , Projetos Piloto , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/farmacocinética , Período Pós-Operatório , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento
20.
Br J Haematol ; 184(2): 269-278, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30443999

RESUMO

Ticagrelor is an antiplatelet agent for adults with coronary artery disease. The inhibition of platelet activation may decrease the frequency of vaso-occlusion crisis (VOC) in sickle cell disease (SCD). The HESTIA2 study (NCT02482298) randomised 87 adults with SCD (aged 18-30 years) 1:1:1 to twice-daily ticagrelor 10, 45 mg or placebo for 12 weeks. Numerical decreases from baseline in mean proportion of days with patient-reported pain (primary endpoint) were seen in all three groups, as well as in pain intensity and analgesic use, with no significant differences between placebo and ticagrelor treatment groups. Plasma ticagrelor concentrations and platelet inhibition increased with dose. Adverse events were distributed evenly across groups and two non-major bleeding events occurred per group. Ticagrelor was well tolerated with a low bleeding risk, but no effect on diary-reported pain was detected. Potential effects on frequency of VOCs will need to be evaluated in a larger and longer study.


Assuntos
Anemia Falciforme , Dor , Inibidores da Agregação de Plaquetas , Ticagrelor , Adolescente , Adulto , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Feminino , Humanos , Masculino , Dor/sangue , Dor/tratamento farmacológico , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/farmacocinética , Ticagrelor/administração & dosagem , Ticagrelor/farmacocinética , Adulto Jovem
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