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2.
Br J Clin Pharmacol ; 85(10): 2194-2197, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31050833

RESUMO

The clinical doses of antithrombotics-antiplatelet and anticoagulant agents-need to balance efficacy and safety. It is not clear from the published literature how the doses currently used in clinical practice have been derived from preclinical and clinical data. There are few large randomised controlled trials (RCTs) that compare outcomes with different doses vs placebo. For newer antithrombotics, RCT doses appear to have been chosen to maximise the probability of demonstrating noninferiority when compared to established agents such as warfarin or clopidogrel. Data from RCTs show that aspirin is an effective antithrombotic at doses below 75 mg daily, and that direct oral anticoagulants reduce the risk of stroke in patients with coronary disease at doses 1/4 of those recommended in atrial fibrillation. Lower doses than those currently recommended are safer and still maintain substantial efficacy.

3.
Br J Clin Pharmacol ; 85(7): 1443-1453, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845346

RESUMO

AIMS: Dietary inorganic nitrate (NO3 - ) lowers peripheral blood pressure (BP) in healthy volunteers, but lacks such effect in individuals with, or at risk of, type 2 diabetes mellitus (T2DM). Whilst this is commonly assumed to be a consequence of chronic hyperglycaemia/hyperinsulinaemia, we hypothesized that acute physiological elevations in plasma [glucose]/[insulin] blunt the haemodynamic responses to NO3 - , a pertinent question for carbohydrate-rich Western diets. METHODS: We conducted an acute, randomized, placebo-controlled, double-blind, crossover study on the haemodynamic and metabolic effects of potassium nitrate (8 or 24 mmol KNO3 ) vs. potassium chloride (KCl; placebo) administered 1 hour prior to an oral glucose tolerance test in 33 healthy volunteers. RESULTS: Compared to placebo, there were no significant differences in systolic or diastolic BP (P = 0.27 and P = 0.30 on ANOVA, respectively) with KNO3 , nor in pulse wave velocity or central systolic BP (P = 0.99 and P = 0.54 on ANOVA, respectively). Whilst there were significant elevations from baseline for plasma [glucose] and [C-peptide], no differences between interventions were observed. A significant increase in plasma [insulin] was observed with KNO3 vs. KCl (n = 33; P = 0.014 on ANOVA) with the effect driven by the high-dose cohort (24 mmol, n = 13; P < 0.001 on ANOVA; at T = 0.75 h mean difference 210.4 pmol/L (95% CI 28.5 to 392.3), P = 0.012). CONCLUSIONS: In healthy adults, acute physiological elevations of plasma [glucose] and [insulin] result in a lack of BP-lowering with dietary nitrate. The increase in plasma [insulin] without a corresponding change in [C-peptide] or [glucose] suggests that high-dose NO3 - decreases insulin clearance. A likely mechanism is via NO-dependent inhibition of insulin-degrading enzyme.

6.
Eur J Clin Pharmacol ; 74(3): 349-356, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29198063

RESUMO

PURPOSE: Gamma-hydroxybutyrate (GHB) withdrawal is a life-threatening condition that does not always respond to standard treatment with benzodiazepines. Baclofen has potential utility as a pharmacological adjunct and anecdotal reports suggest that it is being used by drug users to self-manage GHB withdrawal symptoms. Here, we investigate current patterns of use and the online availably of baclofen. METHODS: Data triangulation techniques were applied to published scientific literature and publicly accessible Internet resources (grey literature) to assess the use of baclofen in GHB withdrawal. An Internet snapshot survey was performed to identify the availability of baclofen for online purchase and the compliance of retailers with the UK regulations. Data were collected according to pre-defined criteria. RESULTS: A total of 37 cases of baclofen use in GHB withdrawal were identified in the scientific literature, as well as 51 relevant discussion threads across eight Internet forums in the grey literature. Baclofen was available to purchase from 38 online pharmacies, of which only one conformed to the UK regulations. CONCLUSIONS: There is limited published evidence on the use of baclofen in GHB withdrawal, but both scientific and grey literature suggests clinical utility. Online pharmacies are readily offering prescription-only-medication without prescription and due to inadequate regulation, pose a danger to the public.


Assuntos
Baclofeno/uso terapêutico , Agonistas dos Receptores de GABA-B/uso terapêutico , Internet , Padrões de Prática Médica , Psicotrópicos/toxicidade , Oxibato de Sódio/toxicidade , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Animais , Baclofeno/economia , Baclofeno/normas , Baclofeno/provisão & distribução , Pesquisa Biomédica/métodos , Tráfico de Drogas/economia , Agonistas dos Receptores de GABA-B/economia , Agonistas dos Receptores de GABA-B/normas , Agonistas dos Receptores de GABA-B/provisão & distribução , Humanos , Internet/economia , Internet/ética , Disponibilidade de Medicamentos Via Internet/economia , Disponibilidade de Medicamentos Via Internet/ética , Disponibilidade de Medicamentos Via Internet/normas , Medicamentos sob Prescrição/economia , Medicamentos sob Prescrição/normas , Medicamentos sob Prescrição/provisão & distribução , Medicamentos sob Prescrição/uso terapêutico , Mídias Sociais/economia , Mídias Sociais/ética , Reino Unido
9.
Clin Med (Lond) ; 16(1): 52-4, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26833514

RESUMO

A conference organised in conjunction with the British Hypertension Society at the Royal College of Physicians (London) assembled an expert panel to present recent advances in the understanding and management of hypertension - the leading reversible risk factor for global morbidity and mortality. Despite recognised therapeutic approaches, less than half of patients on treatment for hypertension achieve blood pressure control to international guideline-based targets. This failure may, in part, be due to uncertainty into optimum treatment strategies, and the PATHWAY studies reporting later this year will hopefully address some outstanding questions relating to the standardised ABCD approach to drug selection. Targeting degradation of natriuretic peptides by LCZ696 (a combination of valsartan and a neutral endopeptidase inhibitor) has demonstrated potential as a novel therapeutic option, with mortality benefits in heart failure beyond that solely attributable to its blood pressure lowering ability. However, critical to any therapeutic strategy is patient involvement, and it is clear that the delivery of patient-centric treatment options is vital to ensure adherence with medication and to facilitate healthier lifestyle decisions.


Assuntos
Hipertensão , Aminobutiratos , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Humanos , Hipertensão/dietoterapia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Adesão à Medicação , Sódio na Dieta , Tetrazóis
10.
Artigo em Inglês | MEDLINE | ID: mdl-25868910

RESUMO

Antiplatelet drugs are prescribed to patients with cardiovascular disease in order to reduce their risk of clinically important atherothrombotic events. However, a proportion of patients fail to appropriately respond to these drugs in a heterogeneous phenomenon known as 'antiplatelet drug resistance'. Individuals who are identified as being resistant have a higher cardiovascular risk, but currently there is no clinically validated approach to identify and treat these individuals. Large randomised control trials have attempted to personalise antiplatelet therapy based on platelet function testing, but these have failed to demonstrate improved clinical outcomes. An alternative approach to this non-specific assessment of platelet function is to consider whether antiplatelet therapy may be personalised based on the identification of molecular mechanisms that are known to confer resistance. Here we present molecular insights into the mechanisms for aspirin and clopidogrel resistance, with a discussion of their clinical implications.


Assuntos
Resistência a Medicamentos , Inibidores da Agregação de Plaquetas/farmacologia , Aspirina/farmacologia , Clopidogrel , Humanos , Ticlopidina/análogos & derivados , Ticlopidina/farmacologia
11.
Br J Clin Pharmacol ; 80(3): 331-41, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25784356

RESUMO

AIMS: Antiplatelet therapy reduces the incidence of ischaemic stroke. Platelet-mediated thrombosis contributes variably to the major subtypes of stroke as defined by the TOAST criteria: large artery atherosclerosis (LAA), cardioembolic (CE) and small vessel occlusion (SVO). The effect of antiplatelet therapy on the incidence of each subtype is unknown and is the subject of this meta-analysis. METHODS: Electronic databases were searched for articles comparing the effect of antiplatelet therapy on the incidence of stroke according to aetiological subtype. Studies containing subjects prescribed anticoagulant therapy or solely investigating subjects with atrial fibrillation were excluded. Pooled odds ratios (ORs) were calculated using a fixed effects model. RESULTS: Nine studies were included (n = 5739). In patients who had an ischaemic stroke, pre-event antiplatelet therapy was associated with significantly decreased incidence of LAA (OR 0.88, 95% CI 0.79, 0.99; P = 0.026), increased incidence of CE (OR 1.23, 95% CI 1.08, 1.41; P = 0.002) and no effect on SVO (OR 0.99, 95% CI 0.88, 1.11; P = 0.806). Concordant non-significant trends were observed in primary prevention populations (n = 751): LAA (OR 0.81, 95% CI 0.57, 1.15; P = 0.240), CE (OR 1.29, 95% CI 0.89, 1.87; P = 0.179) and SVO (OR 0.99, 95% CI 0.73, 1.36; P = 0.970). Subgroup analysis of aspirin monotherapy (n = 3786) demonstrated a significant reduction in LAA (OR 0.87, 95% CI 0.76, 1.00; P = 0.046), but non-significant effects on the incidence of CE (OR 1.17, 95% CI 0.99, 1.39; P = 0.068) and SVO (OR 1.04, 95% CI 0.91, 1.20; P = 0.570). Probability of publication bias was low (P > 0.05). CONCLUSIONS: Antiplatelet therapy preferentially reduces the incidence of LAA stroke compared with CE and SVO subtypes.


Assuntos
Inibidores da Agregação de Plaquetas/uso terapêutico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Aterosclerose/complicações , Aterosclerose/tratamento farmacológico , Aterosclerose/epidemiologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Bases de Dados Factuais , Registros Eletrônicos de Saúde , Humanos , Incidência , Inibidores da Agregação de Plaquetas/administração & dosagem , Prevenção Primária , Prevenção Secundária , Acidente Vascular Cerebral/epidemiologia , Tromboembolia/complicações , Tromboembolia/tratamento farmacológico , Tromboembolia/epidemiologia , Trombose Venosa/complicações , Trombose Venosa/tratamento farmacológico , Trombose Venosa/epidemiologia
12.
JRSM Cardiovasc Dis ; 4: 2048004015610252, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26858830

RESUMO

BACKGROUND: The platelet fibrinogen receptor represents the final common pathway of platelet activation, and is formed from two glycoprotein (GP) subunits (GPIIb/IIIa). Carriage of the mutant PlA2 allele of GPIIIa has been shown to confer an increased risk of cardiovascular events, but published studies have disagreed as to the mechanism for this association. OBJECTIVES: To assess whether carriage of the PlA2 allele conforms to Mendelian patterns of expression and to identify whether carriage of the mutant allele modulates platelet function. METHODS: Expression of the PlA2 allele was assessed in both healthy subjects (n = 25) and patients with known coronary artery disease (n = 90) through the development and validation of a liquid chromatography, tandem mass spectrometry (LC-MS/MS) assay. Platelet function was assessed in the patient cohort in response to multiple agonists, and these data were analysed in the context of the proteomic data. RESULTS: Expression of the wild-type PlA1 allele and mutant PlA2 alleles was readily quantifiable and conformed to Mendelian patterns in both healthy and patient cohorts. Patients who were homozygous for the mutant PlA2 allele had an increased aggregatory response to adenosine diphosphate, collagen, adrenaline, ristocetin, thrombin receptor-activating peptide 6 and U46619, when assessed using agonist-concentration response curves. CONCLUSIONS: These findings support the hypothesis that carriage of the mutant PlA2 allele mediates an increased risk of cardiovascular events through the modulation of platelet reactivity.

13.
Br J Clin Pharmacol ; 78(2): 320-8, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25099258

RESUMO

AIMS: Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects. METHODS: Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2 , and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting. RESULTS: In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance. CONCLUSIONS: In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker.


Assuntos
Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , Resistência a Medicamentos , Integrina beta3/biossíntese , Agregação Plaquetária/efeitos dos fármacos , Adulto , Ácido Araquidônico/farmacologia , Aspirina/administração & dosagem , Aspirina/sangue , Aspirina/urina , Plaquetas/citologia , Plaquetas/metabolismo , Estudos de Coortes , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Voluntários Saudáveis , Humanos , Masculino , Tromboxano B2/análogos & derivados , Tromboxano B2/urina
14.
PLoS One ; 9(7): e101518, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24988220

RESUMO

BACKGROUND: The PlA2 polymorphism of glycoprotein IIIa (GPIIIa) has been previously identified as being associated with myocardial infarction (MI), but whether this represents a true association is entirely unclear due to differences in findings from different studies. We performed a meta-analysis to evaluate whether this polymorphism is a risk factor for MI. METHODS: Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating genetic polymorphisms of GPIIIa. For studies where acute coronary events were recorded in association with genetic analysis, pooled odds ratios (ORs) were calculated using fixed-effects and random-effects models. The primary outcome measure was MI, and a secondary analysis was also performed for acute coronary syndromes (ACS) more generally. FINDINGS: 57 studies were eligible for statistical analysis and included 17,911 cases and 24,584 controls. Carriage of the PlA2 allele was significantly associated with MI (n = 40,692; OR 1.077, 95% CI 1.024-1.132; p = 0.004) but with significant publication bias (p = 0.040). The degree of association with MI increased with decreasing age of subjects (≤45 years old: n = 9,547; OR 1.205, 95% CI 1.067-1.360; p = 0.003) and with adjustment of data for conventional cardiovascular risk factors (n = 12,001; OR 1.240, 95% CI 1.117-1.376; p<0.001). There was a low probability of publication bias for these subgroup analyses (all p<0.05). CONCLUSIONS: The presence of significant publication bias makes it unclear whether the association between carriage of the PlA2 allele and MI is true for the total population studied. However for younger subjects, the relative absence of conventional cardiovascular risk factors results in a significant association between carriage of the PlA2 allele and MI.


Assuntos
Integrina beta3/genética , Infarto do Miocárdio/genética , Polimorfismo Genético , Idoso , Alelos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Fatores de Risco
15.
PLoS One ; 9(7): e100239, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24988537

RESUMO

BACKGROUND: The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been reported to be associated with risk of stroke in some studies, although other studies suggest no such association. This meta-analysis and systematic review was conducted to investigate the hypothesis that carriage of the PlA2 allele is a risk factor for stroke. METHODS: Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating carriage of the PlA2 allele and the incidence of stroke. Pooled odds ratios (ORs) were calculated using fixed-effect and random-effect models. FINDINGS: A total of 35 articles were eligible for inclusion, of which 25 studies were suitable for statistical analysis. For carriage of the PlA2 allele, OR 1.12 (n = 11,873; 95% CI = 1.03-1.22; p = 0.011) was observed for the incidence of stroke in adults, with subgroup analyses identifying the association driven by stroke of an ischaemic (n = 10,494; OR = 1.15, 95% CI = 1.05-1.27; p = 0.003) but not haemorrhagic aetiology (n = 2,470; OR = 0.90, 95% CI = 0.71-1.14; p = 0.398). This association with ischaemic stroke was strongest in individuals homozygous for the PlA2 allele compared to those homozygous for wild-type PlA1 (n = 5,906; OR = 1.74, 95% CI = 1.34-2.26; p<0.001). Subgroup analysis of ischaemic stroke subtypes revealed an increased association with stroke of cardioembolic (n = 1,271; OR 1.56, 95% CI 1.14-2.12; p = 0.005) and large vessel (n = 1,394; OR = 1.76, 95% CI 1.34-2.31; p<0.001) aetiology, but not those of small vessel origin (n = 1,356; OR = 0.99, 95% CI 0.74-1.33; p = 0.950). Egger's regression test suggested a low probability of publication bias for all analyses (p>0.05). CONCLUSIONS: The totality of published data supports the hypothesis that carriage of the PlA2 polymorphism of GPIIIa is a risk factor for ischaemic strokes, and specifically those of cardioembolic and large vessel origin.


Assuntos
Alelos , Isquemia Encefálica/genética , Homozigoto , Integrina beta3/genética , Polimorfismo Genético , Acidente Vascular Cerebral/genética , Adolescente , Adulto , Isquemia Encefálica/epidemiologia , Feminino , Humanos , MEDLINE , Masculino , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia
16.
Pharmacol Ther ; 141(1): 69-78, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23993980

RESUMO

Aspirin is integral to the secondary prevention of cardiovascular disease and acts to impair the development of platelet-mediated atherothromboembolic events by irreversible inhibition of platelet cyclooxygenase-1 (COX-1). Inhibition of this enzyme prevents the synthesis of the potent pro-aggregatory prostanoid thromboxane A2. A large number of patients continue to experience atherothromboembolic events despite aspirin therapy, so-called 'aspirin treatment failure', and this is multifactorial in aetiology. Approximately 10% however do not respond appropriately to aspirin in a phenomenon known as 'aspirin resistance', which is defined by various laboratory techniques. In this review we discuss the reasons for aspirin resistance in a systematic manner, starting from prescription of the drug and ending at the level of the platelet. Poor medication adherence has been shown to be a cause of apparent aspirin resistance, and may in fact be the largest contributory factor. Also important is high platelet turnover due to underlying inflammatory processes, such as atherosclerosis and its complications, leading to faster regeneration of platelets, and hence of COX-1, at a rate that diminishes the efficacy of once daily dosing. Recent developments include the identification of platelet glycoprotein IIIa as a potential biomarker (as well as possible underlying mechanism) for aspirin resistance and the discovery of an anion efflux pump that expels intracellular aspirin from platelets. The absolute as well as relative contributions of such factors to the phenomenon of aspirin resistance are the subject of continuing research.


Assuntos
Aspirina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Resistência a Medicamentos , Tromboembolia/tratamento farmacológico , Aspirina/farmacocinética , Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Ciclo-Oxigenase 1/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase/farmacocinética , Inibidores de Ciclo-Oxigenase/uso terapêutico , Interações de Medicamentos , Humanos , Integrina beta3/efeitos dos fármacos , Integrina beta3/metabolismo , Adesão à Medicação , Taquifilaxia , Tromboembolia/prevenção & controle , Tromboxano A2/antagonistas & inibidores , Tromboxano A2/metabolismo , Falha de Tratamento
17.
Br J Clin Pharmacol ; 77(3): 446-57, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23834376

RESUMO

AIM: The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been associated with both antiplatelet drug resistance and increased cardiovascular events. The aim of this study was to conduct the first meta-analysis investigating the association between carriage of the PlA2 allele and resistance to currently licensed antiplatelet drugs. METHODS: Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating genetic polymorphisms of GPIIIa. For studies where antiplatelet resistance was measured using validated techniques, pooled odds ratios (ORs) were calculated using fixed effects and random effects models. RESULTS: Sixteen studies were eligible for statistical analysis and included 1650 PlA1 homozygous subjects and 668 carriers of the PlA2 allele. For carriers of the PlA2 allele, OR 0.924 (n = 2318; 95% CI 0.743, 1.151; P = 0.481) was observed for resistance to any antiplatelet drug, OR 0.862 (n = 2085; 95% CI 0.685, 1.086; P = 0.208) for resistance to aspirin and OR 1.429 (n = 233; 95% CI 0.791, 2.582; P = 0.237) for resistance to clopidogrel. In the aspirin cohort, sub-group analysis revealed no statistical association in either healthy subjects or those with cardiovascular disease. PlA2 carriage was marginally associated with aspirin sensitivity using the fixed effects model when identified by the PFA-100 assay (n = 1151; OR 0.743, 95% CI 0.558, 0.989; P = 0.041) but with significant heterogeneity (I(2) = 55%; P = 0.002). Significance was lost with analysis using a random effects model. CONCLUSIONS: The totality of published data does not support an association between carriage of the PlA2 allele and antiplatelet drug resistance. Significant heterogeneity indicates the need for larger studies using validated and standardized assays.


Assuntos
Resistência a Medicamentos , Integrina beta3/genética , Inibidores da Agregação de Plaquetas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Polimorfismo Genético , Resistência a Medicamentos/genética , Frequência do Gene , Genótipo , Humanos , Razão de Chances , Fenótipo , Agregação Plaquetária/genética , Testes de Função Plaquetária , Fatores de Risco
19.
Clin Pharmacokinet ; 51(7): 429-42, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22568693

RESUMO

Over the last two decades or more, anti-platelet therapy has become established as a cornerstone in the treatment of patients with ischaemic cardiovascular disease, since such drugs effectively reduce arterial thrombotic events. The original agent used in this context was aspirin (acetylsalicylic acid) but, with the advent of adenosine diphosphate (ADP) receptor antagonists, the use of dual anti-platelet therapy has resulted in further improvement in cardiovascular outcomes when compared with aspirin alone. The first group of platelet ADP receptor antagonists to be developed was the thienopyridine class, which comprise inactive pro-drugs that require in vivo metabolism to their active metabolites before exerting their inhibitory effect on the P2Y(12) receptor. Clopidogrel has been the principal ADP receptor antagonist in use over the past decade, but is limited by variability in its in vivo inhibition of platelet aggregation (IPA). The pharmacokinetics of clopidogrel are unpredictable due to their vulnerability to multiple independent factors including genetic polymorphisms. Expression of the 3435T/T genetic variant encoding the MDR1 gene for the P-glycoprotein efflux transporter results in a significantly reduced maximum drug concentration and area under the plasma concentration-time curve as intestinal absorption of clopidogrel is reduced; and the expression of the mutant *2 allele of CYP2C19 results in similar pharmacokinetic effects as the two cytochrome P450 (CYP)-mediated steps required for the production of the active metabolite of clopidogrel are impaired. These variable pharmacokinetics lead to erratic pharmacodynamics and cannot reliably be overcome with increased dosing. Both prasugrel, a third-generation thienopyridine, and ticagrelor, a cyto-pentyl-triazolo-pyrimidine, have more predictable pharmacokinetics and enhanced pharmacodynamics than clopidogrel. Neither appears to be affected by the same genetic polymorphisms as clopidogrel; prasugrel requires only a single CYP-mediated step to produce its active metabolite and ticagrelor is not a pro-drug. Enhanced IPA by both prasugrel and ticagrelor is achieved at the expense of increased major bleeding, although this is partially mitigated in the case of ticagrelor due to its reversible IPA. However, the reversible binding of ticagrelor to the P2Y(12) receptor requires a twice-daily dosing regimen. Due to limited data from clinical studies, the use of prasugrel is currently restricted to individuals undergoing percutaneous coronary intervention who are ≤75 years old and have a body weight ≥60 kg. The clinical data for ticagrelor are more comprehensive and this drug therefore has a place in the management of patients with acute coronary syndrome at moderate-to-high risk of ischaemic events, irrespective of treatment strategy. Here we review in detail the pharmacokinetics and pharmacodynamics of clopidogrel, prasugrel and ticagrelor, and explore the implications of the differences in these parameters for their clinical use.


Assuntos
Inibidores da Agregação de Plaquetas/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Clopidogrel , Humanos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Ticagrelor , Ticlopidina/análogos & derivados , Ticlopidina/farmacologia , Ticlopidina/uso terapêutico
20.
Lancet ; 379(9829): e52, 2012 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-22608341
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