RESUMO
BACKGROUND AND GOAL: Cytochrome P450 (CYP) enzymes are responsible for the conversion of clopidogrel into its active metabolite and the metabolism of proton pump inhibitors (PPIs), which may also inhibit CYP enzymes. A current Food and Drug Administration advisory suggests avoiding esomeprazole and omeprazole while taking clopidogrel because of concerns that PPIs may compromise clopidogrel's antiplatelet effects. The objective of the present study was to examine the robustness of this interaction using a well-controlled study design in a population of participants free of confounders. MATERIALS AND METHODS: Twenty-eight healthy male participants, with a mean age 24.2 ± 3.2, were randomized to an incomplete crossover design schedule. Participants underwent platelet aggregation testing after clopidogrel alone, while on clopidogrel in combination with 1 of 3 PPIs (40 mg of pantoprazole, 20 mg of omeprazole, 20 mg of rabeprazole, 40 mg of esomeprazole, 30 mg of lansoprazole, or 30 mg of dexlansoprazole), and during 1 week of clopidogrel-only washout periods. FINDINGS: The median platelet aggregation to adenosine diphosphate during a drug-free baseline was 10Ω (2.5 interquartile range) of impedance and decreased to 0Ω on clopidogrel alone. Aggregation did not significantly change with concomitant use of PPIs and clopidogrel. CONCLUSION: These data do not demonstrate a significant interaction between common individual PPIs and clopidogrel in healthy volunteers who respond to clopidogrel alone. This adds data to a growing body of evidence indicating that the addition of a PPI may have a weak effect on clopidogrel's antiplatelet properties, and may only be relevant in specific clinical circumstances.
Assuntos
Inibidores da Agregação Plaquetária/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Bomba de Prótons/administração & dosagem , Adulto , Estudos Cross-Over , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Masculino , New York , Inibidores da Agregação Plaquetária/efeitos adversos , Testes de Função Plaquetária , Inibidores da Bomba de Prótons/efeitos adversos , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Following the expiration of brand name exclusivity of Plavix® in 2012, generic clopidogrel bisulfate was approved. As a widely prescribed medication with significant inter-patient pharmacokinetic and pharmacodynamic variability, data regarding the impact of switching to generic clopidogrel bisulfate on patients is needed. OBJECTIVE: The objective of this study was to determine whether generic clopidogrel bisulfate is as efficacious as Plavix® for the inhibition of platelet aggregation. METHODS: Patients treated with Plavix® monotherapy (n = 254) or generic clopidogrel bisulfate monotherapy (n = 185) were included in this retrospective review. Confounding factors previously found to affect clopidogrel responsiveness (diabetes, female sex, and smoking) were assessed, as well as medications classified as substrates, inducers, and inhibitors of enzymes involved in clopidogrel metabolism. Whole blood impedance aggregometry was used to measure platelet aggregation in response to adenosine diphosphate. Patients were tested after ≥2 weeks of treatment and designated as non-responders if aggregation response exceeded sensitivity thresholds of 6 ohms of impedance. RESULTS: The introduction of generic clopidogrel bisulfate was associated with a decrease in antiplatelet resistance (44% to 31%, p < 0.01) and decreased mean ohms of resistance (5.06 ± 4.55 to 3.32 ± 4.03, p < 0.01). Prior to analysis of secondary outcomes, 217 patients were eliminated due to antiplatelet usage for longer than 3 years (n = 123 for Plavix® and n = 118 for clopidogrel). There was no statistically significant finding in prevalence of secondary events. CONCLUSION: Resistance rates to the antiplatelet, clopidogrel are significantly lower since the switch to generic formulations. Further investigation into the impact of variability between clopidogrel bisulfate formulations is needed.
Assuntos
Inibidores da Agregação Plaquetária , Ticlopidina , Clopidogrel , Medicamentos Genéricos/uso terapêutico , Feminino , Humanos , Agregação PlaquetáriaRESUMO
Legalization of medical cannabis has occurred in 33 states and the District of Columbia, and recreational use has increased exponentially since 2013. As a result, it is important to understand how cannabis interacts with other drugs and has potential risks for patients on concomitant medications. Components of medical cannabis can inhibit or compete for several cytochrome P450 (CYP) hepatic isoenzymes, UDP-glucuronosyltransferases, and P-glycoprotein. These enzymes and transporters are involved in the metabolism and absorption of numerous medications, including anticoagulants (ACs) and antiplatelet agents (APs), potentially causing harmful drug-drug interactions. ACs and/or APs are often prescribed to high-risk patients with cardiac conditions, a history of myocardial infarction, or stroke. Cannabis may cause these medications to be less efficacious and put patients at risk for recurrent cardiovascular and cerebrovascular events. Several case reports show cannabis may inhibit the metabolism of warfarin because of CYP2C9 interactions, resulting in increased plasma concentrations, increased international normalized ratio, and risk of bleeding. Cannabidiol inhibits CYP2C19, an isoenzyme responsible for the transformation of clopidogrel to its active thiol metabolite. This interaction could lead to subtherapeutic levels of active metabolite and possibly increased stroke risk. Within this review, a total of 665 articles were screened from PubMed and EMBASE. Four case reports, 1 in vitro study, and 1 pharmacokinetic article were found to be of relevance. This review serves to examine reported and potential cannabis interactions with APs/ACs to help inform patients and health care providers of possible risks and knowledge gaps.
Assuntos
Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Interações Medicamentosas , Maconha Medicinal/efeitos adversos , Maconha Medicinal/farmacologia , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Bases de Dados Bibliográficas , Humanos , Maconha Medicinal/química , Maconha Medicinal/metabolismoRESUMO
This article addresses the common stroke problems seen in an outpatient or office setting, including transient ischemic attacks (TIAs), minor strokes and carotid stenoses. Expedited, semi-emergent evaluation and prompt appropriate treatment of acute TIAs and minor strokes reduces an otherwise significant risk for stroke. Evaluation requires good-quality neuroimaging, cardiac imaging, and cardiac monitoring. Carotid stenoses may benefit from endarterectomy or stenting procedure under specific circumstances; otherwise, medical management may be more appropriate. In the evaluation and treatment of these conditions in an office setting, stroke neurologists need to be familiar with high-quality neuroimaging to best evaluate and treat these potentially life-threatening or life-altering conditions.
Assuntos
Encéfalo/patologia , Diagnóstico por Imagem/métodos , Pacientes Ambulatoriais , Acidente Vascular Cerebral/diagnóstico , Diagnóstico por Imagem/instrumentação , HumanosRESUMO
OBJECTIVE: The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination. METHODS: Ten healthy volunteers were enrolled in a single-blinded, randomized, three-way crossover study. Treatments consisted of single doses of oral aspirin (325 mg) and ibuprofen (400 mg) and concomitant administration of aspirin (325 mg) and ibuprofen (400 mg). Ex vivo whole blood platelet aggregation induced by collagen (1 microg/mL) or arachidonic acid (0.5 mmol/L) was measured by impedance aggregometry. Model development and population parameter estimation were performed using nonlinear mixed-effects modelling implemented in NONMEM. RESULTS: Relatively complete inhibition of platelet aggregation was achieved following aspirin treatment (approximately 77% inhibition within 2 hours), and return to baseline values occurred within 72-96 hours after dosing. In contrast, treatment with ibuprofen alone or in combination with aspirin produced transient inhibition of platelet aggregation, with complete recovery observed in 6-8 hours. The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (kout) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h(-1) and 0.152 (mg/L)(-1).h(-1), with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration. CONCLUSIONS: A mechanism-based pharmacodynamic model has been developed that characterizes the antiplatelet effects of aspirin and ibuprofen, alone and concomitantly, and predicts a significant inhibition of aspirin antiplatelet effects in the presence of a typical ibuprofen dosing regimen.
Assuntos
Aspirina/farmacologia , Ibuprofeno/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Administração Oral , Adulto , Ácido Araquidônico/farmacologia , Aspirina/sangue , Aspirina/farmacocinética , Colágeno/farmacologia , Estudos Cross-Over , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/farmacocinética , Inibidores de Ciclo-Oxigenase/farmacologia , Meia-Vida , Humanos , Ibuprofeno/sangue , Ibuprofeno/farmacocinética , Pessoa de Meia-Idade , Modelos Biológicos , Método de Monte Carlo , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Método Simples-Cego , Fatores de TempoRESUMO
This study was designed to measure the magnitude and duration of inhibition of platelet aggregation following doses of aspirin or ibuprofen alone or taken in combination in a group of healthy volunteers. Ten normal volunteer subjects underwent 3 randomized treatment sessions: aspirin 325 mg alone, ibuprofen 400 mg alone, and ibuprofen 400 mg, followed by dosing with aspirin 325 mg 2 hours thereafter. In addition, a confirmatory study was performed in patients. Over 27 months, a cohort of patients treated with aspirin for secondary stroke prophylaxis while concomitantly taking a nonsteroidal anti-inflammatory drug (NSAID) was identified. A significant reduction was found in both the magnitude and duration of aspirin's inhibitory effect on platelet aggregation when ibuprofen was given prior to aspirin administration in normal volunteer subjects. During a 27-month period, a cohort of 28 patients took regular daily doses of ibuprofen or naproxen. Of these 28 patients, 18 returned for follow-up testing in the absence of this pharmacodynamic interaction. None of these 18 patients demonstrated inhibition of platelet aggregation while on both NSAID and aspirin; however, all showed inhibition of aggregation following discontinuation of the NSAID. Notably, 13 of these 18 patients (72%) had experienced a recurrent ischemic episode while taking aspirin and NSAIDs concomitantly. These data suggest that ibuprofen prevents the irreversible inhibition of platelet aggregation produced by aspirin needed for secondary stroke prophylaxis, and this interaction can have clinical consequences for patients taking aspirin.
Assuntos
Aspirina/farmacologia , Ibuprofeno/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Análise de Variância , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Estudos de Coortes , Estudos Cross-Over , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Ibuprofeno/uso terapêutico , Masculino , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Método Simples-Cego , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Fatores de Tempo , Resultado do TratamentoRESUMO
To determine the prevalence of platelet nonresponsiveness to aspirin treatment for secondary stroke prophylaxis, the authors studied consecutive patients during a 29-month period. Information regarding their ischemic events, risk factors, and medications was collected. Platelet aggregation in response to collagen and arachidonic acid was used to determine platelet responsiveness to aspirin. A total of 653 patients were evaluated. Of these, 129 patients (20%) were determined to be nonresponsive to aspirin based on continued platelet aggregation in response to collagen, arachidonic acid, or both. A total of 87 (13%) of the 653 patients were clinical aspirin failures (ie, presented with new focal cerebral ischemic symptoms while taking aspirin). Of the patients with new cerebral ischemic symptoms, 57 (66%) were determined to be platelet nonresponsive to aspirin. The odds ratio for platelet nonresponsiveness to aspirin in patients who suffered a recurrent ischemic event while taking aspirin was 14.25 (95% confidence interval: 8.5-23.7; P < .5). Continued platelet aggregation despite aspirin treatment occurred in 20% of ambulatory patients treated for secondary stroke prophylaxis. The prevalence of nonresponsiveness to aspirin was statistically higher in those patients who suffered recurrent cerebral ischemia while taking aspirin (P < .5) compared with patients who remained without new ischemic symptoms.
Assuntos
Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Ataque Isquêmico Transitório/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle , Fatores Etários , Idoso , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Ácido Araquidônico/farmacologia , Aspirina/administração & dosagem , Clopidogrel , Colágeno/farmacologia , Doença da Artéria Coronariana/complicações , Dipiridamol/administração & dosagem , Dipiridamol/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Ataque Isquêmico Transitório/sangue , Masculino , Razão de Chances , Agregação Plaquetária/efeitos dos fármacos , Recidiva , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia , Ticlopidina/administração & dosagem , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêutico , Fatores de Tempo , Falha de TratamentoRESUMO
Aspirin remains the standard for stroke prophylaxis. However, as many as 20%-25% of patients may fail to show a full response to aspirin. Ideally, patients who are resistant to aspirin could be identified, then receive an increased dose of aspirin or be changed to an alternative therapy more efficiently. We have developed an in vitro assay that may make this possible. Healthy volunteers (n = 13) between 18 and 50 years of age were tested for both ex vivo and in vivo responses to aspirin. Dimethyl sulfoxide (DMSO) was selected as the solvent for aspirin in the assay. DMSO can exhibit antiplatelet effects, necessitating the use of a concentration low enough to avoid such antiplatelet effects. Blood samples were tested against DMSO 0%, 0.05%, 0.5%, and 1% w/v with and without aspirin 0, 50, and 100 µM. The effects of both agents were measured via whole-blood aggregometry. A 3-dimensional response model described the data well, quantifying the combinatorial effect of DMSO and aspirin on platelet aggregation. Across all participants, baseline aggregation stimulated with collagen 1 µM or arachidonate 0.5 mM was approximately 18 and 13 Ω, respectively. The response model showed that 0.05% DMSO with 100 µM aspirin would provide platelet aggregation of 3.4 Ω. A DMSO concentration of 0.05% in the absence of aspirin would result in no discernable effects on platelet aggregation (17.7 Ω). Overall, the use of 100 µM of aspirin in 0.05% DMSO provides a robust method to test for ex vivo inhibition of platelet aggregation.
Assuntos
Aspirina/administração & dosagem , Aspirina/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Adulto , Plaquetas/efeitos dos fármacos , Feminino , Humanos , Masculino , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacologia , Testes de Função Plaquetária , Adulto JovemRESUMO
This study tested the capability of an assay to predict aspirin response and reduce ischemic events, and healthcare costs, and delays to optimal treatment. Patients who needed aspirin in the course of normal medical care were included. Patients were excluded if they had disorders affecting platelet function, alcohol use within 24 hours of a test, or NSAID use. Dose escalation of chewable aspirin from 81 mg, to 162 mg, to 325 mg daily occurred based on the results of whole blood impedance aggregation testing to the agonists, collagen (1ug/mL, 5 ug/mL) and arachidonate (0.5 mM) after 10-14 days of treatment. The experimental in vitro test was conducted in triplicate by performing aggregometry on samples spiked to a concentration of 10 uM of aspirin in 0.05% dimethyl sulfoxide. Of the 36 patients who were compliant 16 were found to be resistant to the antiplatelet effects of 81 mg daily aspirin. Nine of these patients were predicted to stay resistant despite dose increase. Once tested at higher doses, ten remained resistant. Seven of the 16 patients were predicted to become sensitive to a higher dose while six actually did. Predicted response to increased doses of aspirin was in good agreement with actual response. Sensitivity of the assay was 83% and specificity was 80%. Results are promising and indicate that it is possible to predict, with reasonable accuracy, if a patient will have an adequate platelet response to aspirin or if the patient will never respond to aspirin necessitating an alternative antiplatelet regimen. Larger, multisite studies are inevitably needed.
Assuntos
Aspirina/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Plaquetária/métodos , Valor Preditivo dos Testes , Estudos Prospectivos , Adulto JovemRESUMO
This study demonstrates that patients who are taking 81 mg of aspirin and are nonresponsive benefit from a dose of 162 mg or greater vs a different antiplatelet therapy. We identified 100 patients who were nonresponsive to aspirin 81 mg via whole blood aggregometry and observed how many patients became responsive at a dose of 162 mg or greater. Platelet nonresponsiveness was defined as >10 Ω of resistance to collagen 1 µg/mL and/or an ohms ratio of collagen 1 µg/mL to collagen 5 µg/mL >0.5 and/or >6 Ω to arachidonate. Borderline response was defined as an improvement in 1 but not both of the above criteria. Of the initial 100 patients who were nonresponsive to an aspirin dose of 81 mg, 79% became responsive at a dose of 162 mg or >162 mg. Only 6% did not respond to any increase in dose. We believe that patients treated with low-dose aspirin who have significant risk for secondary vascular events should be individually assessed to determine their antiplatelet response. Those found to have persistent platelet aggregation despite treatment with 81 mg of aspirin have a higher likelihood of obtaining an adequate antiplatelet response at a higher aspirin dose.
Assuntos
Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Testes de Coagulação Sanguínea/métodos , Plaquetas/metabolismo , Colágeno/metabolismo , Resistência a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Plaquetária/métodosRESUMO
The introduction of computed tomography (CT) scanning in the 1970s revolutionized the way clinicians could diagnose and treat stroke. Subsequent advances in CT technology significantly reduced radiation dose, reduced metallic artifact, and achieved speeds that enable dynamic functional studies. The recent addition of whole-brain volumetric CT perfusion technology has given clinicians a powerful tool to assess parenchymal perfusion parameters as well as visualize dynamic changes in blood vessel flow throughout the brain during a single cardiac cycle. This article reviews clinical applications of volumetric multimodal CT that helped to guide and manage care.