RESUMO
Milvexian, an oral activated Factor XI (FXIa) inhibitor, is in clinical studies where it may be combined with antiplatelet agents, including aspirin and/or clopidogrel, to prevent thromboembolic diseases. This phase I trial assessed safety, pharmacokinetics, and pharmacodynamics of milvexian coadministration with aspirin and/or clopidogrel in healthy participants through 3 drug-drug interaction studies using a 3-period, 3-treatment, crossover design. A total of 113 participants were randomized to receive milvexian (200 mg; twice daily for 5 days) or matched placebo coadministered with once-daily aspirin (325 mg for 5 days) and/or clopidogrel (Day 1: 300 mg; Days 2-5: 75 mg). Milvexian was safe and well tolerated, with and without aspirin and/or clopidogrel. Eight mild bleeding adverse events (AEs) were reported in 5 of 113 participants across various treatment arms. Peak and total exposures of milvexian were similar with or without clopidogrel and/or aspirin. Exposure-dependent prolongation of activated partial thromboplastin time and reduction of FXI clotting activity by milvexian were similar with coadministration of aspirin and/or clopidogrel. Milvexian, with or without coadministration of aspirin and/or clopidogrel, did not affect bleeding time or platelet aggregation. Administration of milvexian alone or with aspirin and/or clopidogrel was safe and well tolerated without increased incidence of AEs, including bleeding. Pharmacokinetic and pharmacodynamic effects of milvexian, including bleeding time, were similar with or without aspirin and/or clopidogrel.ClinicalTrials.gov Identifier: NCT03698513.
Assuntos
Aspirina , Clopidogrel , Interações Medicamentosas , Voluntários Saudáveis , Inibidores da Agregação Plaquetária , Humanos , Clopidogrel/farmacocinética , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Aspirina/farmacocinética , Aspirina/administração & dosagem , Masculino , Feminino , Adulto , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/administração & dosagem , Pessoa de Meia-Idade , Estudos Cross-Over , Adulto JovemRESUMO
BACKGROUND: ADP and ATP are importantly involved in vascular and thrombotic homeostasis, via multiple receptor pathways. Blockade of ADP P2Y12 receptors inhibits platelet aggregation and represents an effective cardiovascular disease prevention strategy. AZD3366 (APT102), a long-acting recombinant form of an optimized CD39L3 human apyrase, has effectively reduced ATP, ADP, and platelet aggregation and provided tissue protection in preclinical models, features that could be very beneficial in treating patients with cardiovascular disease. METHODS AND RESULTS: We conducted this phase 1, first-in-human study of single ascending doses of intravenous AZD3366 or placebo, including doses added to dual antiplatelet therapy with ticagrelor and acetylsalicylic acid. The primary objective was safety and tolerability; secondary and exploratory objectives included pharmacokinetics, pharmacodynamics (measured as inhibition of platelet aggregation), adenosine diphosphatase (ADPase) activity, and ATP/ADP metabolism. In total, 104 participants were randomized. AZD3366 was generally well tolerated, with no major safety concerns observed. ADPase activity increased in a dose-dependent manner with a strong correlation to AZD3366 exposure. Inhibition of ADP-stimulated platelet aggregation was immediate, substantial, and durable. In addition, there was a prompt decrease in systemic ATP concentration and an increase in adenosine monophosphate concentrations, whereas ADP concentration appeared generally unaltered. At higher doses, there was a prolongation of capillary bleeding time without detectable changes in the ex vivo thromboelastometric parameters. CONCLUSIONS: AZD3366 was well tolerated in healthy participants and demonstrated substantial and durable inhibition of platelet aggregation after single dosing. Higher doses prolonged capillary bleeding time without detectable changes in ex vivo thromboelastometric parameters. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04588727.
Assuntos
Apirase , Aspirina , Inibidores da Agregação Plaquetária , Agregação Plaquetária , Ticagrelor , Humanos , Masculino , Ticagrelor/farmacocinética , Ticagrelor/administração & dosagem , Ticagrelor/efeitos adversos , Feminino , Apirase/metabolismo , Apirase/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Aspirina/administração & dosagem , Aspirina/farmacocinética , Aspirina/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Pessoa de Meia-Idade , Adulto , Método Duplo-Cego , Terapia Antiplaquetária Dupla , Quimioterapia Combinada , Adulto Jovem , Difosfato de Adenosina , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Relação Dose-Resposta a Droga , Resultado do Tratamento , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacologiaRESUMO
Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in Cmax and tmax caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented.
Assuntos
Simulação por Computador , Esvaziamento Gástrico , Modelos Biológicos , Período Pós-Prandial , Solubilidade , Esvaziamento Gástrico/fisiologia , Período Pós-Prandial/fisiologia , Humanos , Febuxostat/farmacocinética , Febuxostat/química , Teobromina/farmacocinética , Teobromina/química , Cafeína/farmacocinética , Cafeína/química , Cafeína/administração & dosagem , Citrato de Sildenafila/farmacocinética , Citrato de Sildenafila/química , Liberação Controlada de Fármacos , Aspirina/farmacocinética , Aspirina/química , Aspirina/administração & dosagemRESUMO
Purpose: To study and compare the pharmacokinetic characteristics of enteric-coated sustained-release (EcSr) aspirin tablets with enteric-coated (Ec) aspirin tablets (Bayer S.p.A) in healthy Chinese participants. Patients and Methods: In this open, randomized, single-dose, three-way, crossover study, 18 healthy participants randomly received 100 mg EcSr tablets pre-prandially (a.c.), EcSr tablets post-prandially (p.c.), or Ec tablets a.c. in each period. The concentrations of acetylsalicylic acid (ASA) and salicylic acid (SA) in plasma were determined by the LC-MS/MS method, and the pharmacokinetic parameters were calculated using WinNonlin (version 8.1). Results: The essential PK parameters under the three treatment conditions (ie Ec a.c., EcSr a.c. and EcSr p.c.) were as follows: Cmax, ASA: 758.38±455.34, 222.77±98.04 and 194.54±61.19 ng, Tmax, ASA: 6.75(2,16), 4.5(2,11) and 8.25(5,11) h, T1/2, ASA: 0.43±0.08, 1.44±0.59 and 4.32±10.04 h, AUC0-t, ASA: 1008.88±452.27, 918.04±238.40 and 845.55±183.25 h·ng/mL; Cmax, SA: 6409.38±2098.52, 2863.53±679.73 and 2913.75±853.27ng/mL, Tmax, SA: 7.25(2,24), 10(3.5-14) and 10(7,14) h, T1/2, SA: 2.21±0.46, 2.69±0.72 and 3.51±2.06h, AUC0-t, SA: 29,131.41±9376.23, 27,243.97±7465.16, 27,240.25±7444.67 h·ng/mL. When taking EcSr aspirin tablets, the 90% confidence intervals of the geometric mean ratios (pre-prandial/post-prandial) of AUC0-t, ASA and AUC0-∞, ASA, Cmax, SA, AUC0-t, SA and AUC0-∞, SA were within the range of 80.00%-125.00%. Conclusion: EcSr aspirin tablets showed less inter-individual variation in release and absorption than Ec aspirin tablets, which was well reflected by comparing essential PK parameters. Furthermore, meals had no significant effect on the pharmacokinetics of EcSr aspirin tablets.
Assuntos
Aspirina , Preparações de Ação Retardada , População do Leste Asiático , Humanos , Aspirina/farmacocinética , Cromatografia Líquida , Estudos Cross-Over , Preparações de Ação Retardada/farmacocinética , Voluntários Saudáveis , Ácido Salicílico , Espectrometria de Massas em Tandem , Comprimidos com Revestimento Entérico/farmacocinéticaRESUMO
Low dose enteric-coated aspirin (EC-ASA) is routinely used for secondary cardiovascular event prevention. However, absorption of EC tablets is poor, which can result in subtherapeutic antiplatelet effects. Phospholipid-aspirin liquid filled capsules (PL-ASA) are a novel FDA-approved immediate-release formulation designed to reduce gastrointestinal (GI) injury by limiting direct contact with the stomach lining. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of PL-ASA versus EC-ASA at a low dose. This randomized, open-label, crossover study assessed PK and PD following a single 81-mg dose of PL-ASA versus EC-ASA under fasting conditions in 36 volunteers without cardiovascular disease between 18 and 75 years of age. Volunteers were randomly assigned 1:1 to either PL-ASA then EC-ASA or vice versa with a minimum 14-day washout. Assessments included PK parameters for acetylsalicylic acid and salicylic acid, platelet aggregation in response to arachidonic acid (AA), and serum thromboxane B2 (TxB2) assessments over 24 h. PL-ASA was rapidly absorbed. PL-ASA reached Tmax 3 h earlier (1.01 vs. 4.00 h, p < 0.0001), with almost double the Cmax (720 vs. 368 ng/mL, p < 0.0001) and overall 44% higher exposure of acetylsalicylic acid (AUC0-t: 601 vs. 416 h*ng/mL, p = 0.0013) compared with EC-ASA. Within 1 h of dosing, PL-ASA achieved significantly lower residual platelet aggregation, which persisted for the full 24 h (median AA-LTA was 47% with PL-ASA vs. 80.5% with EC-ASA; p = 0.0022 at hour-24). Treatment with PL-ASA also resulted in significantly lower serum TxB2 concentrations at each time point compared with EC-ASA (all p-values < 0.05). PL-ASA resulted in faster and more complete aspirin absorption paralleled by more prompt and potent platelet inhibition compared with EC-ASA after a single 81 mg dose. PL-ASA represents an attractive novel aspirin formulation for the secondary prevention of cardiovascular events.Clinical Trial Registration ClinicalTrials.gov identifier: NCT04811625.
Assuntos
Aspirina , Inibidores da Agregação Plaquetária , Ácido Araquidônico , Aspirina/farmacocinética , Aspirina/farmacologia , Cápsulas , Estudos Cross-Over , Humanos , Fosfolipídeos , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Estudos Prospectivos , Ácido Salicílico , Comprimidos , Tromboxano B2RESUMO
A biomaterial that is both bioactive and capable of controlled drug release is highly attractive for bone regeneration. In previous works, we demonstrated the possibility of combining activated carbon fiber cloth (ACC) and biomimetic apatite (such as calcium-deficient hydroxyapatite (CDA)) to develop an efficient material for bone regeneration. The aim to use the adsorption properties of an activated carbon/biomimetic apatite composite to synthetize a biomaterial to be used as a controlled drug release system after implantation. The adsorption and desorption of tetracycline and aspirin were first investigated in the ACC and CDA components and then on ACC/CDA composite. The results showed that drug adsorption and release are dependent on the adsorbent material and the drug polarity/hydrophilicity, leading to two distinct modes of drug adsorption and release. Consequently, a double adsorption approach was successfully performed, leading to a multifunctional and innovative ACC-aspirin/CDA-tetracycline implantable biomaterial. In a second step, in vitro tests emphasized a better affinity of the drug (tetracycline or aspirin)-loaded ACC/CDA materials towards human primary osteoblast viability and proliferation. Then, in vivo experiments on a large cortical bone defect in rats was carried out to test biocompatibility and bone regeneration ability. Data clearly highlighted a significant acceleration of bone reconstruction in the presence of the ACC/CDA patch. The ability of the aspirin-loaded ACC/CDA material to release the drug in situ for improving bone healing was also underlined, as a proof of concept. This work highlights the possibility of bone patches with controlled (multi)drug release features being used for bone tissue repair.
Assuntos
Apatitas/química , Aspirina/administração & dosagem , Materiais Biomiméticos/química , Fibra de Carbono/química , Sistemas de Liberação de Medicamentos/métodos , Tetraciclina/administração & dosagem , Adsorção , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Antibacterianos/farmacocinética , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Aspirina/química , Aspirina/farmacocinética , Regeneração Óssea/efeitos dos fármacos , Substitutos Ósseos/química , Osso e Ossos/metabolismo , Carvão Vegetal/química , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Tetraciclina/química , Tetraciclina/farmacocinéticaRESUMO
Complement-mediated intravascular hemolysis occurs in canine immune-mediated hemolytic anemia (IMHA). Complement inhibitors might enhance treatment of this disease. Dimers of acetylsalicylic acid such as 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS) have been reported to inhibit complement. This study aimed to characterize the pharmacokinetics and safety profile of a single 3 mg/kg IV dose of DAS in 6 healthy mixed-breed dogs. Serum concentrations of DAS and its primary metabolites were measured by liquid chromatography-tandem mass spectrometry at baseline and at 5, 10 and 30 min, and 1, 2, 4, 6, 8, 12, 18 and 24 h post-administration. Additional blood samples were collected 7 and 14 days after drug administration. Complete blood counts, serum chemistry panels, C-reactive protein measurements, coagulation testing and cytokine analyses were used for safety monitoring. Following IV administration of 3 mg/kg DAS, the estimated mean maximum plasma concentration was 54,709 ng/mL. Pharmacokinetic modeling suggested that DAS was eliminated with a half-life value of 8.1 h, equivalent to a clearance of 6.93 L/hr kg and a volume of distribution of 56 mL/kg. Plasma concentrations of the metabolites were measured rapidly (within 15-60 min for M1 and M2 respectively). Overall, the relative exposure to M1 and M2 suggest significant biotransformation of DAS occurred, but DAS was the most abundant circulating species. No adverse clinical reactions were noted following DAS administration and safety studies suggested DAS caused no inflammatory response or coagulation disturbance. Further clinical evaluation of DAS is warranted.
Assuntos
Aspirina/análogos & derivados , Compostos Benzidrílicos/farmacocinética , Animais , Aspirina/farmacocinética , Cromatografia Líquida/veterinária , Cães , Infusões Intravenosas/veterinária , CinéticaRESUMO
Acetylsalicylic acid (aspirin) is one of the most used medications worldwide. The antithrombotic agent acts mainly through inhibition of cyclooxygenase-1 and consequently thromboxane A2 synthesis, causing an irreversible suppression of platelet function. Despite of its proven benefit in the treatment and secondary prevention of atherosclerotic diseases, its use for the primary prevention remains controversial due to an unclear balance between the benefits and risks of aspirin. Moreover, the recent evidence indicates that the risk of major bleeding outweighs the potential to reduce ischemic events in patients without atherosclerotic diseases, thus, precluding the general use of aspirin for the primary prevention.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Transtornos Cerebrovasculares/prevenção & controle , Anti-Inflamatórios não Esteroides/farmacocinética , Aspirina/farmacocinética , Humanos , Prevenção Primária/métodos , Fatores de RiscoRESUMO
Sleep deprivation (SD) is commonly associated with decreased attention, reduced responsiveness to external stimuli, and impaired locomotor and cognitive performances. Strong evidence indicates that SD disrupts neuro-immuno-endocrine system which is also linked to cognitive function. Recently Zebrafish have emerged as a powerful model sharing organizational and functional characteristics with other vertebrates, providing great translational relevance with rapid and reliable screening results. In the current study, we examined the effects of acetylsalicylic acid (aspirin) on cognitive and locomotor activity in sleep deprived Zebrafish model. Learning and memory were assessed by T-maze and locomotor activity was assessed by partition preference and swimming time in spinning tasks. Furthermore, brain bioavailability of aspirin was determined by high performance liquid chromatography. Following drug exposure and tasks, histopathology of the brain was performed. It was observed that three-day SD significantly reduces learning and memory and locomotion in the Zebrafish. Aspirin was found to restore SD induced cognitive decline and improve the locomotor functions. Neuro-inflammation and impaired functional network connectivity is linked to cognitive defects, which implicate the possible benefits of immunotherapeutics. In the present study, aspirin decreased neutrophil infiltration, and increased spine density in dentate gyrus granular and shrinkage and basophil in the CA1 neurons of hippocampus. This hints the benefit of aspirin on neuroimmune functions in sleep deprived fish and warrants more studies to establish the clear molecular mechanism behind this protective effect.
Assuntos
Aspirina/farmacologia , Cognição/efeitos dos fármacos , Privação do Sono , Animais , Aspirina/farmacocinética , Aspirina/toxicidade , Disponibilidade Biológica , Masculino , Natação , Testes de Toxicidade Aguda , Peixe-ZebraRESUMO
AIM: To compare the pharmacodynamic effect of an oral loading dose of 'noncoated' ASA 300âmg vs. an intravenous bolus injection of lysine acetylsalicylate 150âmg in patients with STEMI undergoing pPCI. METHODS: This was a prospective single-center, open label, pharmacodynamic study, including nonconsecutive patients presenting at our catheterization laboratory with STEMI undergoing pPCI and not receiving ASA within the previous 7 days. Pharmacodynamic analyses were performed at five time points: baseline, and 1, 2, 4 and 12âh after the loading dose, and measured as ASA reaction units (ARU) by the Verify Now System. An ARU more than 550 was considered as nonresponsiveness to study drugs. The primary end point was the different rate of patients with ARU more than 550 at 2âh after the loading dose of oral vs. intravenous ASA. Secondary end points included the comparison of ARU more than 550 at the other time points and the comparison of continuous ARU at each time point. RESULTS: The study was planned with a sample size of 68 patients, but it was prematurely stopped due to slow enrollment after the inclusion of 23 patients, 12 randomized to oral ASA and 11 to intravenous lysine acetylsalicylate. At 2âh the rate of patients with ARU more than 550 was numerically but not significantly higher in patients receiving oral ASA as compared with intravenous lysine acetylsalicylate (33 vs. 14.2%; Δ -0.19, 95% confidence interval -0.59-0.21, Pâ=â0.58). The difference over time was NS (Pâ=â0.98), though the prevalence of ARU more than 550 was higher at the other time points. Both routes of administration reduced ARU values over time, though with no overall significant difference between profiles (P overallâ=â0.48). CONCLUSION: In patients with STEMI undergoing pPCI the rate of nonresponsiveness to ASA was not different comparing an oral 'noncoated' loading dose of ASA with an intravenous bolus injection of lysine acetylsalicylate. However, as patient enrollment was prematurely terminated, this study is underpowered to draw a definite conclusion.
Assuntos
Aspirina/análogos & derivados , Monitoramento de Medicamentos/métodos , Lisina/análogos & derivados , Intervenção Coronária Percutânea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Administração Oral , Idoso , Aspirina/administração & dosagem , Aspirina/farmacocinética , Unidades de Cuidados Coronarianos/métodos , Unidades de Cuidados Coronarianos/estatística & dados numéricos , Feminino , Humanos , Injeções Intravenosas , Lisina/administração & dosagem , Lisina/farmacocinética , Masculino , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacocinética , Cuidados Pré-Operatórios/métodos , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgiaRESUMO
Veverimer is a polymer being developed as a potential treatment of metabolic acidosis in patients with chronic kidney disease. Veverimer selectively binds and removes hydrochloric acid from the gastrointestinal tract, resulting in an increase in serum bicarbonate. Veverimer is not systemically absorbed, so potential drug-drug interactions (DDIs) are limited to effects on the absorption of other oral drugs through binding to veverimer in the gastrointestinal tract or increases in gastric pH caused by veverimer binding to hydrochloric acid. In in vitro binding experiments using a panel of 16 test drugs, no positively charged, neutral, or zwitterionic drugs bound to veverimer. Three negatively charged drugs (furosemide, aspirin, ethacrynic acid) bound to veverimer; however, this binding was reduced or eliminated in the presence of normal physiologic concentrations (100-170 mM) of chloride. Veverimer increased gastric pH in vivo by 1.5-3 pH units. This pH elevation peaked within 1 hour and had returned to baseline after 1.5-3 hours. Omeprazole did not alter the effect of veverimer on gastric pH. The clinical relevance of in vitro binding and the transient increase in gastric pH was evaluated in human DDI studies using two drugs with the most binding to veverimer (furosemide, aspirin) and two additional drugs with pH-dependent solubility effecting absorption (dabigatran, warfarin). None of the four drugs showed clinically meaningful DDI with veverimer in human studies. Based on the physicochemical characteristics of veverimer and results from in vitro and human studies, veverimer is unlikely to have significant DDIs. SIGNIFICANCE STATEMENT: Patients with chronic kidney disease, who are usually on many drugs, are vulnerable to drug-drug interactions (DDIs). The potential for DDIs with veverimer was evaluated based on the known site of action and physicochemical structure of the polymer, which restricts the compound to the gastrointestinal tract. Based on the findings from in vitro and human studies, we conclude that veverimer is unlikely to have clinically significant DDIs.
Assuntos
Acidose/tratamento farmacológico , Polímeros/farmacocinética , Insuficiência Renal Crônica/tratamento farmacológico , Absorção Fisico-Química , Acidose/etiologia , Administração Oral , Adolescente , Adulto , Aspirina/administração & dosagem , Aspirina/química , Aspirina/farmacocinética , Estudos Cross-Over , Dabigatrana/administração & dosagem , Dabigatrana/química , Dabigatrana/farmacocinética , Interações Medicamentosas , Ácido Etacrínico/administração & dosagem , Ácido Etacrínico/química , Ácido Etacrínico/farmacocinética , Feminino , Furosemida/administração & dosagem , Furosemida/química , Furosemida/farmacocinética , Absorção Gastrointestinal , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Polímeros/administração & dosagem , Polímeros/química , Polimedicação , Insuficiência Renal Crônica/complicações , Solubilidade , Varfarina/administração & dosagem , Varfarina/química , Varfarina/farmacocinética , Adulto JovemRESUMO
The main role of platelets is to contribute to hemostasis. However, under pathophysiological conditions, platelet activation may lead to thrombotic events of cardiovascular diseases. Thus, anti-thrombotic treatment is important in patients with cardiovascular disease. This review focuses on a platelet receptor, a transmembrane protein, the Multidrug Resistance Protein 4, MRP4, which contributes to platelet activation, by extruding endogenous molecules responsible for their activation and accumulation. The regulation of the intracellular concentration levels of these molecules by MRP4 turned to make the protein suspicious and at the same time an interesting regulatory factor of platelet normal function. Especially, the possible role of MRP4 in the excretion of xenobiotic and antiplatelet drugs such as aspirin is discussed, thus imparting platelet aspirin tolerance and correlating the protein with the ineffectiveness of aspirin antiplatelet therapy. Based on the above, this review finally underlines that the development of a highly selective and targeted strategy for platelet MRP4 inhibition will also lead to inhibition of platelet activation and accumulation.
Assuntos
Aspirina , Plaquetas/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária , Aspirina/farmacocinética , Aspirina/uso terapêutico , Humanos , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/uso terapêuticoRESUMO
Low-dose aspirin (ASA) is used to prevent cardiovascular events. The most commonly used formulation is enteric-coated ASA (EC-ASA) that may be absorbed more slowly and less efficiently in some patients. To uncover these "non-responders" patients, the availability of proper analytical methods is pivotal in order to study the pharmacodynamics, the pharmacokinetics and the metabolic fate of ASA. We validated a high-throughput, isocratic reversed-phase, negative MRM, LC-MS/MS method useful for measuring circulating ASA and salicylic acid (SA) in blood and plasma. ASA-d4 and SA-d4 were used as internal standards. The method was applied to evaluate: (a) the "in vitro" ASA degradation by esterases in whole blood and plasma, as a function of time and concentration; (b) the "in vivo" kinetics of ASA and SA after 7 days of oral administration of EC-ASA or plain-ASA (100 mg) in healthy volunteers (three men and three women, 37-63 years). Parameters of esterases activity were Vmax 6.5 ± 1.9 and Km 147.5 ± 64.4 in plasma, and Vmax 108.1 ± 20.8 and Km 803.2 ± 170.7 in whole blood. After oral administration of the two formulations, tmax varied between 3 and 6 h for EC-ASA and between 0.5 and 1.0 h for plain-ASA. Higher between-subjects variability was seen after EC-ASA, and one subject had a delayed absorption over eight hours. Plasma AUC was 725.5 (89.8-1222) for EC-ASA, and 823.1(624-1196) ng h/mL (median, 25-75% CI) for plain ASA. After the weekly treatment, serum levels of TxB2 were very low (< 10 ng/mL at 24 h from the drug intake) in all the studied subjects, regardless of the formulation or the tmax. This method proved to be suitable for studies on aspirin responsiveness.
Assuntos
Aspirina/farmacocinética , Ensaios de Triagem em Larga Escala/métodos , Administração Oral , Adulto , Área Sob a Curva , Aspirina/administração & dosagem , Aspirina/sangue , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Absorção Gastrointestinal , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Ácido Salicílico/sangue , Ácido Salicílico/farmacocinética , Comprimidos com Revestimento Entérico , Espectrometria de Massas em Tandem/métodosRESUMO
This work attempts to resolve one of the key issues related to the design and development of sustained-release spherule of aspirin for oral formulations, tailored to treat COVID-19. For that, in the Design of Experiments (DOE) an arbitrary interface, "coating efficiency" (CE) is introduced and scaled the cumulative percentage coating (CPC) to get predictable control over drug release (DR). Subsequently, the granules containing ASP are converted to spherules and then to Ethyl cellulose (EC) Coated spherules (CS) by a novel bed coating during the rolling (BCDR) process. Among spherules, one with 0.35 mm than 0.71 mm shows required properties. The CS has a low 1200 angle by Optical Microscopy (OM), smooth surface without cracks by scanning electron microscopy (SEM), and better flow properties (Angle of repose 29.69 ± 0.780, Carr's index 6.73 ± 2.24%, Hausner's Ratio 1.07 ± 0.03) than granules and spherules. Once certain structure-dependent control over release is attained (EC coated spherules shows 10% reduction in burst release (BR) than uncoated spherules showing a release of 80-91%) the predictability is achieved and Design of space (DOS) by DOE (CE-70.14%and CPC-200% and DR-61.54%) is established. The results of DOE to experimentally validated results were within 20% deviation. The aspirin is changing its crystal structure by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) from Form-I to Form-II showing polymorphism inside the drug reservoir with respect to the process. This CE and CPC approach in DOE can be used for delivery system design of other labile drugs similar to aspirin in emergency situations.
Assuntos
Aspirina , Tratamento Farmacológico da COVID-19 , Celulose/análogos & derivados , SARS-CoV-2 , Aspirina/química , Aspirina/farmacocinética , Celulose/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Composição de Medicamentos , Liberação Controlada de Fármacos , HumanosRESUMO
BACKGROUND: Inherited genetic variants can modify the cancer-chemopreventive effect of aspirin. We evaluated the clinical and economic value of genotype-guided aspirin use for colorectal cancer chemoprevention in average-risk individuals. METHODS: A decision analytical model compared genotype-guided aspirin use versus no genetic testing, no aspirin. The model simulated 100,000 adults ≥50 years of age with average colorectal cancer and cardiovascular disease risk. Low-dose aspirin daily starting at age 50 years was recommended only for those with a genetic test result indicating a greater reduction in colorectal cancer risk with aspirin use. The primary outcomes were quality-adjusted life-years (QALY), costs, and incremental cost-effectiveness ratio (ICER). RESULTS: The mean cost of using genotype-guided aspirin was $187,109 with 19.922 mean QALYs compared with $186,464 with 19.912 QALYs for no genetic testing, no aspirin. Genotype-guided aspirin yielded an ICER of $66,243 per QALY gained, and was cost-effective in 58% of simulations at the $100,000 willingness-to-pay threshold. Genotype-guided aspirin was associated with 1,461 fewer polyps developed, 510 fewer colorectal cancer cases, and 181 fewer colorectal cancer-related deaths. This strategy prevented 1,078 myocardial infarctions with 1,430 gastrointestinal bleeding events, and 323 intracranial hemorrhage cases compared with no genetic testing, no aspirin. CONCLUSIONS: Genotype-guided aspirin use for colorectal cancer chemoprevention may offer a cost-effective approach for the future management of average-risk individuals. IMPACT: A genotype-guided aspirin strategy may prevent colorectal cancer, colorectal cancer-related deaths, and myocardial infarctions, while minimizing bleeding adverse events. This model establishes a framework for genetically-guided aspirin use for targeted chemoprevention of colorectal cancer with application toward commercial testing in this population.
Assuntos
Aspirina/administração & dosagem , Neoplasias Colorretais/prevenção & controle , Análise Custo-Benefício/estatística & dados numéricos , Infarto do Miocárdio/prevenção & controle , Prevenção Primária/métodos , Aspirina/economia , Aspirina/farmacocinética , Neoplasias Colorretais/economia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Simulação por Computador , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Testes Genéticos/economia , Testes Genéticos/estatística & dados numéricos , Genótipo , Humanos , Pessoa de Meia-Idade , Modelos Econômicos , Infarto do Miocárdio/economia , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Variantes Farmacogenômicos , Medicina de Precisão/economia , Medicina de Precisão/métodos , Prevenção Primária/economia , Anos de Vida Ajustados por Qualidade de VidaAssuntos
Anticoagulantes , Aspirina , Biomarcadores Farmacológicos/sangue , Tratamento Farmacológico da COVID-19 , COVID-19 , Heparina , Testes Imediatos/estatística & dados numéricos , Tromboelastografia/métodos , Negro ou Afro-Americano/estatística & dados numéricos , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Aspirina/administração & dosagem , Aspirina/farmacocinética , Disponibilidade Biológica , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/fisiopatologia , Feminino , Hemostasia/efeitos dos fármacos , Hemostasia/fisiologia , Heparina/administração & dosagem , Heparina/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacocinética , Testes de Função Plaquetária/métodos , Testes de Função Plaquetária/estatística & dados numéricos , SARS-CoV-2 , Estados Unidos/epidemiologiaRESUMO
Stomach pH may vary following bariatric surgery, with implications for drug delivery/bioavailability. Yet, this parameter has not been studied. In this work, gastric content was aspirated from patients before, immediately after, and the day after different bariatric procedures, and pH was immediately measured. Compared to pre-surgery (1.8), pH was increased one day after one-anastomosis gastric bypass (OAGB) and sleeve gastrectomy (LSG) by 3-4 pH units; pH immediately after these procedures was in between the other 2 time points. Post-OAGB pH was significantly higher than post-LSG (6.4 and 4.9, respectively). Prior adjustable gastric band did not significantly alter baseline pH. We then performed drug dissolution studies of the antiplatelet drugs dipyridamole and aspirin, mimicking pre-surgery, post-LSG and post-OAGB conditions, implementing our pH results and other relevant physiological parameters. Dipyridamole, a weak base, completely dissolved (100% of dose) under pre-surgery conditions, while dissolution was hampered under post-LSG (5%) and post-OAGB (0.25%) conditions, due to solubility limit. Aspirin was not released from enteric-coated tablet under pre-surgery or post-LSG gastric conditions, however, >75% dissolved within 15 min under post-OAGB gastric conditions, indicating potential failure of enteric coating, depending on the bariatric procedure. In conclusion, special care should be taken when using pH-dependent drugs and drug products after bariatric surgery, and the use of pH-independent formulations should be preferred. Overall, this research revealed the interim gastric pH after different bariatric procedures, and potentially important effects on post-bariatric oral drug delivery and treatment.
Assuntos
Cirurgia Bariátrica/efeitos adversos , Mucosa Gástrica/metabolismo , Conteúdo Gastrointestinal/química , Concentração de Íons de Hidrogênio , Administração Oral , Adulto , Aspirina/administração & dosagem , Aspirina/farmacocinética , Dipiridamol/administração & dosagem , Dipiridamol/farmacocinética , Liberação Controlada de Fármacos , Feminino , Mucosa Gástrica/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Período Pré-Operatório , ComprimidosRESUMO
BACKGROUND: It is unclear whether the combination of traditional Chinese medicine and Western medicine leads to interactions in pharmacokinetics (PKs) and pharmacodynamics (PDs). In this study, the influence of salvianolate and aspirin on metabolic enzymes, and the relationship between the blood concentration and pharmacodynamic indexes, were determined. METHOD: In this, randomized, parallel-grouped, single-center clinical trial, 18 patients with coronary heart disease were randomly allocated into three groups: aspirin (AP) group, salvianolate (SV) group, and combination (A + S) group. All treatment courses lasted for 10 days, and blood samples were acquired before and after administration at different timepoints. The expression of catechol-O-methyltransferase (COMT), CD62p, procaspase-activating compound 1 (PAC-1), P2Y12, phosphodiesterase, and mitogen-activated protein kinase 8 (MAPK8) were compared with variance analysis The blood concentrations were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: Sixteen subjects completed the study. No significant difference in COMT was found among groups, although there was a decrease in the SV group. The PK results indicated that the absorption time of salicylic acid was shortened and the AUC0-∞ decreased and the elimination time of salvianolic acid B was prolonged and the AUC0-∞ decreased. The PD results declined after administration. A significant difference was found in MAPK8, CD62p, and P2Y12 expression. Compared with the SV group, a significant difference in P2Y12 in the A + S group was found. CONCLUSION: A pharmacokinetic drug-drug interaction was found in the aspirin and salvianolate combination. Pharmacodynamically, there was no difference between the A + S and AP groups. However, P2Y12 expression in the combination group was superior to that in the SV group. TRIAL REGISTRATION NUMBERS: The trial was registered on October 9, 2017, ClinicalTrials.gov, NCT03306550. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0007D8H&selectaction=Edit&uid=U0003QY8&ts=2&cx=oiuc9g.
Assuntos
Aspirina/farmacocinética , Doença das Coronárias/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacocinética , Extratos Vegetais/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Idoso , Aspirina/efeitos adversos , Pequim , Biotransformação , Catecol O-Metiltransferase/sangue , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , Interações Medicamentosas , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Absorção Gastrointestinal , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Proteína Quinase 8 Ativada por Mitógeno/sangue , Selectina-P/sangue , Extratos Vegetais/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Receptores Purinérgicos P2Y12/sangueAssuntos
Aspirina , Infarto do Miocárdio , Inibidores da Agregação Plaquetária , Administração por Inalação , Idoso , Aspirina/administração & dosagem , Aspirina/farmacocinética , Feminino , Humanos , Masculino , Mastigação , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacocinéticaRESUMO
Based on the enhancement of synergistic antitumour activity to treat cancer and the correlation between inflammation and carcinogenesis, the authors designed chitosan nanoparticles for co-delivery of 5-fluororacil (5-Fu: an as anti-cancer drug) and aspirin (a non-steroidal anti-inflammatory drug) and induced synergistic antitumour activity through the modulation of the nuclear factor kappa B (NF-κB)/cyclooxygenase-2 (COX-2) signalling pathways. The results showed that aspirin at non-cytotoxic concentrations synergistically sensitised hepatocellular carcinoma cells to 5-Fu in vitro. It demonstrated that aspirin inhibited NF-κB activation and suppressed NF-κB regulated COX-2 expression and prostaglandin E2 (PGE2) synthesis. Furthermore, the proposed results clearly indicated that the combination of 5-Fu and aspirin by chitosan nanoparticles enhanced the intracellular concentration of drugs and exerted synergistic growth inhibition and apoptosis induction on hepatocellular carcinoma cells by suppressing NF-κB activation and inhibition of expression of COX-2.