Farmacogenética del clopidogrel en pacientes sometidos a neurointervención percutánea

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Farmacología. Fecha de lectura: 20-07-201

Effect of food on the pharmacokinetics of omeprazole, pantoprazole and rabeprazole

Background: The pharmacokinetics of proton pump inhibitors (PPIs) may be affected by food intake. We aimed to evaluate the effect of food on the pharmacokinetics of omeprazole, rabeprazole, and pantoprazole. Setting: The study population comprised 186 healthy volunteers participating in 6 bioequivalence clinical trials. Method: Subjects were evaluated to determine the effect of a high-fat breakfast on the pharmacokinetics of omeprazole (n = 36), rabeprazole (n = 69), and pantoprazole (n = 81). Main outcome measure: Drug plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. Results: Food affected the pharmacokinetics of omeprazole (increased Tmax and decreased AUC and Cmax), pantoprazole (increased Tmax and decreased AUC), and rabeprazole (increased Tmax, Cmax and half-life). Food increased variability in Tmax for all 3 drugs, delaying absorption around 3 to 4 h and until 20 h in some subjects. Conclusion: As food delays the absorption of PPIs and increases their variability, it would be better to administer these drugs under fasting conditions. Trial registration: European Union Drug Regulating Authorities Clinical Trials Database: EudraCT: 2004-003863-59 (registration date 05/MAR/2004), EudraCT 2006-001162-17 (registration date 17-MAR-2006), EudraCT: 2007-002489-37 (registration date 12-JUN-2007), EudraCT: 2007-002490-31 (registration date 12-JUN-2007), EudraCT: 2010-024029-19 (registration date 23-NOV-2010).The analysis, interpretation of data and the manuscript writing was partially funded by Fundación Teófilo Hernando, a nonprofit foundation linked to Universidad Autónoma de Madri

Urgent hospital admissions caused by adverse drug reactions and medication errors: A population-based study in Spain

Background: Adverse drug reactions (ADR) are a public health issue, due to their great impact on morbidity, mortality, and economic cost. Objective: We aimed to study the percentage of patients admitted urgently as a result of an ADR, considered serious adverse event, or medication error. Also, we intended to identify possible risk factors which would lead to improvements in the prescription and use of medications. Methods: This is a retrospective observational study conducted during February 2019, including patients admitted through the emergency department in our hospital. We evaluated the medical records of those with suspected ADR diagnoses to perform a descriptive analysis of the demographic characteristics. Moreover, after applying the Spanish Pharmacovigilance System causality algorithm, we performed a descriptive analysis of the identified ADR and the drugs involved. We also investigated those cases suspected of being a medication error. Results: During the study period, 847 patients were urgently hospitalized. From those, 71 (29 women and 42 men) were admitted due to an ADR (8.4%, 95% CI 6.5%–10.3%). The mean age was 73 ± 15.9 years old and the mean number of prescribed medications was 7.3 ± 3.6 drugs/patient on admission. The most frequent ADR were opportunistic infections due to antineoplastic and immunomodulator drugs, and bleeding due to antiaggregants and anticoagulants. Five suspected medication errors occurred, being the incidence 0.6% (95% CI 0.08%–1.12%) of total admissions. Conclusions: 8.4% of urgent admissions were attributed to an ADR. Age (75% of patients were ≥ 65 years old), comorbidities and polymedication were the main risk factors. Although medication errors had a very low incidence (0.6% of urgent admissions), they were preventable and should be considered as a focus for action

Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects

Background: Validated genomic biomarkers for oncological drugs are expanding to improve targeted therapies. Pharmacogenetics research focusing on the mechanisms underlying imatinib suboptimal response might help to explain the different treatment outcomes and drug safety profiles. Objective: To investigate whether polymorphisms in genes encoding cytochrome P450 (CYP) enzymes and ABCB1 transporter affect imatinib pharmacokinetic parameters.Methods: A prospective, multicenter, pharmacogenetic pilot study was performed in the context of two separate oral imatinib bioequivalence clinical trials, which included 26 healthy volunteers. DNA was extracted in order to analyze polymorphisms in genes CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and ABCB1. Imatinib plasma concentrations were measured by HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin software. Results: Volunteers (n = 26; aged 24 ± 3 years; 69% male) presented regular pharmacokinetic imatinib data (concentration at 24 h, 436 ± 140 ng/mL and at 72 h, 40 ± 26 ng/mL; AUC0-72 32,868 ± 10,713 ng/mL⋅h; and Cmax 2074 ± 604 ng/mL). CYP2B6 516GT carriers showed a significant reduction of imatinib concentration at 24 h (23%, 391 ng/dL vs 511 ng/dL in 516GG carriers, p = 0.005) and elimination half-life (11%, 12.6 h vs 14.1 h in 516GG carriers, p = 0.041). Carriers for CYP3A4 (*22/*22, *1/*20 and *1/*22 variants) showed a reduced frequency of adverse events compared to *1/*1 carriers (0 vs 64%, p = 0.033). The other polymorphisms analyzed did not influence pharmacokinetics or drug toxicity. Conclusion: CYP2B6 G516T and CYP3A4 *20,*22 polymorphisms could influence imatinib plasma concentrations and safety profile, after single-dose administration to healthy subjects. This finding needs to be confirmed before it is implemented in clinical practice in oncological patients under treatment with imatinib

Role of pharmacogenetics in the treatment of acute myeloid leukemia: systematic review and future perspectives

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by remarkable toxicity and great variability in response to treatment. Plenteous pharmacogenetic studies have already been published for classical therapies, such as cytarabine or anthracyclines, but such studies remain scarce for newer drugs. There is evidence of the relevance of polymorphisms in response to treatment, although most studies have limitations in terms of cohort size or standardization of results. The different responses associated with genetic variability include both increased drug efficacy and toxicity and decreased response or resistance to treatment. A broad pharmacogenetic understanding may be useful in the design of dosing strategies and treatment guidelines. The aim of this study is to perform a review of the available publications and evidence related to the pharmacogenetics of AML, compiling those studies that may be useful in optimizing drug administrationM.S.R. research was supported by Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation, through the Sara Borrell Program (CD21/00022). P.Z. contract with CIBERehd is financed by the “Infraestructura de Medicina de Precisión asociada a la Ciencia y Tecnología (IMPaCT, IMP/00009

Sistema de acciones para el mejoramiento del desempeño profesional de profesores de Lengua Inglesa / A system of actions for the improvement of the professional performance of the English language teachers

Introducción: El desempeño profesional de los profesores de Lengua Inglesa debe proyectar su trabajo hacia el desarrollo de lo cognitivo-afectivo, en unidad dialéctica, con el máximo de flexibilidad y responsabilidad en el cumplimiento de sus funciones. La adquisición de saberes en los especialistas ya graduados se materializa mediante la superación.Objetivo: Proponer un sistema de acciones para el mejoramiento del desempeño profesional pedagógico de los profesores de Lengua Inglesa de la Facultad de Estomatología de La Habana.Métodos: Se realizó una propuesta de sistema de acciones a punto de partida del diagnóstico del estado inicial del desempeño profesional pedagógico. Se utilizó el análisis documental, la modelación y la sistematización en un estudio descriptivo, explicativo de corte transversal. Resultados: Se espera el mejoramiento del desempeño profesional pedagógico de los profesores de Lengua Inglesa de la Facultad de Estomatología de La Habana, en el proceso de enseñanza aprendizaje de la comunicación oral. Conclusiones: Las características del sistema que se ha propuesto así como la concatenación de las acciones y tareas entre sí propician el proceso de superación de los docentes de Lengua Inglesa de la Facultad de Estomatología de La Habana

Impact of polymorphisms in transporter and metabolizing enzyme genes on olanzapine pharmacokinetics and safety in healthy volunteers

Olanzapine is an atypical antipsychotic widely used for the treatment of schizophrenia, which often causes serious adverse drug reactions. Currently, there are no clinical guidelines implementing pharmacogenetic information on olanzapine. Moreover, the Dutch Pharmacogenomics Working Group (DPWG) states that CYP2D6 phenotype is not related to olanzapine response or side effects. Thus, the objective of this candidate-gene study was to investigate the effect of 72 polymorphisms in 21 genes on olanzapine pharmacokinetics and safety, including transporters (e.g. ABCB1, ABCC2, SLC22A1), receptors (e.g. DRD2, HTR2C), and enzymes (e.g. UGT, CYP and COMT), in a cohort of healthy volunteers. Polymorphisms in CYP2C9, SLC22A1, ABCB1, ABCC2, and APOC3 were related to olanzapine pharmacokinetic variability. The incidence of adverse reactions was related to several genes: palpitations to ABCB1 and SLC22A1, asthenia to ABCB1, somnolence to DRD2 and ABCB1, and dizziness to CYP2C9. However, further studies in patients are warranted to confirm the influence of these genetic polymorphisms on olanzapine pharmacokinetics and tolerability.D. Koller is financed by the H2020 Marie Sklodowska-Curie Innovative Training Network721236 grant. Marcos Navares-G´omez is cofinaneced by the European Social Fund and the Youth European Initiative, grant number PEJ-2018-TL/MD-1108

Polymorphisms associated with adalimumab and infliximab response in moderate-to-severe plaque psoriasis

Aims. This study evaluated the influence of pharmacogenetics in psoriatic patients treated with adalimumab and/or infliximab. Materials & methods: Prospective observational study evaluating the association of 124 polymorphisms with the response to adalimumab or infliximab (PASI75) in patients with moderate-to-severe plaque psoriasis at 3 months (n = 95) and 6 months of treatment (n = 90). Significant SNPs for univariate analysis were subjected to multivariate analysis. Results: Five SNPs were associated with PASI75 at 3 months: rs6661932 (IVL), rs2546890 (IL-12B), rs2145623 (NFKBIA), rs9304742 (ZNF816A) and rs645544 (SLC9A8). Furthermore, rs1061624 (TNFR1B) was associated with PASI75 at 6 months. Conclusion: Nevertheless, these biomarkers should be validated in large-scale studies before implementation in clinical practice

The effects of aripiprazole and olanzapine on pupillary light reflex and its relationship with pharmacogenetics in a randomized multiple-dose trial

Aims: Pupillography is a noninvasive and cost-effective method to determine autonomic nerve activity. Genetic variants in cytochrome P450 (CYP), dopamine receptor (DRD2, DRD3), serotonin receptor (HTR2A, HTR2C) and ATP-binding cassette subfamily B (ABCB1) genes, among others, were previously associated with the pharmacokinetics and pharmacodynamics of antipsychotic drugs. Our aim was to evaluate the effects of aripiprazole and olanzapine on pupillary light reflex related to pharmacogenetics. Methods: Twenty-four healthy volunteers receiving 5 oral doses of 10 mg aripiprazole and 5 mg olanzapine tablets were genotyped for 46 polymorphisms by quantitative polymerase chain reaction. Pupil examination was performed by automated pupillometry. Aripiprazole, dehydro-aripiprazole and olanzapine plasma concentrations were measured by high-performance liquid chromatography–tandem mass spectrometry. Results: Aripiprazole affected pupil contraction: it caused dilatation after the administration of the first dose, then caused constriction after each dosing. It induced changes in all pupillometric parameters (P '.05). Olanzapine only altered minimum pupil size (P =.046). Polymorphisms in CYP3A, HTR2A, UGT1A1, DRD2 and ABCB1 affected pupil size, the time of onset of constriction, pupil recovery and constriction velocity. Aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics were significantly affected by polymorphisms in CYP2D6, CYP3A, CYP1A2, ABCB1 and UGT1A1 genes. Conclusions: In conclusion, aripiprazole and its main metabolite, dehydro-aripiprazole altered pupil contraction, but olanzapine did not have such an effect. Many polymorphisms may influence pupillometric parameters and several polymorphisms had an effect on aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics. Pupillography could be a useful tool for the determination of autonomic nerve activity during antipsychotic treatment.Consejería de Educación, Juventud y Deporte, Comunidad de Madrid, Grant/Award Number: PEJD-2017-PRE/BMD-4164; H2020 Marie Skłodowska-Curie Actions, Grant/Award Number: 72123