BackgroundIncreased cortisol levels and genetic polymorphisms have been related to both major depressive disorder and antidepressant treatment outcome. The aim of this study is to evaluate the relationship between circadian salivary cortisol levels, cortisol suppression by dexamethasone and genetic polymorphisms in some HPA axis-related genes to the response to placebo and fluoxetine in depressed patients.MethodsThe diagnosis and severity of depression were performed using the Mini International Neuropsychiatric Interview (M.I.N.I.) and Hamilton depression scale (HAM-D17), respectively. Euthyroid patients were treated with placebo (one week) followed by fluoxetine (20 mg) (two months). Severity of depression was re-evaluated after placebo, three weeks and two months of fluoxetine treatments. Placebo response was defined as HAM-D17 score reductions of at least 25% and to < 15. Early response and response were reductions of at least 50% after three weeks and two months, and remission with ≤ 7 after two months. Plasma TSH, free-T4, circadian salivary cortisol levels and cortisol suppression by dexamethasone were evaluated. Seven genetic polymorphisms located in the Corticotrophin-releasing-hormone-receptor-1 (rs242939, rs242941, rs1876828), Corticotrophin-releasing-hormone-receptor-2 (rs2270007), Glucocorticoid-receptor (rs41423247), FK506-binding-protein-5 (rs1360780), and Arginine-vasopressin (rs3729965) genes were determined. Association analyses between response to placebo/fluoxetine and polymorphism were performed by chi-square or Fisher exact test. Cortisol levels were compared by t-test, ANOVA and the general linear model for repeated measures.Results208 depressed patients were recruited, 187 of whom were euthyroid. Placebo responders, fluoxetine responders and remitters exhibited significantly lower circadian cortisol levels than those who did not respond (p-values of 0.014, 0.008 and 0.021 respectively). Patients who abandoned treatment before the third week also exhibited a trend to low cortisol levels (p = 0.057). The polymorphisms rs242939 (CRHR1) and rs2270007 (CRHR2) were not in Hardy-Weinberg equilibrium. Only the rs242939 polymorphism (CRHR1) exhibited association with early response (three weeks) to fluoxetine (p-value = 0.043). No other association between outcomes and polymorphisms was observed.ConclusionsThese results support the clinical relevance of low salivary cortisol levels as a predictor of antidepressant response, either to placebo or to fluoxetine. Only one polymorphism in the CRHR1 gene was associated with the early response. Other factors may be involved in antidepressant response, although further studies are needed to identify them.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-014-0220-0) contains supplementary material, which is available to authorized users.

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218Determinación del polimorfismo de CYP2C9*2 y su relación con la farmacocinética de acenocumarol en voluntarios sanos. Resumen:Antecedentes: La mayoría de los pacientes que reciben tratamientos con anticoagulantes orales por periodos prolongados presentan variabilidad en la respuesta. El acenocumarol es el anticoagulante oral más prescrito en nuestro país, es biotransformado principalmente por CYP2C9 e investigaciones recientes demuestran que la variante CYP2C9*2 es una de las responsables de la variabilidad de respuesta a acenocumarol.Objetivo: Determinar las diferencias en los pará-metros farmacocinéticos de acenocumarol en voluntarios que presentan la variante alélica CYP2C9*2.Métodos: Se estudiaron 24 voluntarios sanos.La detección de genotipos se realizó mediante PCR-RFLP y los parámetros farmacocinéticos se obtuvieron mediante la concentración plasmática de acenocumarol usando un método validado para UPLC-MS/MS.Resultados: Del total de 24 voluntarios,19 tenían el genotipo CYP2C9*1/*1 (wt/wt), 4 tenían genotipo CYP2C9*1/*2 (heterocigoto) y 1 voluntario tenía genotipo de CYP2C9*2/*2 (homocigoto recesivo). Los parámetros farmacocinéticos del acenocumarol no fueron significativamente diferentes entre los individuos con genotipo CYP2C9*2 y CYP2C9*1. Sin embargo, la farmacocinética de acenocumarol del individuo CYP2C9*2/*2 mostró diferencias relevantes con respecto a la observada en el grupo CYP2C9*1/*1 (tmáx aumentó 1,4 veces, ke disminuyó 1,8 veces y t1/2 aumentó 1,7 veces).Conclusión: La farmacocinética de acenocumarol en el individuo con el genotipo CYP2C9*2/*2 refleja una potencial relevancia de este polimorfismo en el tratamiento con acenocumarol. Aim: to determine pharmacokinetics parameters of acenocumarol in volunteers exhibiting the CYP2C9*2 polymorphic variant. Methods:Genotype detection was performed using PCR-RFLP and pharmacokinetics parameters were obtained from the acenocumarol concentrations, using a UPLC-MS/MS validated method. The project was approved by the institutional Ethics Committee of the University of Chile's Faculty of Medicine.Results: 19 out of 24 volunteers had the CYP2C9*1/*1 genotype, 4 the CYP2C9*1/*2 genotype (heterozygous) and 1 subject had the CYP2C9*2/*2 genotype (recessive homozygous). No statistically significant differences between acenocumarol pharmacokinetics parameters of CYP2C9*2 compared to those with normal variant, CYP2C9*1were observed.. However, a single individual with the CYP2C9*2/*2 genotype showed different pharmacokinetics parameters: tmáx and t1/2 were increased 1.4 and 1.7 times, respectively, and kc was 1.8 times lower compared to the group with the CYP2C9*1/*1 genotype. Conclusion:There are clear differences in genotype-dependent acenocoumarol pharmacokinetics in individuals with the CYP2C9*2/*2 genotype, reflecting a potential relevance of this polymorphism in anticoagulation with acenocumarol.Keywords: Pharmacogenetics, CYP2C9*2, anticoagulants, acenocoumarol.Determinación del polimorfismo de CYP2C9*2 y su relación con la farmacocinética de acenocum...

Changes in bioavailability of anticonvulsant drugs such as topiramate may cause loss of or worsened seizure control. Thus, the purpose of this study was to evaluate, in a double-blind crossover design, the bioavailability between two oral formulations of topiramate in healthy volunteers after a single dose. The protocol, approved by the Institutional Committee of Ethics, consisted of administration of 1 tablet of 100 mg of topiramate of each formulation (Toprel™ and Topamax™), to 20 healthy volunteers after a 12 h overnight fast, using an open, two-period, randomized, crossover and double-blind design. Thus, the plasma concentrations (Cp) of topiramate were measured at predetermined intervals of time, from 0 to 24 h, using a validated UPLC-MS/MS method. Based on plasma concentration-time profiles we obtained the following pharmacokinetic parameters:

The aim of this study was to compare the bioavailability of an oral formulation of the coumarin derivative-vitamine K antagonist acenocoumarol (Acebron™ 4 mg, Test) with the reference formulation (Neo-Sintrom™ 4 mg). We performed a single-dose, double-blind, fasting, 2-period, 2-sequence, crossover study design. Plasma concentrations of acenocoumarol were determined using a validated UPLC-MS/MS method. 24 healthy Chilean volunteers (11 male, 13 female) were enrolled and all of them completed the study. Adverse events were monitored throughout the study. The values of the pharmacokinetic parameters were (mean ± SD): AUC0-24 =1 364.38±499.26 ngxh/mL for the test and 1 328.39±429.20 ngxh/mL for the reference; AUC0-∞ =1 786.00±732.85 ngxh/mL for the test and 1 706.71±599.66 ngxh/mL for the reference; Cmax =180.69±35.11 ng/mL with a Tmax of 1.83±0.95 h for the test and 186.97±38.21 ng/mL with a Tmax of 2.19±0.83 h for the reference. Regarding half life measurements, the mean ± SD of t1/2 were 11.84±4.54 h for the test and 11.08±3.28 h for the reference. The 90% confidence intervals for the test/reference ratio using logarithmic transformed data were 97.89-100.87%, 98.62-101.99% and 98.64-102.38% for Cmax, AUC0-t(24) and AUC0-∞. There were no significant differences in pharmacokinetic parameters between groups.The results obtained in this study lead us to conclude, based on FDA criteria, that the test acenocoumarol formulation (Acebron™, 4 mg tablets) is bioequivalent to the reference product (Neo-Sintrom™, 4 mg tablets).