RESUMEN
Over the last few years, fluoxetine has been one of the most prescribed medications for the treatment of diverse psychiatric conditions in Mexico. Fluoxetine therapeutic effect is consequence of the joint action of the parent drug and its active metabolite, norfluoxetine. However, the clinical efficacy of fluoxetine, can be affected due to diverse factors, such as drug-drug interactions and the large interindividual variability in the pharmacokinetics of this drug. The aim of this study was to determine the factors associated with variability in plasma concentrations of fluoxetine and norfluoxetine and its association with the therapeutic response. Fluoxetine and norfluoxetine plasma concentrations were quantified by liquid chromatography in 81 Mexican patients with mental disorders; 25% of the patients had no medication adherence and 40% were below the reference range of fluoxetine plus norfluoxetine plasma concentrations. The results showed that concentrations can be affected by fluoxetine metabolism caused by CYP2D6 phenotype and the concomitant administration of olanzapine. Furthermore, CYP3A5 and CYP2C19 phenotype were associated with lower anxiety and depression control during treatment with fluoxetine. This study can be a starting point to elucidate the causes of fluoxetine variable response in Mexican patients with mental disorders, as well as to detect and support medication adherence.
Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Fluoxetina/farmacocinética , Trastornos Mentales/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Adulto , Antipsicóticos/efectos adversos , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Depresión/tratamiento farmacológico , Depresión/psicología , Interacciones Farmacológicas , Femenino , Fluoxetina/análogos & derivados , Fluoxetina/sangre , Fluoxetina/metabolismo , Genotipo , Humanos , Masculino , Cumplimiento de la Medicación , Trastornos Mentales/psicología , México , Persona de Mediana Edad , Olanzapina/efectos adversos , Variantes Farmacogenómicas , Farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Resultado del TratamientoRESUMEN
Peripheral serotonin regulates energy metabolism in several mammalian species, however, the potential contribution of serotonergic mechanisms as metabolic and endocrine regulators in growing dairy calves remain unexplored. Objectives were to characterize the role of serotonin in glucose and insulin metabolism in dairy calves with increased serotonin bioavailability. Milk replacer was supplemented with saline, 5-hydroxytryptophan (90 mg/d), or fluoxetine (40 mg/d) for 10-d (n = 8/treatment). Blood was collected daily during supplementation and on days 2, 7, and 14 during withdrawal. Calves were euthanized after 10-d supplementation or 14-d withdrawal periods to harvest liver and pancreas tissue. 5-hydroxytryptophan increased circulating insulin concentrations during the supplementation period, whereas both treatments increased circulating glucose concentration during the withdrawal period. The liver and pancreas of preweaned calves express serotonin factors (ie, TPH1, SERT, and cell surface receptors), indicating their ability to synthesize, uptake, and respond to serotonin. Supplementation of 5-hydroxytryptophan increased hepatic and pancreatic serotonin concentrations. After the withdrawal period, fluoxetine cleared from the pancreas but not liver tissue. Supplementation of 5-hydroxytryptophan upregulated hepatic mRNA expression of serotonin receptors (ie, 5-HTR1B, -1D, -2A, and -2B), and downregulated pancreatic 5-HTR1F mRNA and insulin-related proteins (ie, Akt and pAkt). Fluoxetine-supplemented calves had fewer pancreatic islets per microscopic field with reduced insulin intensity, whereas 5-hydroxytryptophan supplemented calves had increased islet number and area with greater insulin and serotonin and less glucagon intensities. After the 14-d withdrawal of 5-hydroxytryptophan, hepatic mRNA expression of glycolytic and gluconeogenic enzymes were simultaneously downregulated. Improving serotonin bioavailability could serve as a potent regulator of endocrine and metabolic processes in dairy calves.
Asunto(s)
Bovinos/metabolismo , Serotonina/fisiología , 5-Hidroxitriptófano/administración & dosificación , Animales , Glucemia/análisis , Fluoxetina/administración & dosificación , Fluoxetina/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Glucagón/análisis , Insulina/análisis , Insulina/sangre , Hígado/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Páncreas/química , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Serotonina/análisis , Serotonina/sangreRESUMEN
In this study, a specific and quick ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was fully developed and validated for simultaneous measurement of the rat plasma levels of vortioxetine (VOR), Lu AA34443 (the major metabolite of VOR), fluoxetine and its metabolite norfluoxetine with diazepam as the internal standard (IS). After a simple protein precipitation with acetonitrile for sample preparation, the separation of the analytes were performed on an Acquity UPLC BEH C18 (2.1 × 50 mm, 1.7 µm) column, with acetonitrile and 0.1% formic acid in water as mobile phase by gradient elution. The detection was achieved on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode via an electrospray ionization source. Good linearity was observed in the calibration curve for each analyte. The data of precision, accuracy, matrix effect, recovery and stability all conformed to the bioanalytical method validation of acceptance criteria of US Food and Drug Administration recommendations. The newly developed UPLC-MS/MS method allowed simultaneous quantification of VOR, fluoxetine and their metabolites for the first time and was successfully applied to a pharmacokinetic study in rats.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Fluoxetina/sangre , Espectrometría de Masas en Tándem/métodos , Vortioxetina/sangre , Animales , Fluoxetina/química , Fluoxetina/farmacocinética , Modelos Lineales , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Vortioxetina/química , Vortioxetina/farmacocinéticaRESUMEN
A rapid, simple, and sensitive technique for the quantitative detection of fluoxetine and norfluoxetine enantiomers in biological fluids was developed based on the combination of field-amplified sample stacking (FASS)-related capillary electrophoresis (CE) with ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME). The extraction efficiency of UA-DLLME was strongly related to extraction time, salt concentration, type of extraction and dispersion solvents, and volume of extraction and dispersion solvents. The extracted fluoxetine and norfluoxetine enantiomers in a mixture of 50% methanol and 50% deionized water were efficiently stacked using FASS and then separated using cyclodextrin-modified CE. Under optimal conditions of FASS (chiral selector, 3 mM trimethyl-ß-cyclodextrin; and background electrolyte, 100 mM phosphate buffer) and UA-DLLME (extraction solvent, 200 µL of acetone; and dispersed solvent, 50 µL of C2H2Cl4 in 1 mL of the sample solution), the obtained enrichment factors of fluoxetine and norfluoxetine enantiomers reached approximately 2000. The linear ranges for the quantification of fluoxetine and norfluoxetine enantiomers were 0.3-150 and 0.6-150 nM, respectively. The relative standard deviations in peak areas and migration time for four analytes were less than 3.3% and 6.3%, respectively. The proposed system provided limits of detection (signal-to-noise ratio of 3) for four analytes corresponding to 0.1 nM. The precision and accuracy for urine and serum samples were less than 6.8 and 8.3%, respectively. These findings suggested that the proposed system exhibited a high potential for the reliable determination of fluoxetine and norfluoxetine enantiomers in clinical samples. Graphical abstract.
Asunto(s)
Líquidos Corporales/química , Electroforesis Capilar/métodos , Fluoxetina/análogos & derivados , Fluoxetina/análisis , Microextracción en Fase Líquida/métodos , Inhibidores Selectivos de la Recaptación de Serotonina/análisis , Sonicación , Fluoxetina/sangre , Fluoxetina/orina , Humanos , Límite de Detección , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/orina , Espectrofotometría Ultravioleta/métodos , EstereoisomerismoRESUMEN
The aim of antidepressant therapy is to induce remission and prevent relapses of major depressive disorder with minimum adverse effects during the treatment. Due to high variability in metabolism, therapeutic drug monitoring is recommended as a useful tool for individualisation of the therapy. For this purpose, we have developed simple and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for quantification of fluoxetine (FLX), venlafaxine (VEN), vortioxetine (VTX) and their active metabolites norfluoxetine (NFLX) and O-desmethylvenlafaxine (ODV). After one-step extraction procedure using OSTRO plate, analytes were separated by gradient elution on Acquity UPLC BEH C18 (50â¯×â¯2.1â¯mm, 1.7⯵m) column with runtime 4.2â¯min. The detection was done on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode with transitions at m/z 310.23 â 148.20 for FLX, m/z 296.23 â 134.20 for NFLX, m/z 278.31 â 121.13 for VEN, m/z 264.31 â 107.14 for ODV and m/z 299.19 â 150.05 for VTX using a positive electrospray ionisation interface. The method was successfully validated according to the European Medicine Agency guideline for the selectivity, linearity and lower limit of detection, precision and accuracy, matrix effect, extraction recovery, carryover, dilution integrity and stability over a concentration range of 1-300â¯ng/mL for FLX, NFLX, VEN, ODV and 0.2-100â¯ng/mL VTX. Extraction recovery for each analyte was > 80 %, and no significant matrix effects were observed. The developed method was employed for quantification of antidepressants in clinical samples from patients treated with either FLX, VEN, or VTX.
Asunto(s)
Fluoxetina/análogos & derivados , Fluoxetina/análisis , Extracción Líquido-Líquido/métodos , Clorhidrato de Venlafaxina/análogos & derivados , Clorhidrato de Venlafaxina/análisis , Vortioxetina/análogos & derivados , Vortioxetina/análisis , Adolescente , Adulto , Anciano , Antidepresivos/sangre , Niño , Cromatografía Líquida de Alta Presión/métodos , Trastorno Depresivo Mayor/sangre , Fluoxetina/sangre , Humanos , Persona de Mediana Edad , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem/métodos , Clorhidrato de Venlafaxina/sangre , Vortioxetina/sangre , Adulto JovenRESUMEN
Aim: Routine therapeutic drug monitoring is highly recommended since common antidepressant combinations increase the risk of drug-drug interactions or overlapping toxicity. Materials & methods: A magnetic solid-phase extraction by using C18-functionalized magnetic silica nanoparticles (C18-Fe3O4@SiO2 NPs) as sorbent was proposed for rapid extraction of venlafaxine, paroxetine, fluoxetine, norfluoxetine and sertraline from clinical plasma and urine samples followed by ultra-HPLC-MS/MS assay. Results: The synthesized C18-Fe3O4@SiO2 NPs showed high magnetization and efficient extraction for the analytes. After cleanup by magnetic solid-phase extraction, no matrix effects were found in plasma and urine matrices. The analytes showed LODs among 0.15-0.75 ng ml-1, appropriate linearity (R ≥ 0.9990) from 2.5 to 1000 ng ml-1, acceptable accuracies 89.1-110.9% with precisions ≤11.0%. The protocol was successfully applied for the analysis of patients' plasma and urine samples. Conclusion: It shows high potential in routine therapeutic drug monitoring of clinical biological samples.
Asunto(s)
Antidepresivos/análisis , Nanopartículas de Magnetita/química , Antidepresivos/aislamiento & purificación , Antidepresivos/metabolismo , Cromatografía Líquida de Alta Presión , Fluoxetina/análogos & derivados , Fluoxetina/sangre , Fluoxetina/aislamiento & purificación , Fluoxetina/orina , Humanos , Concentración de Iones de Hidrógeno , Límite de Detección , Paroxetina/sangre , Paroxetina/aislamiento & purificación , Paroxetina/orina , Reproducibilidad de los Resultados , Sertralina/sangre , Sertralina/aislamiento & purificación , Sertralina/orina , Dióxido de Silicio/química , Extracción en Fase Sólida , Solventes/química , Espectrometría de Masas en Tándem , Clorhidrato de Venlafaxina/sangre , Clorhidrato de Venlafaxina/aislamiento & purificación , Clorhidrato de Venlafaxina/orinaRESUMEN
BACKGROUND: Antidepressants and antipsychotics are widely prescribed drugs for the treatment of mental diseases. Therapeutic drug monitoring (TDM) is recommended for patients taking these drugs to ensure pharmaceutical efficacy, medication compliance and prevent toxicity. OBJECTIVE: An ultra-high performance liquid chromatography/tandem-mass spectrometry (UPLC-MS/ MS) method was developed for simultaneous determination of two Antidepressants-Fluoxetine (FLU) and Escitalopram (ESC), and two antipsychotics-risperidone (RIS) and aripiprazole (ARI), in human plasma. METHODS: The sample was processed by simple protein precipitation and the targeted analytes were separated on a C18 column by gradient elution with a mobile phase containing 0.1% formic acid (v/v) and acetonitrile. All the analytes were qualitative and quantitative measured by electrospray ionization source with Multiple Reaction Monitoring (MRM) in positive ion mode. A total of 56 plasma samples were obtained from out- or in-patients who were taking the cited four drugs for further analysis. RESULTS: The calibration curves for FLU, ESC, RIS and ARI were linear in the range of 45-1800, 4-320, 2-200 and 50-1800 ng/mL, respectively. The entire analytical time for the analytes was 7.0 min for each run and the extraction efficiency was more than 90%. The sample was stable within various storage conditions. The trough concentrations in patients were measured with the validated method. CONCLUSION: The developed method was successfully used for simultaneous determination of FLU, ESC, RIS and ARI in the plasma of the patients, which provides effective technical support for routine TDM of these four drugs and is of great clinic value for individual therapy.
Asunto(s)
Antidepresivos/sangre , Antipsicóticos/sangre , Aripiprazol/sangre , Citalopram/sangre , Fluoxetina/sangre , Risperidona/sangre , Cromatografía Líquida de Alta Presión , Monitoreo de Drogas , Humanos , Espectrometría de Masas en TándemRESUMEN
The pharmacokinetics of two fluoxetine capsulated dosage forms and two amitriptyline tablet forms after a single oral intake was studied in dogs and healthy volunteers. High significant correlations were detected between plasma concentrations of fluoxetine (r=0.96, p<0.00001, n=11) and amitriptyline (r=0.78, p<0.0224, n=8) in dogs and volunteers. A correlation of medium strength (though insignificant) was detected between nortriptyline concentrations in the plasma of dogs and volunteers (r=0.69, p<0.199, n=5). The bioavailability parameters of the test drugs in dogs and volunteers did not differ. Similar trends of fluoxetine and amitriptyline pharmacokinetic parameters were revealed in volunteers and animals. Methods for extrapolation of experimental pharmacokinetics parameters of fluoxetine and amitriptyline obtained on dogs for humans are proposed and validated.
Asunto(s)
Amitriptilina/farmacocinética , Fluoxetina/farmacocinética , Nortriptilina/sangre , Administración Oral , Amitriptilina/administración & dosificación , Amitriptilina/sangre , Animales , Disponibilidad Biológica , Perros , Femenino , Fluoxetina/administración & dosificación , Fluoxetina/sangre , Humanos , MasculinoRESUMEN
Peripheral serotonin has been shown to regulate important physiological functions such as energy homeostasis and immunity, particularly in rodent and humans, but its role is poorly understood in livestock species. Herein, we tested the safety and effectiveness of increasing serotonin bioavailability in preweaned dairy calves by oral supplementation of a serotonin precursor (5-hydroxytryptophan, 5-HTP) or a serotonin reuptake inhibitor (fluoxetine, FLX). Bull Holstein calves (21 ± 2 d old; N = 24) were fed milk replacer (8 L/d) supplemented with either saline as control (CON, 8 mL/d, n = 8), FLX (40 mg/d, approx. 0.8 mg/kg; n = 8), or 5-HTP (90 mg/d, approx. 1.8 mg/kg; n = 8) for 10 consecutive days in a complete randomized block design. Heart rate (HR), respiration rate, rectal temperature, and health scores were recorded daily. Hip height and body weight were measured at d 1, 5, and 10 relative to initiation of supplementation. Blood samples were collected once before the supplementation period (d 1), during the 10-d supplementation period (daily), and during a 14-d withdrawal period (d 2, 3, 4, 7, and 14 relative to initiation of withdrawal). Cerebrospinal fluid and muscle tissue were collected from a subset of calves (n = 12) that were euthanized after the 10-d supplementation or 14-d withdrawal period. Whole blood serotonin concentrations increased in 5-HTP calves and decreased in FLX calves compared with CON (P < 0.001), indicating that serotonin bioavailability was increased in both groups. Whole blood serotonin concentrations of 5-HTP and FLX calves returned to CON levels after 7 d of withdrawal. All calves grew and were considered healthy throughout the study. In fact, calves fed 5-HTP had higher average daily gain compared with CON (0.87 vs 0.66 ± 0.12 kg/d, P = 0.05). Calves fed FLX had lower HR (P = 0.02) and greater red blood cells and hemoglobin counts on d 10 of supplementation compared with CON (P < 0.01). After the 14-d withdrawal period, FLX was not detected in circulation of FLX calves, but was still present in the muscle tissue. Our results demonstrate that manipulation of the serotonin pathway by supplementing FLX or 5-HTP is a feasible and safe approach in preweaned dairy calves; however, it takes more than 14 d for FLX to be completely withdrawn from the body.
Asunto(s)
Conducta Animal/fisiología , Bovinos/crecimiento & desarrollo , Fluoxetina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/farmacología , Animales , Bovinos/sangre , Bovinos/fisiología , Suplementos Dietéticos , Heces/química , Fluoxetina/sangre , Fluoxetina/líquido cefalorraquídeo , Fluoxetina/farmacocinética , Serotonina/sangre , Serotonina/farmacocinética , Distribución TisularRESUMEN
A simple and sensitive chromatographic method has been developed for the quantitative analysis of an antiviral agent, daclatasvir (DCV), that commonly prescribed for the treatment of hepatitis C viral (HCV) infection. The method was applied to detect DCV in human plasma and real blood samples collected from patients diagnosed with HCV and treated with DCV. The analysis strategy was based on recording the native fluorescence of DCV in plasma, after pre-column treatment to precipitate the plasma proteins using a readily applicable protocol. Chromatographic conductions, factors influencing the fluorescence and stability studies were also investigated. Furthermore, the method was validated according to the International Conference on Harmonization (ICH) guidelines and could be used to detect DCV in plasma over a linear range of 1.0-4000 ng/mL, with an acceptable sensitivity as the limit of detection (LOD) was 0.025 ng/mL. In addition, the study was extended to evaluate the pharmacokinetic interaction between DCV and a co-prescribed antidepressant drug, fluoxetine (FLX) in real blood samples, collected from volunteering patients who were diagnosed with HCV and treated with DCV alone or combined with FLX. The results showed a significant influence of FLX on the pharmacokinetic profile of DCV. The findings observed in this study could be used by clinical pharmacists to adjust the DCV dose, when combined with FLX, during the HCV treatment.
Asunto(s)
Fluoxetina/sangre , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/sangre , Área Bajo la Curva , Carbamatos , Cromatografía Líquida de Alta Presión , Interacciones Farmacológicas , Estabilidad de Medicamentos , Fluoxetina/administración & dosificación , Fluoxetina/uso terapéutico , Hepatitis C Crónica/sangre , Humanos , Imidazoles/administración & dosificación , Imidazoles/uso terapéutico , Límite de Detección , Pirrolidinas , Reproducibilidad de los Resultados , Valina/análogos & derivadosRESUMEN
1. The objective was to determine the ontogeny of stereoselective fluoxetine (FX) disposition in postnatal sheep from newborn to adulthood. 2. Catheters were implanted in a carotid artery and jugular vein. FX was administered intravenously, followed by serial arterial blood and cumulative urine collection. The concentrations of R,S-FX and R,S-norfluoxetine (R,S-NFX) in samples were measured using a validated enantioselective LC/MS/MS analytical method. 3. The metabolism of FX at 4.2 ± 0.4 days was limited compared to adults, but had developed compared to the fetus. Total body clearance (ClTB) did not significantly increase up to 33.6 ± 0.9 days, but significantly increased at 98.5 ± 2.0 days, with no further changes up to 397.3 ± 8.5 days. Up to 13.4 ± 0.8 days, the disposition of FX included Phase I metabolism to NFX and trifluoromethylphenol (TFMP), and renal elimination. At 32.9 ± 0.9 days, metabolism included Phase II conjugates of FX and NFX. Renal elimination of these compounds was low. 4. The elimination of FX increased in a non-linear manner during the first year in sheep. The metabolism and disposition of FX and NFX in plasma and urine were stereoselective and this appeared due to both stereoselective protein binding and metabolism.
Asunto(s)
Fluoxetina/farmacocinética , Animales , Animales Recién Nacidos , Proteínas Sanguíneas/metabolismo , Femenino , Fluoxetina/análogos & derivados , Fluoxetina/sangre , Fluoxetina/química , Fluoxetina/metabolismo , Inactivación Metabólica , Inyecciones Intravenosas , Isomerismo , Masculino , Tasa de Depuración Metabólica , OvinosRESUMEN
Depression is the largest cause of disability worldwide, affecting 350 million people. Notwithstanding that clinical trials demonstrate antidepressants efficacy, the efficient response can vary individually concerning therapeutic dosage. Although important, plasma levels monitoring remains an analytical challenge whereas clean-up and pre-concentration represent critical steps. Therefore, this study aims to develop, optimize and validate a method for fluoxetine determination in human plasma, employing a laboratory-made device consisting of a PDMS stir bar sorptive for extraction, coupled with high-performance liquid chromatography-fluorescence detection (SBSE-HPLC-FD). Optimization involved sorption-desorption steps. For sorption, temperature and time were assessed by factorial and central composite design approaches, taking into account the desirability and the response surface results, with stirring speed also examined. For desorption kinetics and ultrasonic and magnetic stirring mode were evaluated. The proposed method after validation was robust, linear (25.00-1000.00 ng mL-1 , R2 > 0.98) and presented good intra- (RSD 4.18%) and inter-day-assay (RSD 11.60%) precision and accuracy (recovery 109.60%), allowing reliable quantitation without interference. The method was successfully applied to real samples. SBSE-HPLC-FD could represent a feasible alternative with good cost-benefit for low-volume samples and therapeutic drug monitoring, as well as contributing to correlation studies between plasma fluoxetine levels and clinical response, which is still little studied.
Asunto(s)
Fraccionamiento Químico/métodos , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Fluoxetina/sangre , Fraccionamiento Químico/instrumentación , Humanos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Espectrometría de FluorescenciaRESUMEN
Animal studies using tests and models have demonstrated that magnesium exerts an antidepressant effect. The literature contains few studies in humans involving attempts to augment antidepressant therapy with magnesium ions. The purpose of our study was to assess the efficacy and safety of antidepressant treatment, in combination with magnesium ions. A total of 37 participants with recurrent depressive disorder who developed a depressive episode were included in this study. As part of this double-blind study, treatment with the antidepressant fluoxetine was accompanied with either magnesium ions (120 mg/day as magnesium aspartate) or placebo. During an 8-week treatment period, each patient was monitored for any clinical abnormalities. Moreover, serum fluoxetine and magnesium levels were measured, and pharmaco-electroencephalography was performed. The fluoxetine + magnesium and fluoxetine + placebo groups showed no significant differences in either Hamilton Depression Rating Scale (HDRS) scores or serum magnesium levels at any stage of treatment. Multivariate statistical analysis of the whole investigated group showed that the following parameters increased the odds of effective treatment: lower baseline HDRS scores, female gender, smoking, and treatment augmentation with magnesium. The parameters that increased the odds of remission were lower baseline HDRS scores, shorter history of disease, the presence of antidepressant-induced changes in the pharmaco-EEG profile at 6 h after treatment, and the fact of receiving treatment augmented with magnesium ions. The limitation of this study is a small sample size.
Asunto(s)
Afecto/efectos de los fármacos , Antidepresivos de Segunda Generación/administración & dosificación , Ácido Aspártico/administración & dosificación , Trastorno Depresivo/tratamiento farmacológico , Suplementos Dietéticos , Fluoxetina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Adulto , Anciano , Antidepresivos de Segunda Generación/sangre , Ácido Aspártico/sangre , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/fisiopatología , Método Doble Ciego , Femenino , Fluoxetina/sangre , Humanos , Masculino , Persona de Mediana Edad , Polonia , Inducción de Remisión , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Adjunctive therapy with olanzapine and fluoxetine has been shown to be beneficial in treatment-resistant depression and the depressive phase of bipolar disorder. Consensus guidelines issued by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie strongly recommend that patients taking olanzapine undergo therapeutic drug monitoring (TDM), and suggest that TDM is useful for patients taking fluoxetine. The aim of the current study was to develop and validate a sensitive, practical, and robust liquid chromatography-tandem mass spectrometry method (LC-MS/MS) for simultaneous determination of olanzapine, fluoxetine, and norfluoxetine in human plasma for routine TDM. Simple liquid-liquid extraction using ethyl acetate was used to extract olanzapine, fluoxetine, and norfluoxetine from 200⯵L of pre-basified human plasma. Analytes were separated on an Agilent Eclipse Plus C18 column (4.6â¯×â¯100â¯mm, 5⯵m) eluted with a mobile phase consisting of methanol:20â¯mM ammonium formate buffer (82.5:17.5, v/v), and then quantified using an electrospray ionization source operated in positive ion multiple reaction monitoring mode. The linear range for the analytes was 0.2-25â¯ng/mL, covering the vast majority of levels encountered in real-life samples. A weighting factor of 1/x2 best fit the calibration curves. The mean internal standard-normalized matrix effects for all analytes were 99.5%-110%. The extraction recoveries were 75%-85% for olanzapine and olanzapined3, and 58%-69% for fluoxetine, norfluoxetine, and their deuterated internal standards. Accuracy and precision values also met the acceptance criteria. The stability assessments showed that QC samples containing the three analytes were stable for at least 1â¯d at room temperature, 21â¯d at -70⯰C, and through three freeze-thaw cycles. Post-preparation storage for 2â¯d in the autosampler did not cause obvious degradation of the investigated compounds. This validated high performance LC-MS/MS method was successfully applied to a pharmacokinetic study in healthy male volunteers.
Asunto(s)
Benzodiazepinas/sangre , Cromatografía Liquida/métodos , Fluoxetina/análogos & derivados , Fluoxetina/sangre , Espectrometría de Masas/métodos , Monitoreo de Drogas , Humanos , Modelos Lineales , Masculino , Olanzapina , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach. METHODS: From January 2015 to August 2015, 64 patients on a stable antidepressant regimen underwent a simultaneous assessment of steady-state antidepressant concentration and DME (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A) and P-glycoprotein transporter activity using a cocktail phenotyping approach. Psychiatric diagnoses were in accordance with DSM-5. RESULTS: We observed a high proportion of subjects (> 20%) with reduced activity of CYP2C19, CYP2D6, CYP3A4, and P-glycoprotein. As expected, higher CYP activity for major metabolic pathways was associated with lower concentration of the parent compound (CYP2C19 and escitalopram, P = .025; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .001), higher concentration of the metabolite (CYP2D6 and O-desmethylvenlafaxine, P = .007), and higher metabolite-to-parent drug ratio (CYP2C19 and escitalopram, P = .03; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .048; CYP2B6 and sertraline, P = .006). Phenotyping also highlighted the relevance of a minor metabolic pathway for venlafaxine (CYP3A4). Insufficient response and adverse reactions to antidepressants were not significantly associated with plasma antidepressant concentration, DME, or P-glycoprotein activity. Tolerance of the phenotypic test in ambulatory settings was found to be excellent. CONCLUSIONS: The phenotypic assessment of DMEs and a transporter is a valuable, well-tolerated method to explore the interindividual variability in drug disposition in clinical settings. The method is able to account for the inhibitory activity of antidepressants themselves and for polymedication, which is frequent in this population of refractory depressed patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02438072.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/sangre , Antidepresivos de Segunda Generación/sangre , Citalopram/sangre , Citocromo P-450 CYP2C19/sangre , Citocromo P-450 CYP2D6/sangre , Citocromo P-450 CYP3A/sangre , Trastorno Depresivo/sangre , Trastorno Depresivo/tratamiento farmacológico , Fluoxetina/sangre , Redes y Vías Metabólicas , Sertralina/sangre , Adulto , Anciano , Trastorno Bipolar/sangre , Trastorno Bipolar/tratamiento farmacológico , Estudios Transversales , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Therapeutic drug monitoring (TDM) of the widely prescribed antidepressant fluoxetine (FLU) is recommended in certain situations, such as occurrence of toxicity, inadequate response or suspect of poor adherence. Dried blood spot (DBS) sampling is an increasingly studied alternative for TDM, particularly for outpatients, due to its ease of collection and inherent stability. OBJECTIVES: The aim of this study was to develop and validate an LC-MS/MS assay for the simultaneous quantification of FLU and norfluoxetine (NFLU) in DBS. DESIGN AND METHODS: The assay is based on a liquid extraction of single DBS with 8mm of diameter, using FLU-D6 as the internal standard, followed by reversed phase separation in an Accucore® C18 column (100×2.1mm, 2.6µm). Mobile phase was composed of water and acetonitrile (gradient from 80:20 to 50:50, v/v), both containing formic acid 0.1%. The assay was validated and applied to 30 patients under FLU pharmacotherapy. RESULTS: The assay was linear in the range 10-750ngmL-1. Precision assays presented CV% of 3.13-9.61 and 3.54-7.99 for FLU and NFLU, respectively, and accuracy in the range of 97.98-110.44% and 100.25-105.8%. FLU and NFLU were stable at 25 and 45°C for 7days. The assay was evaluated in 30 patients under FLU treatment. Concentrations of both compounds were higher in DBS than in plasma, and the use of the multiplying factors 0.71 and 0.68 for FLU and NFLU, respectively, allowed acceptable estimation of plasma concentrations, with median prediction bias of -0.55 to 0.55% and mean differences of 0.4 to 2.2ngmL-1. CONCLUSIONS: The presented data support the clinical use of DBS for therapeutic drug monitoring of FLU.
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Cromatografía Líquida de Alta Presión/métodos , Fluoxetina/análogos & derivados , Fluoxetina/análisis , Espectrometría de Masas en Tándem/métodos , Cromatografía Liquida/métodos , Pruebas con Sangre Seca/métodos , Monitoreo de Drogas/métodos , Fluoxetina/sangre , Hematócrito , Humanos , Reproducibilidad de los ResultadosRESUMEN
Deficits in neuronal inhibition via gamma-aminobutyric acid (GABA) type A receptors (GABAA-Rs) are implicated in the pathophysiology of major depressive disorder and the therapeutic effects of current antidepressant treatments, however, the relevant GABAA-R subtype as defined by its alpha subunit is still unknown. We previously reported anxiety- and depressive-like behavior in alpha2+/- and alpha2-/- mice, respectively (Vollenweider, 2011). We sought to determine whether this phenotype could be reversed by chronic antidepressant treatment. Adult male mice received 4 or 8mg/kg fluoxetine or 53mg/kg desipramine in their drinking water for four weeks before undergoing behavioral testing. In the novelty suppressed feeding test, desipramine had anxiolytic-like effects reducing the latencies to bite and to eat the pellet in both wild-type and alpha2+/- mice. Surprisingly, 4mg/kg fluoxetine had anxiogenic-like effects in alpha2+/- mice increasing latency to bite and to eat while 8mg/kg fluoxetine increased the latency to eat in both wild-type and alpha2+/- mice. In the forced swim and tail suspension tests, chronic desipramine treatment increased latency to immobility in wild-type and alpha2-/- mice. In contrast, chronic fluoxetine treatment increased immobility in alpha2-/- mice in both tasks while generally having no effect in wild-type mice. These findings suggest that in preclinical paradigms of anxiety and behavioral despair the antidepressant-like effects of desipramine are independent of alpha2-containing GABAA-Rs, while a reduction in alpha2 expression leads to an increased sensitivity to anxiogenic- and prodepressant-like effects with chronic fluoxetine treatment, pointing to a potential role of alpha2-containing GABAA-Rs in the response to serotonin-selective antidepressants.
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Inhibidores de Captación Adrenérgica/farmacología , Antidepresivos/farmacología , Desipramina/farmacología , Fluoxetina/farmacología , Receptores de GABA-A/deficiencia , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores de Captación Adrenérgica/sangre , Animales , Antidepresivos/sangre , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Desipramina/sangre , Relación Dosis-Respuesta a Droga , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Fluoxetina/análogos & derivados , Fluoxetina/sangre , Masculino , Ratones de la Cepa 129 , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Fenotipo , Receptores de GABA-A/genética , Inhibidores Selectivos de la Recaptación de Serotonina/sangreRESUMEN
The objective of this study was to compare serum concentrations of transdermal fluoxetine compounded in Lipoderm base versus commercially available oral fluoxetine tablets. Sixteen clinically healthy, client-owned cats that were at least one year of age were enrolled. Cats weighed between three and seven kilograms, had no comorbidities, and were behavior medication naïve. Cats were recruited from January 2016 through April 2016. Eight cats were assigned to each medication group based on owner preference. The cats received either oral (1 mg/kg) or transdermal (5 mg/kg; maximum 25 mg daily) fluoxetine compounded in a transdermal base (PCCA Lipoderm), administered daily for 60 days. Serum levels of fluoxetine and norfluoxetine were assessed as a surrogate for relative efficacy. Serum was collected and analyzed by high-performance liquid chromatography-mass spectrometry/mass spectrometry at baseline and days 5, 10, 30, 45, and 60 post-drug start. Adverse effects were monitored during physical exams, speaking with owners, and laboratory analysis of liver function tests at baseline and days 5, 30, and 60 post-drug start. Serum fluoxetine concentrations significantly differed between the treatment groups at days 45 and 60 post-drug start. Norfluoxetine concentrations significantly differed at days 30, 45, and 60 post-drug start. Blood concentrations of fluoxetine and norfluoxetine significantly differed between oral and transdermal routes after 30 days of treatment. Oral fluoxetine concentrations were consistently higher. Transdermal fluoxetine appeared to be well-tolerated, but a lack of knowledge regarding effective blood levels makes it unclear if a clinical effective response would be obtained at the blood concentrations achieved.
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Fluoxetina/administración & dosificación , Fluoxetina/sangre , Administración Cutánea , Administración Oral , Animales , Gatos , Fluoxetina/análogos & derivados , Comprimidos/administración & dosificaciónRESUMEN
A sensitive and rapid method based on alcohol-assisted dispersive liquid-liquid microextraction followed by high-performance liquid chromatography for the determination of fluoxetine in human plasma and urine samples was developed. The effects of six parameters on the extraction recovery were investigated and optimized utilizing Plackett-Burman design and Box-Benken design, respectively. According to the Plackett-Burman design results, the volume of disperser solvent, extraction time, and stirring speed had no effect on the recovery of fluoxetine. The optimized conditions included a mixture of 172 µL of 1-octanol as extraction solvent and 400 µL of methanol as disperser solvent, pH of 11.3 and 0% w/v of salt in the sample solution. Replicating the experiment in optimized condition for five times, gave the average extraction recoveries equal to 90.15%. The detection limit of fluoxetine in human plasma was obtained 3 ng/mL, and the linearity was in the range of 10-1200 ng/mL. The corresponding values for human urine were 4.2 ng/mL with the linearity range from 10 to 2000 ng/mL. Relative standard deviations for intra and inter day extraction of fluoxetine were less than 7% in five measurements. The developed method was successfully applied for the determination of fluoxetine in human plasma and urine samples.