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1.
Drug Metab Pharmacokinet ; 35(2): 191-200, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32184039

RESUMEN

Atomoxetine is an approved medicine for attention-deficit/hyperactivity disorder and a cytochrome P450 2D6 (CYP2D6) probe substrate. Simple physiologically based pharmacokinetic (PBPK) models and compartment models were set up to account for drug monitoring results of 33 Japanese patients (6-15 years of age) to help establish the correct dosage for the evaluation of clinical outcomes. The steady-state one-point drug monitoring data for the most participants indicated the extensive biotransformation of atomoxetine to 4-hydroxyatomoxetine under individually prescribed doses of atomoxetine. However, 5 participants (with impaired CYP2D6 activity scores based on the CYP2D6 genotypes) showed high plasma concentrations of atomoxetine (0.53-1.5 µM) compared with those of total 4-hydroxyatomoxetine (0.49-1.4 µM). Results from full PBPK models using the in-built Japanese pediatric system of software Simcyp, one-compartment models, and new simple PBPK models (using parameters that reflected the subjects' small body size and normal/reduced CYP2D6-dependent clearance) could overlay one-point measured drug/metabolite plasma concentrations from almost common 28 participants within threefold ranges. Validated one-compartment or simple PBPK models can be used to predict steady-state plasma concentrations of atomoxetine and/or its primary metabolites in Japanese pediatric patients (>6 years) who took a variety of individualized doses in a clinical setting.


Asunto(s)
Clorhidrato de Atomoxetina/farmacocinética , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Citocromo P-450 CYP2D6/genética , Modelos Biológicos , Fenoles/farmacocinética , Propilaminas/farmacocinética , Adolescente , Clorhidrato de Atomoxetina/sangre , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Niño , Citocromo P-450 CYP2D6/metabolismo , Monitoreo de Drogas , Femenino , Genotipo , Humanos , Masculino , Fenoles/sangre , Propilaminas/sangre
2.
Forensic Sci Int ; 291: e1-e3, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30228015

RESUMEN

For the new psychoactive drug 5-(2-aminopropyl) benzofuran (5-APB), very limited knowledge is available regarding lethal concentrations. We present a case and report the post mortem blood concentration of a fatal outcome for a 25 year old man related to the consumption of 5-APB. After intake, he became unconscious and stopped breathing. Cardiopulmonary resuscitation was started without success. After 30min he was declared dead at the scene. During autopsy, whole blood from the femoral vein was collected and screened for a wide range of medicinal drugs and drugs of abuse. 5-APB was initially identified by ultra high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) and subsequently confirmed by using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The only toxicological findings were ethanol 0.6g/L, tetrahydrocannabinol (THC) 0.0024mg/L and 5-APB 0.86mg/L. The cause of death was attributed to intake of 5-APB. Only one previous report of a fatal 5-APB concentration as the main toxicological agent exist in the literature, and the present concentration indicated that 5-APB could be lethal in lower concentrations than previously reported.


Asunto(s)
Benzofuranos/sangre , Benzofuranos/envenenamiento , Drogas de Diseño/análisis , Drogas de Diseño/envenenamiento , Propilaminas/sangre , Propilaminas/envenenamiento , Adulto , Benzofuranos/química , Cromatografía Líquida de Alta Presión , Drogas de Diseño/química , Resultado Fatal , Humanos , Masculino , Espectrometría de Masas , Estructura Molecular , Propilaminas/química , Edema Pulmonar/patología , Trastornos Relacionados con Sustancias/complicaciones
3.
Forensic Sci Int ; 245: 126-32, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25447185

RESUMEN

The emergence of a large number of new psychoactive substances (NPSs) in recent years poses a serious problem to clinical and forensic toxicologists. Here we report a patient who administrated ca. 500mg of 3-MMC (3-methyl-N-methylcathinone) and 400mg of 5-APB (5-(2-aminopropyl)benzofuran) in combination with 80g of ethyl alcohol. The clinical manifestations included agitation, seizures, hypertension, tachycardia, hyperthermia and bradycardia. The patient did not recover and died around 4h after the use of drugs. The cause of death was acute cardiovascular collapse that occurred following mixed intoxication with NPSs and alcohol. Toxicological analysis of post-mortem blood revealed 3-MMC and 5-APB in concentrations of 1.6µg/mL and 5.6µg/mL, respectively. Moreover, the serum alcohol concentration was 1.4g/L in ante-mortem sample collected 1h after admission to the hospital. This is the first report on blood concentration of 3-MMC and 5-APB in fatal intoxication.


Asunto(s)
Benzofuranos/envenenamiento , Estimulantes del Sistema Nervioso Central/envenenamiento , Drogas de Diseño/envenenamiento , Sobredosis de Droga , Metanfetamina/análogos & derivados , Propilaminas/envenenamiento , Consumo de Bebidas Alcohólicas/efectos adversos , Benzofuranos/sangre , Nivel de Alcohol en Sangre , Estimulantes del Sistema Nervioso Central/sangre , Drogas de Diseño/análisis , Toxicología Forense , Humanos , Masculino , Metanfetamina/sangre , Metanfetamina/envenenamiento , Propilaminas/sangre , Trastornos Relacionados con Sustancias/sangre , Adulto Joven
4.
Brain ; 137(Pt 7): 1986-97, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24893708

RESUMEN

Noradrenergic dysfunction may play a significant role in cognition in Parkinson's disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson's disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P = 0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R(2) = 0.23, F(1,16) = 5.83, P = 0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R(2) = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P = 0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson's disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder.


Asunto(s)
Inhibidores de Captación Adrenérgica/uso terapéutico , Conducta Impulsiva/tratamiento farmacológico , Conducta Impulsiva/etiología , Enfermedad de Parkinson/complicaciones , Propilaminas/uso terapéutico , Anciano , Clorhidrato de Atomoxetina , Atención , Toma de Decisiones/efectos de los fármacos , Método Doble Ciego , Femenino , Juegos Experimentales , Humanos , Inhibición Psicológica , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Persona de Mediana Edad , Pruebas Neuropsicológicas , Propilaminas/sangre , Tiempo de Reacción/efectos de los fármacos , Aprendizaje Verbal/efectos de los fármacos
5.
J Clin Psychopharmacol ; 34(1): 139-42, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24346747

RESUMEN

Atomoxetine is a selective norepinephrine reuptake inhibitor indicated for the treatment of attention-deficit/hyperactivity disorder. Atomoxetine metabolism is mediated by CYP2D6 and CYP2C19. This study aimed to investigate the effect of the CYP2C19 genetic polymorphism on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine. A single 40-mg oral dose of atomoxetine was administered to 40 subjects with different CYP2C19 genotypes (all participants carried the CYP2D6*1/*10 genotype). Concentrations of atomoxetine and its metabolites were analyzed using high-performance liquid chromatography with tandem mass spectrometry in plasma samples that were collected up to 24 hours after drug intake. For atomoxetine, the CYP2C19 poor metabolizer (PM) group showed significantly increased maximum plasma concentration and AUC0-∞ (area under the plasma concentration-time curve from 0 to infinity) and decreased apparent oral clearance compared with samples of the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer (IM) groups (P < 0.001 for all). The half-life of atomoxetine in the CYP2C19PM group was also significantly longer than in the other genotype groups (P < 0.01 for CYP2C19EM and P < 0.05 for CYP2C19IM groups). The maximum plasma concentration and AUC 0-∞ of 4-hydroxyatomoxetine were significantly higher in the CYP2C19PM group compared with those in the CYP2C19EM and IM groups (P < 0.001 for CYP2C19EM and P < 0.05 for CYP2C19IM, respectively), whereas the corresponding values for N-desmethylatomoxetine in the CYP2C19PM group were significantly lower than those in the 2 genotype groups (P < 0.001 for both genotype groups). These results suggest that the genetic polymorphisms of CYP2C19 significantly affect the pharmacokinetics of atomoxetine.


Asunto(s)
Inhibidores de Captación Adrenérgica/farmacocinética , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Polimorfismo Genético , Propilaminas/farmacocinética , Administración Oral , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/sangre , Área Bajo la Curva , Clorhidrato de Atomoxetina , Biotransformación , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP2C19 , Genotipo , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Farmacogenética , Fenoles/sangre , Fenotipo , Éteres Fenílicos/sangre , Propilaminas/administración & dosificación , Propilaminas/sangre , Espectrometría de Masas en Tándem
6.
Drug Test Anal ; 5(6): 446-52, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22589233

RESUMEN

Atomoxetine (ATX) is a non-stimulant drug approved for the treatment of children and adolescents with attention deficit/hyperactivity disorder (ADHD). We aimed to study the excretion profile of ATX and its principal metabolites 4-hydroxyatomoxetine (4-OH-ATX) and N-desmethylatomoxetine (desmethyl-ATX) in oral fluid and plasma of ADHD paediatric subjects, after administration of different dosage regimens. Oral fluid and plasma samples were obtained from one child and five adolescents treated with different ATX doses (18-60 mg/day). ATX and its metabolites were measured in oral fluid and plasma by liquid chromatography-mass spectrometry (LC-MS). Apparent pharmacokinetic parameters of ATX in oral fluid and plasma were estimated for each subject. All analytes under investigation were detected in plasma samples with concentrations from 0.6 to 1065.7 ng/ml for ATX, 0.7 to 17.1 ng/ml for 4-OH-ATX and 0.7 to 126.2 ng/ml for desmethyl-ATX. Only ATX and 4-OH-ATX were detected in oral fluid samples with concentrations from 0.5 to 36.0 ng/ml and 0.5 to 4.7 ng/ml, respectively. ATX concentrations in oral fluid were between one and two orders of magnitude lower than those in plasma. 4-OH-ATX was found in oral fluid at a peak concentration approximately one-fourth those in plasma with a mean tmax of 2.3 in plasma and 3.0 h in oral fluid. The correlations between ATX and 4-OH-ATX concentrations in the two biological fluids indicate that oral fluid concentrations of this drug and its principal metabolite may be a predictor of plasma concentrations, even if values are too low and variable to be considered an alternative to plasma.


Asunto(s)
Inhibidores de Captación Adrenérgica/sangre , Inhibidores de Captación Adrenérgica/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Propilaminas/sangre , Propilaminas/metabolismo , Saliva/metabolismo , Adolescente , Inhibidores de Captación Adrenérgica/análisis , Inhibidores de Captación Adrenérgica/uso terapéutico , Clorhidrato de Atomoxetina , Trastorno por Déficit de Atención con Hiperactividad/sangre , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Niño , Humanos , Propilaminas/análisis , Propilaminas/uso terapéutico
7.
Int J Clin Pharmacol Ther ; 50(4): 307-14, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22456303

RESUMEN

The novel Type B gamma-aminobutyric acid (GABAB)-receptor agonist lesogaberan (AZD3355) has been evaluated as an add-on to proton pump inhibitor treatment for gastroesophageal reflux disease, but the effect of food on the bioavailability of this compound has not been assessed. In this openlabel crossover study, healthy males received single 100 mg doses of lesogaberan (oral solution (A) or oral modified release (MR) capsules with a dissolution rate of 50% (B) or 100% (C) over 4 h) with and without food. Blood plasma concentrations of lesogaberan were assessed over 48 h. A log-transformed geometric mean Cmax and AUC ratio within the 90% confidence interval (CI) range (0.80 - 1.25) was defined as excluding a clinically relevant food effect. Overall, 57 subjects completed the study. Only the oral lesogaberan solution had a fed/fasting Cmax ratio outside the 90% CI range (Cmax ratio: 0.76). AUC ratios were within the 90% CI limits for all three lesogaberan formulations. The only substantial change in tmax associated with food intake was observed for the oral solution (1.0 h without food, 1.8 h with food). In conclusion, a clinically relevant food effect could be excluded for the lesogaberan MR formulations, but not for the oral lesogaberan solution.


Asunto(s)
Interacciones Alimento-Droga , Agonistas del GABA/administración & dosificación , Agonistas del GABA/farmacocinética , Ácidos Fosfínicos/administración & dosificación , Ácidos Fosfínicos/farmacocinética , Propilaminas/administración & dosificación , Propilaminas/farmacocinética , Administración Oral , Adolescente , Adulto , Análisis de Varianza , Área Bajo la Curva , Disponibilidad Biológica , Cápsulas , Estudios Cruzados , Preparaciones de Acción Retardada , Agonistas del GABA/efectos adversos , Agonistas del GABA/sangre , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Ácidos Fosfínicos/efectos adversos , Ácidos Fosfínicos/sangre , Propilaminas/efectos adversos , Propilaminas/sangre , Adulto Joven
8.
Biomed Chromatogr ; 26(11): 1364-70, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22275222

RESUMEN

A simple, rapid and sensitive method for quantification of atomoxetine by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. This assay represents the first LC-MS/MS quantification method for atomoxetine utilizing electrospray ionization. Deuterated atomoxetine (d3-atomoxetine) was adopted as the internal standard. Direct protein precipitation was utilized for sample preparation. This method was validated for both human plasma and in vitro cellular samples. The lower limit of quantification was 3 ng/mL and 10 nm for human plasma and cellular samples, respectively. The calibration curves were linear within the ranges of 3-900 ng/mL and 10 nm to 10 µm for human plasma and cellular samples, respectively (r(2) >0.999). The intra- and inter-day assay accuracy and precision were evaluated using quality control samples at three different concentrations in both human plasma and cellular lysate. Sample run stability, assay selectivity, matrix effect and recovery were also successfully demonstrated. The present assay is superior to previously published LC-MS and LC-MS/MS methods in terms of sensitivity or the simplicity of sample preparation. This assay is applicable to the analysis of atomoxetine in both human plasma and in vitro cellular samples.


Asunto(s)
Cromatografía Liquida/métodos , Espacio Intracelular/química , Propilaminas/análisis , Propilaminas/sangre , Espectrometría de Masas en Tándem/métodos , Clorhidrato de Atomoxetina , Estabilidad de Medicamentos , Células HEK293 , Humanos , Modelos Lineales , Propilaminas/química , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
9.
Artículo en Inglés | MEDLINE | ID: mdl-22237133

RESUMEN

4-Hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (N-DAT) are major metabolites of atomoxetine, a potent and selective inhibitor of the presynaptic norepinephrine transporter that is used for the treatment of attention deficit/hyperactivity disorder. The pharmacological activity of 4-HAT is similar to that of atomoxetine. We have developed and validated a simple, rapid and sensitive liquid chromatography analytical method with tandem mass spectrometry (LC-MS/MS) for the determination of 4-HAT and N-DAT in human plasma. After liquid-liquid extraction with methyl t-butyl ether, chromatographic separation of analytes was performed using a reversed-phase Luna C(18) column (2.0mm×100mm, 3µm particles) with a mobile phase of 10mM ammonium formate buffer (pH 3.5)-methanol (10:90, v/v) and quantified by MS/MS detection in ESI positive ion mode. The flow rate of the mobile phase was 250µL/min and the retention times of 4-HAT, N-DAT and internal standard (IS, metoprolol) were 0.9, 1.0 and 1.0min, respectively. The calibration curves were linear over the range of 0.05-20ng/mL for 4-HAT and 0.1-20ng/mL for N-DAT. The lower limits of quantification, using 200µL human plasma, were 0.05 and 0.1ng/mL for 4-HAT and N-DAT, respectively. The mean accuracy and precision for intra- and inter-day validation of 4-HAT and N-DAT were both within the acceptable limits. This LC-MS/MS method showed improved sensitivity for quantification of the two main metabolites of atomoxetine in human plasma compared with previously described analytical methods. The validated method was successfully applied to a pharmacokinetic study in humans.


Asunto(s)
Cromatografía Liquida/métodos , Fenoles/sangre , Éteres Fenílicos/sangre , Propilaminas/sangre , Espectrometría de Masas en Tándem/métodos , Clorhidrato de Atomoxetina , Estabilidad de Medicamentos , Humanos , Masculino , Fenoles/farmacocinética , Éteres Fenílicos/farmacocinética , Propilaminas/metabolismo , Propilaminas/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto Joven
10.
J Pharm Biomed Anal ; 60: 26-31, 2012 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-22142618

RESUMEN

A procedure based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) is described for determination of atomoxetine (ATX) and its metabolites 4-hydroxyatomoxetine (4-OH-ATX) and N-des-methylatomoxetine (N-des-ATX) in plasma, urine, oral fluid and sweat using duloxetine as internal standard. Analytes were extracted from 0.5 mL biological fluids and sweat patch with 2 mL aliquots of tert-butyl methyl ether. The organic layer was evaporated and redissolved in mobile phase. Chromatographic separation was carried out on reverse-phase column and an isocratic mobile phase formed by 40% water and 60% 5mM ammonium acetate, 47.2 mM formic acid, 4 mM trifluoroacetic acid in acetonitrile-water (85:15, v/v) at a flow rate of 0.5 mL/min. Separated analytes were identified and quantified by positive electrospray ionization tandem mass spectrometry and in multiple reaction monitoring acquisition mode. Limits of quantifications for the three analytes were 0.5 ng/mL plasma and oral fluid, 10 ng/mL urine and 1 ng/patch using 0.5 mL biological fluids or one sweat-patch per assay. Calibration curves were linear over the calibration ranges with r²>0.99. At three concentrations spanning the linear dynamic range of the assay, mean recoveries in different biological matrices were always higher than 65%. This method was applied to therapeutic monitoring of ATX and its metabolites 4-OH-ATX and N-des-ATX in conventional and non-conventional biological matrices from individuals in drug treatment.


Asunto(s)
Inhibidores de Captación Adrenérgica/farmacocinética , Cromatografía Liquida/métodos , Propilaminas/farmacocinética , Saliva/metabolismo , Sudor/metabolismo , Espectrometría de Masas en Tándem/métodos , Adolescente , Inhibidores de Captación Adrenérgica/sangre , Inhibidores de Captación Adrenérgica/orina , Clorhidrato de Atomoxetina , Cromatografía Liquida/estadística & datos numéricos , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Límite de Detección , Masculino , Propilaminas/sangre , Propilaminas/orina , Espectrometría de Masas en Tándem/estadística & datos numéricos
11.
Patol Fiziol Eksp Ter ; (2): 44-6, 2011.
Artículo en Ruso | MEDLINE | ID: mdl-21846061

RESUMEN

It is investigated conditions of system "lipid peroksidation - antioxidant protection" at rats of the line Wistar at prolonged formation alimentary dyslipidemia (DLP). It is established, that at formation DLP during 46 days in cells there was no increase in resistance and capacity of processes antioxidant protection. In prolonged DLP (90 days) was characterized by occurrence of the compensation-adaptive answer in the system "lipid peroksidation - antioxidant protection".


Asunto(s)
Dislipidemias/sangre , Peroxidación de Lípido , Propilaminas/sangre , Animales , Masculino , Ratas , Ratas Wistar
12.
J Anal Toxicol ; 35(1): 54-9, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21219704

RESUMEN

A death involving abuse of propylhexedrine and mitragynine is reported. Propylhexedrine is a potent α-adrenergic sympathomimetic amine found in nasal decongestant inhalers. The decedent was found dead in his living quarters with no signs of physical trauma. Analysis of his computer showed information on kratom, a plant that contains mitragynine, which produces opiumlike effects at high doses and stimulant effects at low doses, and a procedure to concentrate propylhexedrine from over-the-counter inhalers. Toxicology results revealed the presence of 1.7 mg/L propylhexedrine and 0.39 mg/L mitragynine in his blood. Both drugs, as well as acetaminophen, morphine, and promethazine, were detected in the urine. Quantitative results were achieved by gas chromatography-mass spectrometry monitoring selected ions for the propylhexedrine heptafluorobutyryl derivative. Liquid chromatography-tandem mass spectrometry in multiple reactions monitoring mode was used to obtain quantitative results for mitragynine. The cause of death was ruled propylhexedrine toxicity, and the manner of death was ruled accidental. Mitragynine may have contributed as well, but as there are no published data for drug concentrations, the medical examiner did not include mitragynine toxicity in the cause of death. This is the first known publication of a case report involving propylhexedrine and mitragynine.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Propilaminas/toxicidad , Alcaloides de Triptamina Secologanina/toxicidad , Trastornos Relacionados con Sustancias/diagnóstico , Acetaminofén/orina , Cromatografía Liquida , Estudios de Evaluación como Asunto , Resultado Fatal , Cromatografía de Gases y Espectrometría de Masas , Humanos , Modelos Lineales , Masculino , Morfina/orina , Prometazina/orina , Propilaminas/sangre , Propilaminas/orina , Alcaloides de Triptamina Secologanina/sangre , Alcaloides de Triptamina Secologanina/orina , Detección de Abuso de Sustancias/métodos , Espectrometría de Masas en Tándem , Adulto Joven
13.
Drug Test Anal ; 2(6): 284-91, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20564607

RESUMEN

A rapid and highly sensitive method for the determination of alverine (ALV) and its metabolite, para hydroxy alverine (PHA), in human plasma using LC-MS/MS in positive ion electrospray ionization (ESI) in multiple reactions monitoring (MRM) mode was developed and validated. The procedure involves a simple solid phase extraction (SPE). Chromatographic separation was carried out on a Hypersil GOLD C(18) column (50 mm x 4.6 mm, 5 microm) with an isocratic mobile phase and a total run time of 1.5 min. The standard calibration curves showed excellent linearity within the range of 0.060-10.051 ng/mL for ALV and 0.059-10.017 ng/mL for PHA (r > or = 0.990). This method was successfully applied to a pharmacokinetic study after oral administration of alverine citrate 120 mg capsule in Indian healthy male volunteers.


Asunto(s)
Cromatografía Liquida/métodos , Fenoles/sangre , Propilaminas/sangre , Propilaminas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Administración Oral , Cápsulas , Estudios Cruzados , Humanos , Masculino , Reproducibilidad de los Resultados , Extracción en Fase Sólida , Espectrometría de Masa por Ionización de Electrospray/métodos , Equivalencia Terapéutica
14.
Eur J Nucl Med Mol Imaging ; 36(8): 1308-14, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19300997

RESUMEN

PURPOSE: In a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atomoxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner. METHODS: Two rhesus monkeys were examined using a high-resolution PET system with (S,S)-[(18)F]FMeNER-D(2) under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12 mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BP(ND) obtained with the simplified reference tissue model. RESULTS: NET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16 ng/ml. CONCLUSION: The results indicate that clinical doses of atomoxetine would occupy NET almost completely.


Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Morfolinas , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Propilaminas/administración & dosificación , Propilaminas/metabolismo , Anestésicos por Inhalación , Animales , Clorhidrato de Atomoxetina , Relación Dosis-Respuesta a Droga , Femenino , Macaca mulatta , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Propilaminas/análisis , Propilaminas/sangre , Radiactividad , Distribución Tisular
15.
Drug Metab Dispos ; 37(1): 137-42, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18936112

RESUMEN

A comprehensive in vivo evaluation of brain penetrability and central nervous system (CNS) pharmacokinetics of atomoxetine in rats was conducted using brain microdialysis. We sought to determine the nature and extent of transport at the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCB) and to characterize brain extracellular and cellular disposition. The steady-state extracellular fluid (ECF) to plasma unbound (uP) concentration ratio (C(ECF)/C(uP)=0.7) and the cerebrospinal fluid (CSF) to plasma unbound concentration ratio (C(CSF)/C(uP)=1.7) were both near unity, indicating that atomoxetine transport across the BBB and BCB is primarily passive. On the basis of the ratios of whole brain concentration to C(ECF) (C(B)/C(ECF)=170), brain cell (BC) concentration to C(ECF) (C(BC)/C(ECF)=219), and unbound brain cell concentration to C(ECF) (C(uBC)/C(ECF)=2.9), we conclude that whole brain concentration does not represent the concentration in the biophase and atomoxetine primarily partitions into brain cells. The distributional clearance at the BBB (Q(BBB)=0.00110 l/h) was estimated to be 12 times more rapid than that at the BCB (Q(BCB)=0.0000909 l/h) and similar to the clearances across brain parenchyma (CL(ECF-BC)=0.00216 l/h; CL(BC-ECF)=0.000934 l/h). In summary, the first detailed examination using a quantitative microdialysis technique to understand the brain disposition of atomoxetine was conducted. We determined that atomoxetine brain penetration is high, movements across the BBB and BCB occur predominantly by a passive mechanism, and rapid equilibration of ECF and CSF with plasma occurs.


Asunto(s)
Inhibidores de Captación Adrenérgica/farmacocinética , Encéfalo/metabolismo , Propilaminas/farmacocinética , Médula Espinal/metabolismo , Inhibidores de Captación Adrenérgica/sangre , Inhibidores de Captación Adrenérgica/líquido cefalorraquídeo , Animales , Clorhidrato de Atomoxetina , Barrera Hematoencefálica , Masculino , Microdiálisis , Propilaminas/sangre , Propilaminas/líquido cefalorraquídeo , Ratas , Ratas Wistar
16.
J Chromatogr B Analyt Technol Biomed Life Sci ; 877(3): 197-206, 2009 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-19110477

RESUMEN

The present research work involves a first of its kind rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method developed and validated for simultaneous analysis of Alverine (ALV) and one of its hydroxy metabolites, para hydroxy Alverine (PHA) in human plasma. The analytes were extracted from the matrix using a simple solid-phase extraction procedure. Mebeverine was used as the internal standard for both analytes. A Kromasil C8 column provided chromatographic separation of analytes followed by detection with mass spectrometry. The method involves simple isocratic chromatography conditions and mass spectrometric detection in the positive ionization mode using an API 5000 MS/MS system. The proposed method has been validated with a linear range of 100-10,000 pg/mL for both ALV and PHA. The interrun and intrarun precision values are within 6.3%, 3.7% for ALV and 6.3%, 3.2% for PHA at LOQ levels. The intrarun accuracy in terms of % RE was within the range of -7.0% to -0.1% and -8.1% to -1.7% for ALV and PHA, respectively whereas the interrun accuracy was within the range of -5.1% to -0.5% for ALV and -8.6% to 0.4% for PHA, respectively. The overall recoveries for ALV and PHA were 83.5% and 86.2% respectively. Total elution time was about 4 min which allowed quantitation of more than 150 plasma samples per day. This validated method was used successfully for analysis of real samples from a bioequivalence study.


Asunto(s)
Propilaminas/sangre , Propilaminas/metabolismo , Cromatografía Liquida , Humanos , Análisis de los Mínimos Cuadrados , Fenetilaminas/análisis , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Extracción en Fase Sólida , Espectrometría de Masas en Tándem , Equivalencia Terapéutica
17.
Biol Psychiatry ; 65(7): 550-5, 2009 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-19026407

RESUMEN

BACKGROUND: Atomoxetine, a selective noradrenaline reuptake inhibitor (SNRI) licensed for the treatment of attention-deficit/hyperactivity disorder (ADHD), has been shown to improve response inhibition in animals, healthy volunteers, and adult patients. However, the mechanisms by which atomoxetine improves inhibitory control have yet to be determined. METHODS: The effects of atomoxetine (40 mg) were measured with a stop-signal functional magnetic resonance imaging (fMRI) paradigm in 19 healthy volunteers, in a within-subject, double-blind, placebo-controlled design. RESULTS: Atomoxetine improved inhibitory control and increased activation in the right inferior frontal gyrus when volunteers attempted to inhibit their responses (irrespective of success). Plasma levels of drug correlated significantly with right inferior frontal gyrus activation only during successful inhibition. CONCLUSIONS: These results show that atomoxetine exerts its beneficial effects on inhibitory control via modulation of right inferior frontal function, with implications for understanding and treating inhibitory dysfunction of ADHD and other disorders.


Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Lóbulo Frontal/efectos de los fármacos , Inhibición Psicológica , Propilaminas/farmacología , Tiempo de Reacción/efectos de los fármacos , Inhibidores de Captación Adrenérgica/sangre , Adulto , Clorhidrato de Atomoxetina , Método Doble Ciego , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Placebos , Propilaminas/sangre
18.
Atten Defic Hyperact Disord ; 1(2): 201-10, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20234828

RESUMEN

The purpose of this study was to examine whether atomoxetine plasma concentration predicts attention-deficit/hyperactivity disorder (ADHD) or oppositional defiant disorder (ODD) response. This post-hoc analysis assessed the relationship between atomoxetine plasma concentration and ADHD and ODD symptoms in patients (with ADHD and comorbid ODD) aged 6-12 years. Patients were randomly assigned to atomoxetine 1.2 mg/kg/day (n=156) or placebo (n=70) for 8 weeks (Study Period II). At the end of 8 weeks, ODD non-remitters (score >9 on the SNAP-IV ODD subscale and CGI-I > 2) with atomoxetine plasma concentration <800 ng/ml at 2 weeks were re-randomized to either atomoxetine 1.2 mg/kg/day or 2.4 mg/kg/day for an additional 4 weeks (Study Period III). ODD remitters and non-remitters with plasma atomoxetine ≥800 ng/ml remained on 1.2 mg/kg/day atomoxetine for 4 weeks. Patients who received atomoxetine, completed Study Period II, and entered Study Period III were included in these analyses. All the groups demonstrated improvement on the SNAP-IV ODD and ADHD-combined subscales (P<.001). At the end of Study Periods II and III, ODD and ADHD improvement was significantly greater in the remitter group compared with the non-remitter groups. Symptom improvement was numerically greater in the non-remitter (2.4 mg/kg/day compared with the non-remitter 1.2 mg/kg/day) group. Atomoxetine plasma concentration was not indicative of ODD and ADHD improvement after 12 weeks of treatment. ADHD and ODD symptoms improved in all the groups with longer duration on atomoxetine. Results suggest atomoxetine plasma concentration does not predict ODD and ADHD symptom improvement. However, a higher atomoxetine dose may benefit some patients.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Déficit de la Atención y Trastornos de Conducta Disruptiva/tratamiento farmacológico , Propilaminas/sangre , Inhibidores de Captación Adrenérgica/efectos adversos , Inhibidores de Captación Adrenérgica/sangre , Inhibidores de Captación Adrenérgica/uso terapéutico , Clorhidrato de Atomoxetina , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Déficit de la Atención y Trastornos de Conducta Disruptiva/complicaciones , Niño , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Propilaminas/efectos adversos , Propilaminas/uso terapéutico
19.
Pediatrics ; 121(2): e314-20, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18245404

RESUMEN

OBJECTIVE: In this study we examined the effectiveness of atomoxetine for the treatment of oppositional defiant disorder comorbid with attention-deficit/hyperactivity disorder. METHODS: Patients were aged 6 to 12 years and met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnostic criteria for attention-deficit/hyperactivity disorder with a Swanson, Nolan, and Pelham Rating Scale-Revised attention-deficit/hyperactivity disorder subscale score above age and gender norms; Clinical Global Impressions-Severity Scale score of > or = 4; and Swanson, Nolan, and Pelham Rating Scale-Revised oppositional defiant disorder subscale score of > or = 15. Patients were randomly assigned in a 2:1 ratio to receive 1.2 mg/kg per day of atomoxetine (n = 156) or placebo (n = 70) for 8 weeks. Treatment effect on oppositional defiant disorder and attention-deficit/hyperactivity disorder symptoms was measured by using the investigator-rated Swanson, Nolan, and Pelham Rating Scale-Revised. RESULTS: Repeated-measures analysis demonstrated a statistically significant difference favoring atomoxetine over placebo in the reduction of Swanson, Nolan, and Pelham Rating Scale-Revised oppositional defiant disorder total scores. There were significant pairwise treatment differences at weeks 2 and 5 but not at week 8 postbaseline. A last-observation-carried-forward analysis showed Swanson, Nolan, and Pelham Rating Scale-Revised scores at endpoint for the atomoxetine and placebo groups were significantly different for attention-deficit/hyperactivity disorder symptoms but not for oppositional defiant disorder symptoms. Atomoxetine was superior to placebo in a last-observation-carried-forward analysis of Clinical Global Impression-Improvement and Clinical Global Impression-Severity scores. CONCLUSIONS: This study confirms previous findings that patients with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder show statistically and clinically significant improvement in attention-deficit/hyperactivity disorder symptoms and global clinical functioning when treated with atomoxetine. It remains uncertain, however, whether atomoxetine exerts a specific and enduring effect on oppositional defiant disorder symptoms.


Asunto(s)
Inhibidores de Captación Adrenérgica/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Déficit de la Atención y Trastornos de Conducta Disruptiva/tratamiento farmacológico , Propilaminas/uso terapéutico , Inhibidores de Captación Adrenérgica/efectos adversos , Inhibidores de Captación Adrenérgica/sangre , Clorhidrato de Atomoxetina , Niño , Método Doble Ciego , Femenino , Humanos , Masculino , Análisis Multivariante , Propilaminas/efectos adversos , Propilaminas/sangre , Resultado del Tratamiento
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