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1.
J Clin Psychiatry ; 81(5)2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32857933

RESUMO

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018. METHODS: Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes. RESULTS: Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo. CONCLUSIONS: Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02818751.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Citalopram/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Área Sob a Curva , Criança , Citalopram/análogos & derivados , Citalopram/sangue , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/farmacocinética , Resultado do Tratamento
2.
Int J Clin Pharmacol Ther ; 58(8): 426-438, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32449675

RESUMO

BACKGROUND: Atomoxetine and escitalopram are potent and selective drugs approved for noradrenergic or serotonergic modulation of neuronal networks in attention-deficit hyperactivity disorder (ADHD) or depression, respectively. High-performance liquid chromatography (HPLC) methods still play an important role in the therapeutic drug monitoring (TDM) of psychopharmacological drugs, and coupled with tandem mass spectrometry are the gold standard for the quantification of drugs in biological matrices, but not available everywhere. The aim of this work was to develop and validate a HPLC method for neuroscientific studies using atomoxetine or escitalopram as a test drug. MATERIALS AND METHODS: A HPLC method from routine TDM determination of atomoxetine or citalopram in plasma was adapted and validated for use in neuroscientific research. Using photo diode array detection with UV absorption at 205 nm, the variation of internal standard within one chromatographic method enables separate drug monitoring for concentration-controlled explorative studies in healthy humans and patients with Parkinson's disease. RESULTS: The method described here was found to be linear in the range of 0.002 - 1.4 mg/L for atomoxetine and 0.0012 - 0.197 mg/L for escitalopram, with overall mean intra-day and inter-day imprecision and accuracy bias < 10% for both drugs. The method was successfully applied in concentration-controlled neuroimaging studies in populations of healthy humans and patients with Parkinson's disease. CONCLUSION: A simple, sensitive, robust HPLC method capable of monitoring escitalopram and atomoxetine is presented and validated, as a useful tool for drug monitoring and the study of pharmacokinetics in neuroscientific study applications.


Assuntos
Cloridrato de Atomoxetina/sangue , Citalopram/sangue , Cromatografia Líquida de Alta Pressão , Monitoramento de Medicamentos , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
3.
Curr Pharm Biotechnol ; 21(1): 60-69, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31470784

RESUMO

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.


Assuntos
Antidepressivos/sangue , Antipsicóticos/sangue , Aripiprazol/sangue , Citalopram/sangue , Fluoxetina/sangue , Risperidona/sangue , Cromatografia Líquida de Alta Pressão , Monitoramento de Medicamentos , Humanos , Espectrometria de Massas em Tandem
5.
Basic Clin Pharmacol Toxicol ; 124(3): 285-297, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30220109

RESUMO

Therapeutic drug monitoring (TDM) is used to determine the concentration of drug in plasma/serum to adjust the dose of the therapeutic drug. Selective and sensitive analytical methods are used to determine drug and metabolite levels for the successful application of TDM. The aim of the study was to develop and validate using LC-MS/MS to analyse quantitative assay of escitalopram (S-CT) and metabolites in human plasma samples. In order to provide a convenient and safe treatment dose, it was aimed to determine the levels of S-CT and its metabolites in the patients' plasma. A new method with short sample preparation and analysis time was developed and validated using LC-MS/MS to analyse quantitative assay of S-CT and its metabolites in plasma. Also, plasma samples of 30 patients using 20 mg S-CT between the ages of 18 and 65 years were analysed by the validated method. The mean values of S-CT, demethyl escitalopram and didemethyl escitalopram in plasma of patients were 27.59, 85.52 and 44.30 ng/mL, respectively. At the end of the analysis, the metabolic ratio of S-CT and metabolites was calculated. It is considered that the method for the quantitative analysis of S-CT and its metabolites in human plasma samples may contribute to the literature on account of its sensitive and easy application. Additionally, the use of our data by physicians will contribute to the effective drug treatment for their patients who take S-CT.


Assuntos
Citalopram/sangue , Transtornos Mentais/sangue , Adolescente , Adulto , Idoso , Cromatografia Líquida/métodos , Citalopram/administração & dosagem , Citalopram/farmacocinética , Monitoramento de Medicamentos/métodos , Humanos , Transtornos Mentais/tratamento farmacológico , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacocinética , Espectrometria de Massas em Tandem/métodos , Adulto Jovem
6.
Ann Pharm Fr ; 77(2): 112-120, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30528254

RESUMO

OBJECTIVES: A novel, fast and sensitive HPLC method has been developed for the simultaneous bioanalytical determination of Donepezil hydrochloride (DON) and Citalopram hydrobromide (CTP) in raw materials, spiked human plasma and tablets. MATERIALS AND METHODS: Elution of both drugs was achieved with very good resolution using a RP-C18 chromatographic column, samples were analyzed using Hypersil Gold (100mm×4.6mm), 5µm particle size column and an isocratic binary mobile phase consists of phosphate buffer (0.05 M): acetonitrile (65:35). A Diode array detector at wavelength 232nm was used. Chromatographic separation was within a short run time (less than 7minutes) for both drugs. RESULTS: Retention times for DON and CTP were 4.5 and 5.8min, respectively. Linear calibration curves were obtained for DON and CTP over the concentration ranges of 0.1-10 and 0.1-50µg/mL. The mean extraction recoveries from spiked plasma were 93.22 and 92.64 for DON and CTP, respectively. The limits of detection and quantification were 0.017, 0.035µg/mL and 0.052, 0.106µg/mL for DON and CTP, respectively. CONCLUSION: The proposed method was successfully applied to the analysis of the cited drugs in raw materials, spiked human plasma and tablets with excellent accuracy and precision.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antidepressivos de Segunda Geração/análise , Citalopram/análise , Donepezila/análise , Nootrópicos/análise , Antidepressivos de Segunda Geração/sangue , Cromatografia Líquida de Alta Pressão , Citalopram/sangue , Donepezila/sangue , Combinação de Medicamentos , Humanos , Indicadores e Reagentes , Limite de Detecção , Nootrópicos/sangue , Plasma/química , Controle de Qualidade , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Comprimidos/análise
7.
Z Kinder Jugendpsychiatr Psychother ; 47(2): 168-170, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30185094

RESUMO

The use of selective serotonin reuptake inhibitors (SSRIs) like citalopram in the clinical treatment of depressive symptoms in children and adolescents has become increasingly common, although application is mostly off-label. The increasing number of prescriptions is not only due to their good efficacy, but also due to their good tolerability and the comparatively low risk in cases of intoxication. However, there is discussion about the cardiac safety of overdose ingestion of citalopram. Here, we report in detail on an adolescent with depressive symptoms who used 800 mg of citalopram in order to attempt suicide. In contrast to other case reports in adults, our patient showed only mild neurological symptoms and no cardiac toxicity or symptoms of a serotonin syndrome, despite a high citalopram blood concentration measured about two hours following ingestion of citalopram (633 ng/ml; therapeutic reference range for adults 50-110 ng/ml).


Assuntos
Citalopram/administração & dosagem , Citalopram/envenenamento , Overdose de Drogas , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/envenenamento , Tentativa de Suicídio , Adolescente , Citalopram/sangue , Depressão , Testes Diagnósticos de Rotina , Feminino , Humanos , Inibidores de Captação de Serotonina/sangue
8.
J Anal Toxicol ; 42(7): e65-e68, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29718282

RESUMO

Mitragynine is a novel psychoactive substance (NPS) that has emerged as a designer opioid being distributed on the street. Mitragynine, also known as kratom, has dose-dependent pharmacological effects and possesses both stimulant-like and sedative effects due to dual-binding of α-adrenergic and µ-opioid receptors. This herbal remedy readily available online has caused adverse effects including tachycardia, agitation, tremors, hallucination and death; however, this is the first reported suspected driving under the influence case involving mitragynine. Additional testing outside of the normal routine protocol for suspected impaired driving cases was performed based on the admission of kratom use from the suspect to the drug recognition expert (DRE) officer. Based on the evaluation, the DRE officer concluded that the driver was under the influence of a central nervous system stimulant and cannabis. An alkaline drug screen identified mitragynine in a 37-year-old female driver who was suspected of driving under the influence after nearly striking an oncoming vehicle. A blood amphetamine concentration was quantified at 0.052 mg/L and mitragynine and citalopram were reported qualitatively. The goal of this case study is to provide demographic history, adverse effects and a DRE evaluation in a driver known to have abused mitragynine.


Assuntos
Acidentes de Trânsito , Dirigir sob a Influência , Psicotrópicos/sangue , Alcaloides de Triptamina e Secologanina/efeitos adversos , Alcaloides de Triptamina e Secologanina/sangue , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Adulto , Anfetaminas/sangue , Citalopram/sangue , Feminino , Toxicologia Forense/métodos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Psicotrópicos/efeitos adversos , Detecção do Abuso de Substâncias/métodos , Transtornos Relacionados ao Uso de Substâncias/sangue
9.
Ther Drug Monit ; 40(3): 351-355, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29746434

RESUMO

BACKGROUND: Therapeutic drug monitoring has become increasingly important in psychiatric therapy. However, it is not yet implemented as a daily routine in clinical settings. To evaluate new, noninvasive procedures, we compared blood and saliva venlafaxine, quetiapine, and citalopram concentrations in samples collected from psychiatric patients. METHODS: We collected blood and saliva samples from 75 psychiatric patients (39 venlafaxine, 19 quetiapine, and 17 citalopram). Saliva sampling was achieved by the use of cotton pads. Venlafaxine (and its metabolite O-desmethylvenlafaxine) and quetiapine were analyzed by LC-MS/MS, whereas citalopram was analyzed by HPLC. RESULTS: We observed significant correlations between concentrations of venlafaxine (ratio saliva/serum ± SD: 18.3 ± 9.5, P < 0.01, r = 0.895) and its metabolite O-desmethylvenlafaxine (ratio saliva/serum ± SD: 4.1 ± 3.2, P < 0.05, r = 0.344), quetiapine (ratio saliva/serum ± SD: 0.2 ± 0.2, P < 0.01, r = 0.935), and citalopram (ratio saliva/serum ± SD: 2.6 ± 1.2, P < 0.05, r = 0.54) in serum and in saliva. Furthermore, measured concentrations of venlafaxine (and its metabolite O-desmethylvenlafaxine) and citalopram were higher in saliva than in serum, whereas measured concentrations of quetiapine were higher in serum than in saliva. CONCLUSIONS: Using cotton pad saliva sampling, venlafaxine and quetiapine demonstrate high correlations between saliva and serum concentrations, whereas for O-desmethylvenlafaxine and citalopram, other methods of sampling might be preferable. Saliva therapeutic drug monitoring of psychoactive drugs might become a useful approach to achieving individual treatment regimens.


Assuntos
Citalopram/sangue , Succinato de Desvenlafaxina/sangue , Transtornos Mentais/sangue , Fumarato de Quetiapina/sangue , Saliva/metabolismo , Cloridrato de Venlafaxina/sangue , Adulto , Idoso , Antidepressivos/sangue , Antidepressivos/uso terapêutico , Antidepressivos de Segunda Geração/sangue , Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/uso terapêutico , Succinato de Desvenlafaxina/uso terapêutico , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Transtornos Mentais/tratamento farmacológico , Pessoa de Meia-Idade , Ligação Proteica/fisiologia , Fumarato de Quetiapina/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/sangue , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Adulto Jovem
10.
Ther Drug Monit ; 40(3): 356-361, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29570504

RESUMO

BACKGROUND: Plasma concentrations of the S-enantiomer of citalopram were different between extensive and poor CYP2C19 metabolizers in healthy subjects and depressed patients. However, most studies applied dose-corrected concentrations. Thus, we studied the effects of polymorphisms of the CYP2C19 gene on raw plasma drug concentrations in Japanese patients with depression. METHODS: Subjects in this study consisted of 412 depressed patients receiving 5, 10, 15, or 20 mg of escitalopram once a day. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using HPLC. CYP2C19 genotypes were identified using polymerase chain reaction methods. RESULTS: There were no differences in the steady-state plasma concentrations of escitalopram or desmethylescitalopram in each dose group (5, 10, 15, or 20 mg of escitalopram) among CYP2C19 genotype groups. However, 1-way analysis of variance showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram but not in the dose-adjusted plasma concentration of desmethylescitalopram. Analysis of covariance including age, sex, and body weight showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram and the ratio of desmethylescitalopram to escitalopram. CONCLUSIONS: These findings suggest that the CYP2C19 variants are associated with steady-state plasma concentrations of escitalopram to some extent but are not associated with desmethylescitalopram.


Assuntos
Citalopram/análogos & derivados , Citalopram/sangue , Citocromo P-450 CYP2C19/genética , Depressão/sangue , Depressão/genética , Genótipo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antidepressivos de Segunda Geração/sangue , Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/uso terapêutico , Depressão/tratamento farmacológico , Depressão/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
11.
J Clin Psychiatry ; 79(2)2018.
Artigo em Inglês | MEDLINE | ID: mdl-29570971

RESUMO

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.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Antidepressivos de Segunda Geração/sangue , Citalopram/sangue , Citocromo P-450 CYP2C19/sangue , Citocromo P-450 CYP2D6/sangue , Citocromo P-450 CYP3A/sangue , Transtorno Depressivo/sangue , Transtorno Depressivo/tratamento farmacológico , Fluoxetina/sangue , Redes e Vias Metabólicas , Sertralina/sangue , Adulto , Idoso , Transtorno Bipolar/sangue , Transtorno Bipolar/tratamento farmacológico , Estudos Transversais , Humanos , Pessoa de Meia-Idade , Adulto Jovem
12.
J Mass Spectrom ; 53(5): 385-399, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29448310

RESUMO

Liquid chromatography-mass spectrometry (LC-MS) method revealed the plasma metabolite profiles in major depressive disorder patients treated with escitalopram (ECTP) (n = 7). Depression severity was assessed according to the 17-item Hamilton Depression Rating Scale. Metabolic profiles were derived from major depressive disorder subject blood samples collected after ECTP treatment. Blood plasma was separated and processed in order to effectively extract metabolites, which were then analyzed using LC-MS. We identified 19 metabolites and elucidated their structures using LC-tandem MS (LC-MS/MS) combined with elemental compositions derived from accurate mass measurements. We further used online H/D exchange experiments to verify the structural elucidations of each metabolite. Identifying molecular metabolites may provide critical insights into the pharmacological and clinical effects of ECTP treatment and may also provide useful information informing the development of new antidepressant treatments. These detailed plasma metabolite analyses may also be used to identify optimal dose concentrations in psychopharmacotherapeutic treatment through drug monitoring, as well as forming the basis for response predictions in depressed subjects.


Assuntos
Citalopram/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Metaboloma , Adulto , Idoso , Cromatografia Líquida de Alta Pressão , Citalopram/sangue , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Adulto Jovem
13.
J Anal Toxicol ; 42(3): 149-156, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29244076

RESUMO

Postmortem blood samples may not accurately reflect antemortem drug concentrations, as the levels of some drugs increase due to postmortem redistribution (PMR). The brain has been suggested as an alternative sampling site. The anatomically secluded site of the brain limits redistribution and prolongs the detection window, thereby enabling sampling from deceased individuals where blood is no longer suitable for analysis. We report concentrations in brain tissue and blood from 91 cases for the four antidepressants citalopram, duloxetine, mirtazapine and sertraline. The cases were classified according to their role in the cause of death, as follows: (A) concentrations where the drug was the sole cause of fatal intoxication; (B) concentrations where the drug contributed to a fatal outcome; and (C) concentrations where the drug was not related to the cause of death. The analytical method was successfully validated in brain tissue in terms of linearity, process efficiency, precision and accuracy. Quantification of analytes was performed by ultra-performance liquid chromatography with tandem mass spectrometry. Correlations between blood and brain concentrations were achieved with R2-values between 0.67 and 0.91. The following median brain-blood ratios were obtained: 3.71 for citalopram (range: 1.4-5.9), 11.0 for duloxetine (range: 5.0-21.6), 1.53 for mirtazapine (range: 1.02-4.71) and 7.38 for sertraline (range: 3.2-14.2). The S/R ratio of racemic citalopram was the same in brain (0.80) and blood (0.85), whereas the median citalopram/N-desmethylcitalopram ratio was higher in brain (9.1) than blood (4.1). The results of this study may serve as reference concentrations in brain for forensic cases.


Assuntos
Antidepressivos/sangue , Encéfalo/metabolismo , Citalopram/sangue , Overdose de Drogas/sangue , Cloridrato de Duloxetina/sangue , Mianserina/análogos & derivados , Sertralina/sangue , Calibragem , Causas de Morte , Cromatografia Líquida/normas , Overdose de Drogas/diagnóstico , Overdose de Drogas/mortalidade , Toxicologia Forense/normas , Humanos , Modelos Lineares , Mianserina/sangue , Mirtazapina , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/normas , Espectrometria de Massas em Tandem/normas
14.
AAPS J ; 20(1): 6, 2017 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-29181593

RESUMO

A quantitative systems toxicology (QST) model for citalopram was established to simulate, in silico, a 'virtual twin' of a real patient to predict the occurrence of cardiotoxic events previously reported in patients under various clinical conditions. The QST model considers the effects of citalopram and its most notable electrophysiologically active primary (desmethylcitalopram) and secondary (didesmethylcitalopram) metabolites, on cardiac electrophysiology. The in vitro cardiac ion channel current inhibition data was coupled with the biophysically detailed model of human cardiac electrophysiology to investigate the impact of (i) the inhibition of multiple ion currents (IKr, IKs, ICaL); (ii) the inclusion of metabolites in the QST model; and (iii) unbound or total plasma as the operating drug concentration, in predicting clinically observed QT prolongation. The inclusion of multiple ion channel current inhibition and metabolites in the simulation with unbound plasma citalopram concentration provided the lowest prediction error. The predictive performance of the model was verified with three additional therapeutic and supra-therapeutic drug exposure clinical cases. The results indicate that considering only the hERG ion channel inhibition of only the parent drug is potentially misleading, and the inclusion of active metabolite data and the influence of other ion channel currents should be considered to improve the prediction of potential cardiac toxicity. Mechanistic modelling can help bridge the gaps existing in the quantitative translation from preclinical cardiac safety assessment to clinical toxicology. Moreover, this study shows that the QST models, in combination with appropriate drug and systems parameters, can pave the way towards personalised safety assessment.


Assuntos
Citalopram/toxicidade , Coração/efeitos dos fármacos , Toxicologia/métodos , Citalopram/sangue , Canal de Potássio ERG1/antagonistas & inibidores , Eletrocardiografia/efeitos dos fármacos , Humanos , Canais Iônicos/efeitos dos fármacos , Medição de Risco , Biologia de Sistemas
15.
Prog Neuropsychopharmacol Biol Psychiatry ; 79(Pt B): 213-219, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28663113

RESUMO

RATIONALE: Aim of the study was to measure and correlate citalopram concentrations in maternal blood, amniotic fluid and umbilical cord blood to account for the distribution of the drug between these three compartments. METHODS: Concentrations of citalopram were measured in twelve mother infant pairs at the time of delivery. Data are provided as median values, first (Q1) and third (Q3) quartiles as well as ranges. To account for the penetration ratio into amniotic fluid and cord blood, the concentration of citalopram in was divided by the concentration in maternal serum. Correlations between daily dosage, maternal serum concentrations and umbilical cord blood concentrations were computed for twelve patients. As amniotic fluid was only available for nine mother infant pairs, appropriate calculations are provided for these mother-infant pairs. RESULTS: The median daily dosage of citalopram was 20mg (Q1: 10mg, Q3: 20mg; range 10-40mg). The relation between the daily dosage of citalopram and its concentrations in maternal serum was highly significant (r=0.667, p=0.018). Maternal serum concentrations and cord blood concentrations were positively correlated (r=0.790, p=0.002) with a median penetration ratio into the fetal circulation of 0.78 (Q1: 0.52, Q3: 1.16, range 0.46-1.66). The median penetration ratio into amniotic fluid was 1.8 (Q1: 1.07, Q3: 2.64; range 0.52-6.97). CONCLUSIONS: Citalopram concentrations in amniotic fluid and cord blood give evidence that maternally administered citalopram is constantly accessible to the fetus via amniotic fluid. A high correlation between maternal serum concentrations of citalopram and umbilical cord blood concentrations highlights a predictive role of quantifying drug concentrations in maternal serum for assessing drug concentrations in the fetal circulation. Findings support the important role of therapeutic drug monitoring in maintaining the safety of pregnant women and exposed infants.


Assuntos
Líquido Amniótico/metabolismo , Citalopram/farmacocinética , Monitoramento de Medicamentos , Sangue Fetal/metabolismo , Complicações na Gravidez/tratamento farmacológico , Inibidores de Captação de Serotonina/farmacocinética , Adulto , Citalopram/sangue , Citalopram/uso terapêutico , Cordocentese , Relação Dose-Resposta a Droga , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Complicações na Gravidez/metabolismo , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/uso terapêutico , Adulto Jovem
16.
PLoS One ; 12(7): e0181082, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28708853

RESUMO

BACKGROUND: Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women. METHODS: Using patient data from two routine therapeutic drug monitoring (TDM) services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women's own baseline (non-pregnant) values, using a linear mixed model. FINDINGS: Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only), we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (-51%; 95% confidence interval [CI], -66%, -30%; p<0.001), fluvoxamine (-56%; CI, -75%, -23%; p = 0.004) and citalopram (-24%; CI, -38%, -7%; p = 0,007), and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001). For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly. CONCLUSIONS: For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.


Assuntos
Antidepressivos/sangue , Monitoramento de Medicamentos , Inibidores de Captação de Serotonina/sangue , Cloridrato de Venlafaxina/sangue , Adulto , Antidepressivos/uso terapêutico , Citalopram/sangue , Citalopram/uso terapêutico , Bases de Dados Factuais , Transtorno Depressivo/tratamento farmacológico , Feminino , Fluvoxamina/sangue , Fluvoxamina/uso terapêutico , Humanos , Noruega , Paroxetina/sangue , Paroxetina/uso terapêutico , Gravidez , Terceiro Trimestre da Gravidez , Inibidores de Captação de Serotonina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico
17.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1061-1062: 103-109, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28715684

RESUMO

A method for enantiomeric separation and quantification of R/S-citalopram in serum was developed and validated using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS). Sample preparation prior to UHPSFC-MS/MS analysis consisted of protein precipitation with acidic acetonitrile and filtration through a phospholipid removal plate. The UHPSFC-MS/MS method used an UPC2 Trefoil CEL2 column with a mobile phase consisting of CO2 and methanol/acetonitrile (70:30, v/v) with 10mM ammonium acetate. The injection volume was 1µL and run time was 4min. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions (m/z 325.1>262.0 and m/z 325.1>109.0). The calibration range was 5-500nM for each analyte. The between-assay relative standard deviations were in the range of 3.4-4.5%. Recovery was 81-91% and matrix effects ranged from 96 to 101% (corrected with internal standard). After development and initial testing, the method has been successfully implemented in routine use in our laboratory for both separation and quantification of R/S-citalopram in more than 250 serum samples for therapeutic drug monitoring.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Citalopram/sangue , Espectrometria de Massas em Tandem/métodos , Citalopram/química , Monitoramento de Medicamentos , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Estereoisomerismo
18.
Eur Neuropsychopharmacol ; 27(9): 940-944, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28648553

RESUMO

Major Depression Disorder (MDD) has a highly variable treatment response due to the large inter-individual variation in the pharmacokinetics and pharmacodynamics of drug treatments. In detail the correlation between plasma level and efficacy has been much debated. Among first-line drugs for MDD, one of the most used is escitalopram. In the present study we investigated the association between serum concentration of escitalopram (SCE) and antidepressant response (AR). 70 MDD patients treated with escitalopram monotherapy were recruited and followed for three months. Hamilton Depression Rating Scale - 21 (HAMD-21) was administrated at baseline, month 1, and month 3 to assess AR. SCE was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCE and AR. We found an association between SCE and AR both at month 1 (p<0.001) and month 3 (p=0.0003), which persists also excluding 3 patients with SCE equal to 0. Interestingly, by excluding patients with SCE < 20ng/mL, i.e. with a SCE lower than the putative therapeutic threshold, these associations disappeared. The curvilinear function AR = a + (SCE-SCE2) explained a higher proportion of variance compared to the linear other models (p<0.001). Our results suggest that for escitalopram the association between SCE and AR likely follows a nearly-asymptotic function, with poor AR at sub-therapeutic SCE and stable AR response at therapeutic SCE. Thus, when a patient reaches the therapeutic SCE range, further increase of escitalopram dosage seems to be useless, although further studies are needed to confirm our findings.


Assuntos
Antidepressivos de Segunda Geração/sangue , Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/sangue , Citalopram/uso terapêutico , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Adulto , Feminino , Seguimentos , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
19.
PLoS One ; 12(6): e0179927, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28644875

RESUMO

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.


Assuntos
Gânglios da Base/efeitos dos fármacos , Citalopram/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Administração Intravenosa , Administração Oral , Animais , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/metabolismo , Benzilaminas , Mapeamento Encefálico , Radioisótopos de Carbono , Citalopram/sangue , Cães , Esquema de Medicação , Feminino , Imagem por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Inibidores de Captação de Serotonina/sangue
20.
Drug Test Anal ; 9(10): 1549-1554, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28178765

RESUMO

Citalopram is one of the most frequently used antidepressants in Denmark. It is marketed as a racemic mixture (50:50) of S- and R-enantiomers as well as of the S-enantiomer alone, which is the active enantiomer named escitalopram that processes the inhibitory effects. In this study, a chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is developed for the measurement of citalopram and demethylcitalopram enantiomers in whole blood and is applied to forensic cases. Whole blood samples (0.10 g) were extracted with butyl acetate after adjusting the pH with 2 M NaOH. The analytes were separated on a 250 × 4.6 mm Chirobiotic V, 5 µm column by isocratic elution with methanol:ammonia:acetic acid (1000:1:1) using an ultra-high-pressure liquid chromatography (UHPLC) system. Quantification was performed by tandem mass spectrometry (MS/MS) using multiple reaction monitoring (MRM) in the positive mode. The total chromatographic run time was 20 min. The limit of detection (LOD) and quantification (LOQ) were 0.001 and 0.005 mg/kg of all four enantiomers, respectively. Linear behaviour was obtained for all four enantiomers from LOQ to 0.50 mg/kg blood with absolute recoveries from 71 to 80%. The method showed an acceptable precision and accuracy as the obtained coefficient of variation, and bias values were ≤16% for all enantiomers. After the validation of the method, a correlation with the racemic method was assessed and found to be acceptable. Then, the method was successfully applied to authentic blood samples from forensic investigations demonstrating that escitalopram was less frequent than citalopram among all forensic cases. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Antidepressivos de Segunda Geração/sangue , Cromatografia Líquida de Alta Pressão/métodos , Citalopram/análogos & derivados , Citalopram/sangue , Espectrometria de Massas em Tandem/métodos , Antidepressivos de Segunda Geração/isolamento & purificação , Autopsia , Citalopram/isolamento & purificação , Toxicologia Forense/métodos , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/isolamento & purificação , Estereoisomerismo
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