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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.
Clin Pharmacol Ther ; 107(3): 662-670, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31628858

RESUMO

We previously reported that testis-specific Y-encoded-like protein (TSPYLs) are transcription regulators for CYP3A4, CYP2C9, and CYP2C19. Here, we observed dual roles for TSPYLs in mediating serotonin transport and the metabolism of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD). The widely prescribed SSRIs, citalopram, and escitalopram are metabolized mainly by CYP2C19. The TSPYL1 rs3828743 single nucleotide polymorphism (SNP), which decreases its suppression of CYP2C19 expression, was associated with rapid escitalopram metabolism and worse treatment response in the Mayo PGRN-AMPS clinical trial. We also found that TSPYLs can regulate expression of the serotonin transporter protein, SLC6A4, and, in turn, serotonin transport into cells. The SNPs in tight linkage disequilibrium with the TSPYL1 rs10223646 SNP were significantly correlated with baseline severity of depression in patients with MDD in the Sequenced Treatment Alternatives to Relieve Depression and International SSRI Pharmacogenomics Consortium clinical trials. Our findings suggest that genetic variation in TSPYL genes may be novel indicators for baseline severity of depression and SSRI poor response.


Assuntos
Citalopram/administração & dosagem , Citocromo P-450 CYP2C19/genética , Transtorno Depressivo Maior/tratamento farmacológico , Proteínas Nucleares/genética , Inibidores de Captação de Serotonina/administração & dosagem , Células CACO-2 , Citalopram/farmacocinética , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/fisiopatologia , Células Hep G2 , Humanos , Desequilíbrio de Ligação , Farmacogenética , Polimorfismo de Nucleotídeo Único , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/farmacocinética , Índice de Gravidade de Doença
3.
Eur J Pharm Sci ; 139: 105061, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31479720

RESUMO

Understanding the influence of ethnicity on drug exposure is key to patient safety and could minimize repetitive clinical studies. This analysis aimed to evaluate the ability of physiologically-based pharmacokinetic modelling to predict exposure of CYP2C19 substrates (lansoprazole, (es)citalopram, voriconazole) across Caucasian and East Asian populations. CYP2C19 abundance levels in Japanese and Chinese populations have been re-assessed based on clinical evidence. Model performance in each population was evaluated by predicted-over-observed AUC ratios and comparison of observed data with simulated plasma concentration profiles. Exposures in 84.4% (76 out of 90) of the clinical studies were predicted within 1.5-fold of observed values. The reported concentration-time profiles were well-captured within the 90% prediction intervals. With specified CYP2C19 phenotype, PBPK modelling is capable to predict systemic exposure of drugs largely metabolized by CYP2C19 in different ethnic populations. This study demonstrated PBPK modelling can be applied to assess genotype-dependent exposure difference across ethnicities.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Grupo com Ancestrais do Continente Europeu/genética , Lansoprazol/farmacocinética , Modelos Biológicos , Voriconazol/farmacocinética , Citocromo P-450 CYP2C19/metabolismo , Feminino , Humanos , Masculino , Polimorfismo Genético
4.
J Clin Psychopharmacol ; 39(5): 485-488, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31343441

RESUMO

BACKGROUND: Tobacco smoking rates in depressive patients are higher compared with the general population. Smoking was demonstrated to accelerate the metabolism of different drugs metabolized by CYP1A2, but possibly also by CYP2C19 and CYP3A4. The principle aim of the present investigation from 2015 to 2018 was to determine the differences in the pharmacokinetics of escitalopram between smokers and nonsmokers. METHODS: A group of nonsmokers (n = 88) was compared with smokers (n = 36), both receiving escitalopram, using the Mann-Whitney U test. Linear regression analysis was used to account for the impact of escitalopram dose, age, and sex in addition to smoking on the steady-state serum concentration of escitalopram. RESULTS: Smokers received by mean 17.6% higher doses of escitalopram (P = 0.026) but showed 31.9% lower serum concentrations (P = 0.031). To control for confounders, linear regression analysis showed that dose (P < 0.001), sex (P = 0.03), and smoking tobacco (P = 0.027) did significantly influence serum concentrations of escitalopram with higher levels in women and nonsmokers. CONCLUSIONS: Notwithstanding higher daily doses, smokers had significantly lower serum concentrations of escitalopram. In concordance with previous results, besides CYP1A2, a possible induction of CYP2C19 and CYP3A4 by tobacco smoke, resulting in lower serum concentrations of escitalopram in smokers than in nonsmokers, is suggested. Therefore, to provide personalized therapy, clinicians should consider smoking status and inform patients on the interactions of smoking and escitalopram metabolism.


Assuntos
Citalopram/administração & dosagem , Transtorno Depressivo/tratamento farmacológico , Inibidores de Captação de Serotonina/administração & dosagem , Fumar Tabaco/epidemiologia , Adulto , Idoso , Citalopram/farmacocinética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/farmacocinética , Fumantes , Fumar Tabaco/metabolismo
5.
Sci Rep ; 9(1): 10505, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324853

RESUMO

P-glycoprotein (P-gp) largely influences the pharmacokinetics (PK) and toxicities of xenobiotics in a patient-specific manner so that personalized drug scheduling may lead to significant patient's benefit. This systems pharmacology study investigated P-gp activity in mice according to organ, sex, feeding status, and circadian time. Sex-specific circadian changes were found in P-gp ileum mRNA and protein levels, circadian amplitudes being larger in females as compared to males. Plasma, ileum and liver concentrations of talinolol, a pure P-gp substrate, significantly differed according to sex, feeding and circadian timing. A physiologically-based PK model was designed to recapitulate these datasets. Estimated mesors (rhythm-adjusted mean) of ileum and hepatic P-gp activity were higher in males as compared to females. Circadian amplitudes were consistently higher in females and circadian maxima varied by up to 10 h with respect to sex. Fasting increased P-gp activity mesor and dampened its rhythm. Ex-vivo bioluminescence recordings of ileum mucosae from transgenic mice revealed endogenous circadian rhythms of P-gp protein expression with a shorter period, larger amplitude, and phase delay in females as compared to males. Importantly, this study provided model structure and parameter estimates to refine PK models of any P-gp substrate to account for sex, feeding and circadian rhythms.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Ritmo Circadiano , Citalopram/farmacocinética , Ingestão de Alimentos/fisiologia , Jejum/fisiologia , Propanolaminas/farmacocinética , Caracteres Sexuais , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Transporte Biológico , Colo/metabolismo , Cruzamentos Genéticos , Feminino , Regulação da Expressão Gênica , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Propanolaminas/análise , RNA Mensageiro/biossíntese
6.
Am J Emerg Med ; 37(10): 1993.e5-1993.e6, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31257122

RESUMO

INTRODUCTION: Citalopram is a selective serotonin reuptake inhibitor used for treatment of depression. Metabolism is primarily through CYP3A4 and CYP2C19; activity of the latter can vary depending on genetics. Although rare after single agent exposure, large citalopram ingestions can lead to serotonin syndrome. We report a case of citalopram overdose in an intermediate CYP2C19 metabolizer complicated by severe serotonin syndrome. CASE DETAILS: A 25-year-old female presented after intentional citalopram overdose with seizures, tachycardia, persistent neuromuscular findings, and severe hyperthermia requiring aggressive sedation and cooling. Protracted symptoms required critical care services throughout a 14 day hospital stay despite traditional treatment of serotonin syndrome. Pharmacogenomic studies revealed intermediate CYP2C19 metabolism which reduces citalopram inactivation and may cause increased levels and toxicity. DISCUSSION: In the majority of serotonin syndrome cases, symptoms resolve rapidly after treatment initiation and discontinuation of the offending agents. Severe cases are typically associated with ingestion of multiple serotonergic agents. Our patient had severe toxicity after single agent ingestion. Pharmacogenetic testing identified abnormal CYP2C19 activity and previous cases have associated enzyme dysfunction and citalopram toxicity. CONCLUSION: Citalopram overdose may be associated with severe serotonin syndrome and further investigation is warranted to understand the impact of enzyme genotype on toxicity.


Assuntos
Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Variantes Farmacogenômicos/genética , Síndrome da Serotonina/genética , Inibidores de Captação de Serotonina/farmacocinética , Tentativa de Suicídio , Adulto , Citalopram/envenenamento , Overdose de Drogas , Feminino , Genótipo , Humanos , Inibidores de Captação de Serotonina/envenenamento , Resultado do Tratamento
7.
Br J Clin Pharmacol ; 85(9): 2022-2032, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31144347

RESUMO

AIMS: The aims of this study were to characterize escitalopram pharmacokinetic profile, to identify factors influencing drug exposure, notably drug-drug interactions with antiretrovirals, and to simulate expected exposure under standard dosage regimen. METHODS: A population pharmacokinetic analysis was performed using NONMEM. A total of 159 plasma concentration measurements were obtained from 39 human immunodeficiency virus (HIV)-infected and 71 uninfected psychiatric patients. The influence of age, weight, sex, HIV and psychiatric cohorts, racemic citalopram treatment, and comedications on oral clearance was examined. Simulations served to calculate the percentage of patients expected to be under- or over-exposed, considering established therapeutic targets (15-80 ng/mL). RESULTS: A 1-compartment model with first-order absorption and elimination described the data adequately. The average escitalopram clearance and volume of distribution were 23.1 L/h (interindividual variability 51%), and 920 L, respectively. Escitalopram disposition did not differ between HIV-infected and uninfected patients, and was not affected by antiretroviral treatments. Coadministration of at least 1 proton-pump inhibitor (CYP2C19 inhibitor) modestly influenced escitalopram elimination (clearance decreased by 19%), with limited clinical relevance. Model-based simulations showed that, under a standard regimen of 10 mg once daily, a significant proportion of patients (56%) might be under-exposed. CONCLUSION: The variability in escitalopram disposition is large and poorly explained by demographic, clinical and environmental covariates, thus suggesting a role for dosage individualization based on therapeutic drug monitoring in case of poor clinical response. Escitalopram disposition is modestly impacted by comedications and therefore no a priori dosage adjustments are needed in patients receiving antiretroviral treatments, including boosted regimens.


Assuntos
Fármacos Anti-HIV/farmacocinética , Antidepressivos de Segunda Geração/farmacocinética , Citalopram/farmacocinética , Transtorno Depressivo/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Adulto , Fármacos Anti-HIV/administração & dosagem , Antidepressivos de Segunda Geração/administração & dosagem , Variação Biológica da População , Citalopram/administração & dosagem , Simulação por Computador , Transtorno Depressivo/sangue , Transtorno Depressivo/etiologia , Transtorno Depressivo/psicologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Monitoramento de Medicamentos , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , Infecções por HIV/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos
8.
Eur Neuropsychopharmacol ; 29(6): 711-719, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31076187

RESUMO

Pharmacological imaging of the effects of selective serotonin reuptake inhibitors (SSRI) may aid the clarification of their mechanism of action and influence treatment of highly prevalent neuropsychiatric conditions if the detected effects could be related to patient outcomes. In a randomized double-blind design, 38 healthy participants received a constant infusion of 8 mg citalopram or saline during either their first or second of two PET/MR scans. Resting-state functional MRI (fMRI) was acquired simultaneously with PET data on the binding of serotonin transporters (5-HTT) using [11C]DASB. Three different approaches for modeling of pharmacological fMRI response were tested separately. These relied on the use of regressors corresponding to (1) the drug infusion paradigm, (2) time courses of citalopram plasma concentrations and (3) changes in 5-HTT binding measured in each individual, respectively. Furthermore, the replication of results of a widely used model-free analysis method was attempted which assesses the deviation of signal in discrete time bins of fMRI data acquired after start of drug infusion. Following drug challenge, average 5-HTT occupancy was 69±7% and peak citalopram plasma levels were 111.8 ±â€¯21.1 ng/ml. None of the applied methods could detect significant differences in the pharmacological response between SSRI and placebo scans. The failed replication of SSRI effects reported in the literature despite a threefold larger sample size highlights the importance of appropriate correction for family-wise error in order to avoid spurious results in pharmacological imaging. This calls for the development of analysis methods which take regional specialization and the dynamics of brain activity into account.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Citalopram/farmacologia , Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Inibidores de Captação de Serotonina/farmacologia , Adolescente , Adulto , Encéfalo/metabolismo , Citalopram/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacocinética , Adulto Jovem
9.
Anal Chem ; 91(13): 8062-8069, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31074958

RESUMO

Drug monitoring is crucial for providing accurate and effective care; however, current methods (e.g., blood draws) are inconvenient and unpleasant. We aim to develop a non-invasive method for the detection and monitoring of drugs via human skin. The initial development toward this aim required information about which drugs, taken orally, can be detected via the skin. Untargeted liquid chromatography-mass spectrometry (LC-MS) was used as it was unclear if drugs, known drug metabolites, or other transformation products were detectable. In accomplishing our aim, we analyzed samples obtained by swabbing the skin of 15 kidney transplant recipients in five locations (forehead, nasolabial area, axillary, backhand, and palm), bilaterally, on two different clinical visits. Untargeted LC-MS data were processed using molecular networking via the Global Natural Products Social Molecular Networking platform. Herein, we report the qualitative detection and location of drugs and drug metabolites. For example, escitalopram/citalopram and diphenhydramine, taken orally, were detected in forehead, nasolabial, and hand samples, whereas N-acetyl-sulfamethoxazole, a drug metabolite, was detected in axillary samples. In addition, chemicals associated with environmental exposure were also detected from the skin, which provides insight into the multifaceted chemical influences on our health. The proof-of-concept results presented support the finding that the LC-MS and data analysis methodology is currently capable of the qualitative assessment of the presence of drugs directly via human skin.


Assuntos
Monitoramento de Medicamentos/métodos , Absorção Cutânea , Pele/metabolismo , Administração Oral , Cromatografia Líquida/métodos , Citalopram/administração & dosagem , Citalopram/farmacocinética , Difenidramina/administração & dosagem , Difenidramina/farmacocinética , Humanos , Espectrometria de Massas/métodos , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacocinética , Medicamentos Indutores do Sono/administração & dosagem , Medicamentos Indutores do Sono/farmacocinética
10.
Clin Pharmacol Ther ; 106(4): 855-865, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31012492

RESUMO

We set out to determine whether machine learning-based algorithms that included functionally validated pharmacogenomic biomarkers joined with clinical measures could predict selective serotonin reuptake inhibitor (SSRI) remission/response in patients with major depressive disorder (MDD). We studied 1,030 white outpatients with MDD treated with citalopram/escitalopram in the Mayo Clinic Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS; n = 398), Sequenced Treatment Alternatives to Relieve Depression (STAR*D; n = 467), and International SSRI Pharmacogenomics Consortium (ISPC; n = 165) trials. A genomewide association study for PGRN-AMPS plasma metabolites associated with SSRI response (serotonin) and baseline MDD severity (kynurenine) identified single nucleotide polymorphisms (SNPs) in DEFB1, ERICH3, AHR, and TSPAN5 that we tested as predictors. Supervised machine-learning methods trained using SNPs and total baseline depression scores predicted remission and response at 8 weeks with area under the receiver operating curve (AUC) > 0.7 (P < 0.04) in PGRN-AMPS patients, with comparable prediction accuracies > 69% (P ≤ 0.07) in STAR*D and ISPC. These results demonstrate that machine learning can achieve accurate and, importantly, replicable prediction of SSRI therapy response using total baseline depression severity combined with pharmacogenomic biomarkers.


Assuntos
Citalopram/farmacocinética , Transtorno Depressivo Maior , Adulto , Algoritmos , Biomarcadores Farmacológicos/sangue , Regras de Decisão Clínica , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Aprendizado de Máquina , Masculino , Testes Farmacogenômicos/métodos , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Indução de Remissão , Inibidores de Captação de Serotonina/farmacocinética
11.
Drug Test Anal ; 11(7): 1083-1093, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30817095

RESUMO

In recent years, the use of skeletal tissue as an alternative matrix in forensic toxicology has received new interest. In cases where extreme decomposition has taken place, analysis of skeletal tissue is often the only option left. In this article, a fully validated method is presented and the distribution of clomipramine, citalopram, midazolam, and metabolites after chronically administration is examined within skeletal tissue. Rats were chronically dosed with respectively clomipramine, citalopram, or midazolam. Extracts were quantitatively analyzed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Clomipramine, citalopram, and metabolites, respectively desmethylclomipramine and desmethylcitalopram are shown to be detectable in all bone types sampled. Midazolam and its metabolite α-OH-midazolam could not be detected. The absence of midazolam in extracts gives an indication that drugs with pKa values under physiological pH are badly or not incorporated in bone tissue. Bone and post-mortem blood concentrations were compared. A range of different bone types was compared and showed that the concentration is strongly dependent on the bone type. In concordance with previous publications, the humerus shows the highest drug levels. Skeletal tissue concentrations found ranged from 1.1 to 587.8 ng/g. Comparison of the same bone type between the different rats showed high variances. However, the drugs-metabolite ratio proved to have lower variances (<20%). Moreover, the drugs-metabolite ratio in the sampled bones is in close concordance to the ratios seen in blood within a rat. From this, we can assume that the drugs-metabolite ratio in skeletal tissue may prove to be more useful than absolute found concentration.


Assuntos
Ansiolíticos/farmacocinética , Antidepressivos/farmacocinética , Osso e Ossos/metabolismo , Citalopram/farmacocinética , Clomipramina/farmacocinética , Midazolam/farmacocinética , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/metabolismo , Antidepressivos/administração & dosagem , Antidepressivos/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Citalopram/administração & dosagem , Citalopram/metabolismo , Clomipramina/administração & dosagem , Clomipramina/metabolismo , Limite de Detecção , Masculino , Midazolam/administração & dosagem , Midazolam/metabolismo , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
12.
J Child Adolesc Psychopharmacol ; 29(5): 340-347, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30817183

RESUMO

Objective: Cytochrome P4502C19 (CYP2C19) is a highly polymorphic gene that encodes an enzyme that metabolizes escitalopram and sertraline, two selective serotonin reuptake inhibitors (SSRIs) that are FDA approved for pediatric use and commonly used to treat anxiety and depressive disorders in youth. Using pharmacokinetic (PK) models in adolescents, we sought to (1) model SSRI dosing across CYP2C19 phenotypes to compare SSRI exposure (area under curve, AUC) and maximum concentration (Cmax), (2) evaluate the impact of b.i.d. dosing (in rapid metabolizers [RM] and ultrarapid metabolizers [UM]) on SSRI exposure and Cmax, and (3) determine pharmacogenomically-informed dosing strategies to provide similar exposure across CYP2C19 phenotypes in adolescents. Methods: Using PK parameters in CYP2C19 phenotype groups and previously reported pediatric PK data for escitalopram and sertraline, we modeled exposure (AUC0-24) and Cmax and determined CYP2C19-guided dosing strategies. Results: Compared with normal CYP2C19 metabolizers treated with either escitalopram or sertraline, Cmax and AUC0-24 were higher in slower metabolizers and lower in patients with increased CYP2C19 activity, although the magnitude of these differences was more pronounced for escitalopram than for sertraline. For escitalopram, poor metabolizers (PMs) require 10 mg/day and UMs require 30 mg/day to achieve an exposure that is equivalent to 20 mg/day in a normal metabolizer (NM). For sertraline, to achieve AUC0-24 and Cmax similar to NMs receiving 150 mg/day, PMs require 100 mg/day, whereas a dose of 200 mg/day was required in rapid and UMs. For UMs, b.i.d. escitalopram dosing was necessary to achieve comparable trough levels and exposure to NMs. Conclusions: This simulation study raises the possibility that achieving similar escitalopram and sertraline plasma concentrations could require dose adjustments in CYP2C19 poor metabolizers and UMs, although the magnitude of these differences were more pronounced for escitalopram than for sertraline. However, prospective trials of pharmacogenomically guided dosing in the pediatric population are needed to extend the findings of these modeling studies.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Transtorno Depressivo Maior/tratamento farmacológico , Inibidores de Captação de Serotonina/farmacocinética , Sertralina/farmacocinética , Adolescente , Citalopram/uso terapêutico , Feminino , Humanos , Masculino , Testes Farmacogenômicos , Fenótipo , Polimorfismo Genético , Inibidores de Captação de Serotonina/uso terapêutico , Sertralina/uso terapêutico
13.
Int J Neuropsychopharmacol ; 22(4): 286-291, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753467

RESUMO

BACKGROUND: Selective serotonin reuptake inhibitors are often used in alcohol use disorders. Clinical trials with selective serotonin reuptake inhibitors for alcohol use disorders, however, have yielded mixed results. The goal of this project was to assess whether a single i.v. dose of a selective serotonin reuptake inhibitor reduces craving for alcohol and/or simultaneously increases striatal dopamine concentration in individuals with alcohol dependence. METHODS: Alcohol-dependent (DSM-IV-TR criteria) volunteers and matched controls (n = 10/group) underwent a double-blind, placebo-controlled, within-subjects study. Participants received i.v. citalopram (40 mg) or saline (counter-balanced) followed by a cue-induced craving assessment and [18F]-fallypride positron emission tomography scanning. RESULTS: In the alcohol-dependent individuals, the citalopram (compared with saline) resulted in decreased cue-induced craving for alcohol. For the whole study group, cue-induced alcohol craving was inversely correlated with thalamic (but not striatal) dopamine D2/3 receptor availability. CONCLUSIONS: Acute serotonin reuptake inhibition reduces cue-induced alcohol craving. Furthermore, thalamic dopamine abnormalities and the striatal hyperdopaminergic hypothesis of alcohol use disorder are supported.


Assuntos
Alcoolismo/tratamento farmacológico , Citalopram/farmacocinética , Corpo Estriado/efeitos dos fármacos , Fissura/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacocinética , Tálamo/efeitos dos fármacos , Administração Intravenosa , Adulto , Benzamidas , Citalopram/administração & dosagem , Sinais (Psicologia) , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Pirrolidinas , Inibidores de Captação de Serotonina/administração & dosagem
14.
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
15.
Int J Legal Med ; 133(2): 353-363, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30173302

RESUMO

Depression is known to be a risk factor for suicide. Currently, the most used antidepressants are selective serotonin reuptake inhibitors (SSRIs). Not all users, however, benefit from them. In such cases, treatment failure can be explained in part by genetic differences. In this study, we investigated the role of pharmacogenetic factors in citalopram-positive completed suicides (n = 349). Since citalopram is metabolized by CYP2C19 and CYP2D6 enzymes, the study population was genotyped for clinically relevant CYP2C19 and CYP2D6 polymorphisms and CYP2D6 copy number variation. To assess genetic differences between suicide cases and Finns in general, Finnish population samples (n = 855) were used as controls. Also, the role of drug interactions among suicide cases was evaluated. We found enrichment of a combined group of genetically predicted poor and ultrarapid metabolizer phenotypes (gMPs) of CYP2C19 among suicide victims compared to controls 0.356 [0.31-0.41] vs. 0.265 [0.24-0.30] (p = 0.0065). In CYP2D6 gMPs, there was no difference between cases and controls when the study population was analyzed as a whole. However, there were significantly more poor metabolizers among females who committed suicide by poisoning compared to female controls. In 8% of all drug poisoning deaths, lifetime drug-drug interaction was evaluated having a contribution to the fatal outcome. From clinical perspective, pharmacogenetic testing prior to initiation of SSRI drug could be beneficial. It may also be useful in medico-legal settings as it may elucidate obscure poisoning cases. Also, the possibility of unintentional drug interactions should be taken into account in drug poisoning deaths.


Assuntos
Citalopram/envenenamento , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Genótipo , Variantes Farmacogenômicos/genética , Inibidores de Captação de Serotonina/envenenamento , Suicídio , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Citalopram/farmacocinética , Variações do Número de Cópias de DNA , Interações Medicamentosas/genética , Feminino , Finlândia , Toxicologia Forense , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Inibidores de Captação de Serotonina/farmacocinética
16.
Arch Womens Ment Health ; 22(3): 383-390, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30116895

RESUMO

Despite increasing prescription rates of antidepressants in pregnant and breastfeeding women over the past decades, evidence of drug exposure for neonates through lactation is very sparse. Concentrations of three antidepressants citalopram, sertraline, and venlafaxine were measured in maternal blood and breast milk in 17 women receiving antidepressant therapy during breastfeeding period. We also computed concentration-by-dose-ratios (C/D) and milk to serum (plasma) penetration ratios (M/P). Non-parametric tests were applied. Serum concentration of citalopram and daily dosage correlated positively while daily dosage and mother milk concentration did not (rho = 0.939, p = 0.005, and rho = 0.772, p > 0.05 respectively). A significant correlation was also found between serum and milk concentrations (rho = 0.812, p = 0.05). Venlafaxine daily dosage correlated positively with the active moiety milk concentration (rho = 0.949, p = 0.014). No significant correlations were reported for sertraline. The amount of antidepressant concentrations to which neonates may be exposed, assessed as absolute infant dose (AID), was particularly low with the highest median AID being 0.16 mg/kg/day for venlafaxine. No significant difference was detected for the M/P ratios between different drugs (p > 0.05), whereas the comparison of C/D ratios revealed lower values in the sertraline group, with the highest values reported for citalopram group (p = 0.007 for serum concentrations and p = 0.008 for mother milk). Findings suggest that breastfeeding under antidepressant treatment constantly exposes children with measurable drug concentrations. As daily dosage and serum concentration of the antidepressants did not predict drug concentrations in mother milk, measuring of drug concentrations in milk helps to quantify drug exposure during breastfeeding. More data-even data of drug concentrations in breastfed children-are needed to better assess the effects of drug exposure on children's development.


Assuntos
Antidepressivos/farmacocinética , Leite Humano/química , Adulto , Antidepressivos/análise , Aleitamento Materno/efeitos adversos , Desenvolvimento Infantil/efeitos dos fármacos , Citalopram/análise , Citalopram/farmacocinética , Depressão/tratamento farmacológico , Feminino , Humanos , Lactente , Leite Humano/metabolismo , Gravidez , Inibidores de Captação de Serotonina/análise , Inibidores de Captação de Serotonina/farmacocinética , Inibidores da Recaptação de Serotonina e Norepinefrina/análise , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacocinética , Sertralina/análise , Sertralina/farmacocinética , Cloridrato de Venlafaxina/análise , Cloridrato de Venlafaxina/farmacocinética , Adulto Jovem
17.
Brain Behav ; 8(6): e00975, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-30106253

RESUMO

INTRODUCTION: Serving as a pilot study of poststroke pharmacotherapy, the present investigation was intended to establish the effect of a single dose of escitalopram on motor task performance in normal volunteers. METHODS: Ten healthy volunteers of median age 63 years including four females performed a well-studied tactile manipulation task in two fMRI sessions using a double-blind cross-over design. The sessions began approximately three hours after ingestion of 20 mg escitalopram or placebo presented in pseudorandom order. The fMRI image sequences were submitted to principal component analysis (PCA). RESULTS: Based on volume correlations of task-related principal components with the mean component images derived in our previous study, we established the reproducibility of two networks of sensorimotor activity proposed there. The network reflecting motor control (cerebral pattern I) appeared invariably in placebo and verum conditions. In contrast, the other network, attributed to diminished motor control due to distracting mental processing (cerebral pattern II), emerged less regularly and exhibited more variability. Second-level PCAs of both conditions confirmed the findings of the initial analysis. Specifically, it validated the dominant and invariable expression of cerebral pattern I after application of a single dose of escitalopram. Dynamic causal modeling confirmed enhanced motor output as a result of a significantly increased connectivity between primary motor cortex and dorsal premotor cortex. CONCLUSION: This pilot study suggests the promise of stimulation by a specific serotonin reuptake inhibitor in regard to recovery and preservation of motor control after stroke.


Assuntos
Desempenho Psicomotor/efeitos dos fármacos , Córtex Sensório-Motor/efeitos dos fármacos , Acidente Vascular Cerebral , Citalopram/administração & dosagem , Citalopram/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Análise de Componente Principal , Reprodutibilidade dos Testes , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacocinética , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia
18.
Naunyn Schmiedebergs Arch Pharmacol ; 391(12): 1361-1371, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30094458

RESUMO

The main goal of the present study was to evaluate the influence of the adenosine A1 receptor (A1R) antagonist - DPCPX - on depressive-like behavior in mice, as well as the effect of DPCPX on the activity of imipramine, escitalopram, and reboxetine, each at non-effective doses. The influence of DPCPX on behavior and its influence on the activity of selected antidepressants was evaluated in the forced swim test (FST) and the tail suspension test (TST) in mice. Locomotor activity was measured to verify and exclude false-positive data obtained in the FST and TST. Moreover, serum and brain concentrations of tested antidepressants were determined using HPLC. DPCPX, at doses of 2 and 4 mg/kg, exhibited antidepressant activity in the FST and TST, which was not related to changes in the spontaneous locomotor activity. Co-administration of DPCPX with imipramine, escitalopram, or reboxetine, each at non-active doses, significantly reduced the immobilization period in the FST and TST in mice, which was not due to the increase in locomotor activity. Both antagonists of 5-HT receptors (WAY 100635 and ritanserin) completely antagonized the effect elicited by DPCPX in the behavioral tests. Results of assessment of the nature of the interaction between DPCPX and test drugs show that in the case of DPCPX and imipramine or reboxetine, there were pharmacodynamic interactions, whereas the DPCPX-escitalopram interaction is at least partially pharmacokinetic in nature. Presented outcomes indicate that an inhibition of A1Rs and an increase of monoaminergic transduction in the CNS may offer a novel strategy for the development of antidepressant drugs.


Assuntos
Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Depressão/tratamento farmacológico , Imipramina/uso terapêutico , Reboxetina/uso terapêutico , Xantinas/uso terapêutico , Animais , Antidepressivos/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Citalopram/farmacocinética , Depressão/metabolismo , Interações Medicamentosas , Quimioterapia Combinada , Elevação dos Membros Posteriores , Imipramina/farmacocinética , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Reboxetina/farmacocinética , Antagonistas da Serotonina/farmacologia
19.
Clin Pharmacokinet ; 57(12): 1603-1611, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29651785

RESUMO

BACKGROUND: Escitalopram is used for post-partum depression; however, there are limited pharmacokinetic data of escitalopram in milk and plasma of infants breastfed by women taking the drug. OBJECTIVE: The objective of this study was to apply physiologically-based pharmacokinetic (PBPK) modelling to predict infant drug exposure (plasma area under the curve from time zero to infinity [AUC∞]) based on drug monitoring data of escitalopram in breast milk. METHODS: Using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, we quantified escitalopram concentrations in milk samples of 18 breastfeeding women with escitalopram therapy at steady state, collected at three to five time points. The escitalopram concentrations in breast milk were used with infant feeding parameters from the literature to simulate infant daily dose. We used PK-Sim® to develop an adult PBPK model for escitalopram and extrapolated it to a population of 1600 infants up to 12 months of age. An integration of the simulated infant daily dose and the virtual infants with variable physiological-pharmacological parameters was used to predict drug exposure (plasma AUC∞) distribution in the population of infants breastfed by women receiving escitalopram 20 mg/day. RESULTS: Escitalopram concentrations in milk were 50 ± 17 ng/mL (mean ± standard deviation). The simulated infant plasma AUC∞ following escitalopram exposure through breast milk was low, with a median of 1.7% (range 0.5-5.9%) of the corresponding maternal plasma AUC∞, indicating no substantial exposure. CONCLUSIONS: Infant exposure levels to escitalopram in breast milk are low. A PBPK modeling approach can be used to translate data on drug monitoring in milk into a population distribution of infant plasma levels for drug safety assessment.


Assuntos
Aleitamento Materno , Citalopram/administração & dosagem , Leite Humano/metabolismo , Modelos Biológicos , Adulto , Área Sob a Curva , Cromatografia Líquida/métodos , Citalopram/farmacocinética , Simulação por Computador , Depressão Pós-Parto/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Lactação/metabolismo , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacocinética , Espectrometria de Massas em Tandem/métodos , Fatores de Tempo
20.
Pharmacoepidemiol Drug Saf ; 27(6): 621-629, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29575226

RESUMO

PURPOSE: Co-prescription of paroxetine/fluoxetine (a strong CYP2D6 inhibitor) in metoprolol (a CYP2D6 substrate) users is common, but data on the clinical consequences of this drug-drug interaction are limited and inconclusive. Therefore, we assessed the effect of paroxetine/fluoxetine initiation on the existing treatment with metoprolol on the discontinuation and dose adjustment of metoprolol among elderly. METHODS: We performed a cohort study using the University of Groningen IADB.nl prescription database (www.IADB.nl). We selected all elderly (≥60 years) who had ever been prescribed metoprolol and had a first co-prescription of paroxetine/fluoxetine, citalopram (weak CYP2D6 inhibitor), or mirtazapine (negative control) from 1994 to 2015. The exposure group was metoprolol and paroxetine/fluoxetine co-prescription, and the other groups acted as controls. The outcomes were early discontinuation and dose adjustment of metoprolol. Logistic regression was applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Combinations of metoprolol-paroxetine/fluoxetine, metoprolol-citalopram, and metoprolol-mirtazapine were started in 528, 673, and 625 patients, respectively. Compared with metoprolol-citalopram, metoprolol-paroxetine/fluoxetine was not significantly associated with the early discontinuation and dose adjustment of metoprolol (OR = 1.07, 95% CI:0.77-1.48; OR = 0.87, 95% CI:0.57-1.33, respectively). In comparison with metoprolol-mirtazapine, metoprolol-paroxetine/fluoxetine was associated with a significant 43% relative increase in early discontinuation of metoprolol (OR = 1.43, 95% CI:1.01-2.02) but no difference in the risk of dose adjustment. Stratified analysis by gender showed that women have a significantly high risk of metoprolol early discontinuation (OR = 1.62, 95% CI:1.03-2.53). CONCLUSION: Paroxetine/fluoxetine initiation in metoprolol prescriptions, especially for female older patients, is associated with the risk of early discontinuation of metoprolol.


Assuntos
Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Fluoxetina/farmacocinética , Metoprolol/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Citalopram/administração & dosagem , Citalopram/farmacocinética , Estudos de Coortes , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Prescrições de Medicamentos/estatística & dados numéricos , Quimioterapia Combinada , Feminino , Fluoxetina/administração & dosagem , Humanos , Masculino , Metoprolol/metabolismo , Metoprolol/farmacocinética , Pessoa de Meia-Idade , Mirtazapina/administração & dosagem , Mirtazapina/farmacocinética , Países Baixos , Paroxetina
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