Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 73
Filtrar
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.
J Pharm Biomed Anal ; 164: 173-180, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30390559

RESUMO

A micellar liquid chromatographic method has been developed for the simultaneous determination of citalopram hydrobromide (CTA) with its two demethylated metabolites namely; desmethyl citalopram hydrochloride (DCTA) and didesmethyl citalopram tartrate (DDCTA). Separation was conducted on a C18 column using a mobile phase composed of 0.18 M sodium dodecyl sulphate (SDS), 15% 1-propanol, 0.3% tri-ethylamine, adjusted to pH 4 with 0.2 M o-phosphoric acid and adopting UV detection at 240 nm. Analysis was performed at 60 °C applying a flow rate of 2 mL/min. The proposed method was linear over the concentration ranges of 1.0-200.0, 0.6-200.0, and 0.5-200.0 µg/mL for CTA, DCTA, and DDCTA respectively, with corresponding limits of detection (LOD) of 0.5, 0.4, and 0.3 µg/mL and limits of quantification (LOQ) of 0.8, 0.5, and 0.4 µg/mL. The method was fully validated which allowed its application for the determination of CTA in its tablets. Moreover, the proposed method was extended to assay CTA with its metabolites in rat tissue organs samples which allowed the method to be used as a diagnostic tool in forensic toxicology.


Assuntos
Citalopram/análogos & derivados , Citalopram/análise , Toxicologia Forense/métodos , Animais , Autopsia , Fracionamento Químico , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Toxicologia Forense/instrumentação , Limite de Detecção , Fígado/química , Micelas , Modelos Animais , Miocárdio/química , Ratos , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta/instrumentação , Espectrofotometria Ultravioleta/métodos , Comprimidos
3.
Bioorg Med Chem Lett ; 28(21): 3431-3435, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30266542

RESUMO

To date, the development of photoaffinity ligands targeting the human serotonin transporter (hSERT), a key protein involved in disease states such as depression and anxiety, have been radioisotope-based (i.e., 3H or 125I). This letter instead highlights three derivatives of the selective serotonin reuptake inhibitor (SSRI) (S)-citalopram that were rationally designed and synthesized to contain a photoreactive benzophenone or an aryl azide for protein target capture via photoaffinity labeling and a terminal alkyne or an aliphatic azide for click chemistry-based proteomics. Specifically, clickable benzophenone-based (S)-citalopram photoprobe 6 (hSERT Ki = 0.16 nM) displayed 11-fold higher binding affinity at hSERT when compared to (S)-citalopram (hSERT Ki = 1.77 nM), and was subsequently shown to successfully undergo tandem photoaffinity labeling-biorthogonal conjugation using purified hSERT. Given clickable photoprobes can be used for various applications depending on which reporter is attached by click chemistry subsequent to photoaffinity labeling, photoprobe 6 is expected to find value in structure-function studies and other research applications involving hSERT (e.g., imaging).


Assuntos
Azidas/química , Benzofenonas/química , Citalopram/análogos & derivados , Marcadores de Fotoafinidade/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Azidas/síntese química , Azidas/efeitos da radiação , Benzofenonas/síntese química , Benzofenonas/efeitos da radiação , Citalopram/síntese química , Citalopram/efeitos da radiação , Química Click , Células HEK293 , Humanos , Ligantes , Marcadores de Fotoafinidade/síntese química , Marcadores de Fotoafinidade/efeitos da radiação , Estereoisomerismo , Raios Ultravioleta
4.
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
5.
Eur J Med Chem ; 138: 396-406, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28688279

RESUMO

A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58-84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 µM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 µM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2. However, size and position of the substituents affected enzyme inhibitions. . In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of -64.92,-203.25 and -140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values -170.91, -256.84 and -235.97 kcal/mol, respectively.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Citalopram/análogos & derivados , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Citalopram/síntese química , Citalopram/química , Citalopram/farmacologia , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Estrutura Molecular , Relação Estrutura-Atividade
6.
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
7.
Bioorg Med Chem Lett ; 27(3): 470-478, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28041833

RESUMO

The recent publication of X-ray structures of SERT includes structures with the potent antidepressant S-Citalopram (S-Cit). Earlier predictions of ligand binding at both a primary (S1) and an allosteric modulator site (S2), were confirmed. We provide herein examples of a series of Citalopram analogs, showing distinct structure-activity relationship (SAR) at both sites that is independent of the SAR at the other site. Analogs with a higher affinity and selectivity than benchmark R-Citalopram (R-Cit) for the S2 versus the S1 site were identified. We deploy structural and computational analyses to explain this SAR and demonstrate the potential utility of the newly emerging X-ray structures within the neurotransmitter:sodium Symporter family for drug design.


Assuntos
Citalopram/análogos & derivados , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Sítio Alostérico , Sítios de Ligação , Citalopram/síntese química , Citalopram/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Simulação de Dinâmica Molecular , Estrutura Terciária de Proteína , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Inibidores de Captação de Serotonina/síntese química , Inibidores de Captação de Serotonina/química , Inibidores de Captação de Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
8.
ACS Chem Neurosci ; 8(5): 1011-1018, 2017 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27959497

RESUMO

Previous studies of transgenic mice carrying a single isoleucine to methionine substitution (I172M) in the serotonin transporter (SERT) demonstrated a loss of sensitivity to multiple antidepressants (ADs) at SERT. However, the ability of AD metabolites to antagonize SERT was not assessed. Here, we evaluated the selectivity and potency of these metabolites for inhibition of SERT in mouse brain-derived synaptosomes and blood platelets from wild-type (I172 mSERT) and the antidepressant-insensitive mouse M172 mSERT. The metabolites norfluoxetine and desmethylsertraline lost the selectivity demonstrated by the parent compounds for inhibition of wild-type mSERT over M172 mSERT, whereas desvenlafaxine and desmethylcitalopram retained selectivity. Furthermore, we show that the metabolite desmethylcitalopram accumulates in the brain and that the metabolites desmethylcitalopram, norfluoxetine, and desvenlafaxine inhibit serotonin uptake in wild-type mSERT at potencies similar to those of their parent compounds, suggesting that metabolites may play a role in effects observed following AD administration in wild-type and M172 mice.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Sinaptossomos/efeitos dos fármacos , Animais , Citalopram/análogos & derivados , Citalopram/farmacologia , Fluoxetina/análogos & derivados , Fluoxetina/farmacologia , Camundongos , Sertralina/análogos & derivados , Sertralina/farmacologia , Sinaptossomos/metabolismo
9.
J Pharm Biomed Anal ; 131: 233-245, 2016 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-27606925

RESUMO

A high performance liquid chromatography (HPLC) tandem mass spectrometry (MS/MS) method was developed for the simultaneous, stereoselective quantification of the antidepressant citalopram and its active metabolite desmethylcitalopram in human plasma and breast milk. Sample preparation was performed by a two-step approach, including generic protein precipitation with acetonitrile followed by solid phase extraction. Enantiospecific separation of analytes was achieved on a Phenomenex® Lux Cellulose-2 column (4.6mm×150mm; 5µm), using reversed phase chromatography conditions characterized by a gradient elution of ammonium acetate buffer (pH 9.0; 20mM) and acetonitrile at a flow rate of 0.6ml/min. The compounds were detected by a tandem quadrupole mass spectrometer equipped with an electrospray ionization source and operating in multiple reaction monitoring mode. The method was fully validated in both biological fluids over a large concentration range of 0.1-100ng/ml for S-(+)- and R-(-)-citalopram, and 0.3-100ng/ml for S-(+)- and R-(-)-desmethylcitalopram. Trueness (90.0-113.3% and 97.1-103.6%), repeatability (0.9-15.9% and 0.9-8.4%) and intermediate precision (1.3-17.8% and 0.9-9.6%) in plasma and breast milk, respectively, meet international guidelines for method validation. Internal standard-normalized matrix effects ranged between 99 and 101% and 98-105%, respectively. The accuracy profiles (total error of trueness and precision) were mostly within the acceptance limits for biological samples defined as ±30%. The method was successfully applied to patient samples in a clinical trial setting.


Assuntos
Citalopram/análogos & derivados , Citalopram/sangue , Citalopram/metabolismo , Leite Humano/metabolismo , Estereoisomerismo , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Humanos , Reprodutibilidade dos Testes , Extração em Fase Sólida , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
10.
Ther Drug Monit ; 38(4): 483-6, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27002781

RESUMO

BACKGROUND: The aim of this study was to determine the impact of fluvoxamine, an inhibitor of Cytochrome P450 (CYP) 2C19 (CYP2C19), on the pharmacokinetics of escitalopram, a substrate of CYP2C19. METHODS: Thirteen depressed patients initially received a 20-mg/d dose of escitalopram alone. Subsequently, a 50-mg/d dose of fluvoxamine was administered because of the insufficient efficacy of escitalopram. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using high-performance liquid chromatography before and after fluvoxamine coadministration. The QT and corrected QT (QTc) intervals were measured before and after fluvoxamine coadministration. RESULTS: Fluvoxamine significantly increased the plasma concentrations of escitalopram (72.3 ± 36.9 ng/mL versus 135.2 ± 79.7 ng/mL, P < 0.01) but not those of desmethylescitalopram (21.5 ± 7.0 ng/mL versus 24.9 ± 12.0 ng/mL, no significance [ns]). The ratios of desmethylescitalopram to escitalopram were significantly decreased during fluvoxamine coadministration (0.37 ± 0.21 versus 0.21 ± 0.10, P < 0.01). The CYP2C19 genotype did not fully explain the degree of the change. Fluvoxamine coadministration did not change the QT or QTc intervals. CONCLUSIONS: The results of this study suggest that adjunctive treatment with fluvoxamine increases the concentration of escitalopram. The QTc interval did not change in this condition.


Assuntos
Citalopram/análogos & derivados , Citalopram/sangue , Inibidores do Citocromo P-450 CYP2C19/sangue , Depressão/tratamento farmacológico , Fluvoxamina/administração & dosagem , Inibidores de Captação de Serotonina/sangue , Grupo com Ancestrais do Continente Asiático , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/metabolismo , Inibidores do Citocromo P-450 CYP2C19/administração & dosagem , Inibidores do Citocromo P-450 CYP2C19/farmacocinética , Depressão/sangue , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacocinética
11.
Int Clin Psychopharmacol ; 31(3): 119-26, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26650488

RESUMO

The aim of this study was to measure blood and cerebrospinal fluid concentrations of citalopram and its weakly active N-demethylated metabolite desmethylcitalopram to account for the distribution between the two compartments. The findings are discussed in the context with own preceding studies on the distribution pattern of different antidepressants. Concentrations of citalopram were measured in blood serum and cerebrospinal fluid of 18 patients treated with daily doses of 10-40 mg. Daily doses were correlated with serum and cerebrospinal fluid concentrations, and serum concentrations were correlated with concentrations in cerebrospinal fluid. Serum concentrations of citalopram and desmethylcitalopram showed no significant correlation to the daily dose, r=0.164, P=0.515, and r=0.174, P=0.505, respectively, whereas citalopram concentrations in serum and cerebrospinal fluid were highly correlated (r=0.763, P<0.001). The cerebrospinal fluid/serum ratio for citalopram (total=bound+unbound concentration) varied between 0.14 and 0.86 (mean 0.35, SD 0.16). By correcting the mean cerebrospinal fluid/serum ratio for 80% plasma protein binding, cerebrospinal fluid concentrations of citalopram were on average 77% higher than the calculated unbound serum concentration with a ratio of 1.77 (SD 0.81, range 0.68-4.29). Findings indicate a very good ability of citalopram to cross the blood-brain and cerebrospinal fluid barrier. High concentrations of citalopram in the cerebrospinal fluid are indicative of active transport of citalopram into or missing active transport out of the cerebrospinal fluid. The results suggest a high ability of citalopram to enter the brain with sufficiently high drug concentrations at the target sites within the brain, contributing toward clinical efficacy.


Assuntos
Citalopram/análogos & derivados , Citalopram/sangue , Citalopram/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/farmacocinética , Citalopram/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
Br J Pharmacol ; 173(5): 925-36, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26699847

RESUMO

BACKGROUND AND PURPOSE: The 5-HT transporter (SERT) is a target for antidepressant drugs. SERT possesses two binding sites: the orthosteric (S1) binding site, which is the presumed target for current SERT inhibitors, and an allosteric (S2) site for which potential therapeutic effects are unknown. The antidepressant drug citalopram displays high-affinity S1 binding and low-affinity S2 binding. To elucidate a possible therapeutic role of allosteric inhibition of SERT, a drug that specifically targets the allosteric site is required. The purpose of this study was to find a compound having higher selectivity towards the S2 site. EXPERIMENTAL APPROACH: We performed a systematic structure-activity relationship study based on the scaffold of citalopram and the structurally closely related congener, talopram, which shows low-affinity S1 binding in SERT. The role of the four chemical substituents, which distinguish citalopram from talopram in conferring selectivity towards the S1 and S2 site, respectively, was assessed by determining the binding of 14 citalopram/talopram analogous to the S1 and S2 binding sites in SERT using membranes of COS7 cells transiently expressing SERT. KEY RESULTS: The structure-activity relationship study revealed that dimethyl citalopram possesses the highest affinity for the allosteric site relative to the S1 site in SERT and has approximately twofold selectivity for the allosteric site relative to the S1 site in SERT. CONCLUSIONS AND IMPLICATIONS: The compound could be a useful lead for future synthesis of drugs with high affinity and high selectivity towards the allosteric binding site.


Assuntos
Sítio Alostérico , Citalopram/análogos & derivados , Citalopram/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Células COS , Chlorocebus aethiops , Humanos , Mutação , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Relação Estrutura-Atividade
13.
J Pharmacokinet Pharmacodyn ; 43(1): 99-109, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26611790

RESUMO

The citalopram for Alzheimer's disease trial evaluated citalopram for the management for agitation in Alzheimer's disease patients. Sparse data was available from this elderly patient population. A nonlinear mixed effects population pharmacokinetic modeling approach was used to describe the pharmacokinetics of R- and S-citalopram and their primary metabolite (desmethylcitalopram). A structural model with 4 compartments (one compartment/compound) with linear oral absorption and elimination described the data adequately. Overall, the model showed that clearance of the R-enantiomer was slower than the clearance of the S-enantiomer. Without accounting for any patient-specific covariates, the population estimate of the metabolic clearance of citalopram was 8.6 (R-citalopram) and 14 L/h (S-citalopram). The population estimate of the clearance of desmethylcitalopram was 23.8 (R-Dcit) and 38.5 L/h (S-Dcit). Several patient-specific covariates were found to have a significant effect on the pharmacokinetics of R,S-citalopram and desmethylcitalopram. A significant difference in the metabolic clearance of R-citalopram between males and females (13 vs 9.05 L/h) was identified in this analysis. Both R- and S-citalopram metabolic clearance decreased with age. Additionally, consistent with literature reports S-citalopram metabolic clearance increased with increasing body weight and was significantly influenced by CYPC19 genotype, with a difference of 5.8 L/h between extensive/rapid and intermediate/poor metabolizers. R,S-desmethylcitalopram clearance increased with increasing body weight. This model may allow for the opportunity to delineate the effect of R- and S-citalopram on pharmacodynamics outcomes related to the management of agitation in Alzheimer's disease.


Assuntos
Doença de Alzheimer/metabolismo , Antidepressivos/farmacocinética , Citalopram/análogos & derivados , Agitação Psicomotora/metabolismo , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Algoritmos , Doença de Alzheimer/complicações , Antidepressivos/química , Citalopram/química , Citalopram/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Agitação Psicomotora/complicações , Caracteres Sexuais , Estereoisomerismo , Relação Estrutura-Atividade
14.
J Pharmacokinet Pharmacodyn ; 42(6): 721-33, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26395999

RESUMO

A population PK model was developed in order to simultaneously describe citalopram and its major metabolite, n-desmethyl citalopram, plasma concentrations in two different strain of rats after intravenous (IV) and oral (PO) administration of citalopram. Citalopram was administered to Sprague-Dawley (SD) rats at doses: 0.3, 1, 3, and 10 mg/kg IV and 10 mg/kg PO. The compound was dosed orally to Wistar rats at doses: 0.3, 1, 3, 10, 30 and 60 mg/kg. Plasma samples were collected for citalopram and metabolite. Pharmacokinetic analyses were conducted using NONMEM 7.2. Values below the quantification limit (BLQ < 0.1 ng/mL) were included in the analyses and treated as censored information. The disposition of citalopram was best described by a 3-compartment model and its desmethyl metabolite by a 2-compartment model. Several models for the absorption rate were explored (e.g. first, zero order and combined first and zero order absorption, Michaelis-Menten, lag time) in combination with dose and/or time dependent covariate effects. Dose dependent oral bioavailability properties were also identified in this analysis. Citalopram IV clearance and metabolite formation rate were adequately described as linear processes. Metabolite clearance was adequately described using a Michaelis-Menten clearance with different parameters depending on the strain. This analysis demonstrates a very complex absorption/metabolism process explaining the highly non-linear pharmacokinetics observed across all the doses. This is the first combined parent/metabolite population PK analysis in both SD and Wistar rats over a wide range of IV and PO dosages for citalopram, a compound that exhibits highly nonlinear oral pharmacokinetics in rats.


Assuntos
Antidepressivos de Segunda Geração/farmacocinética , Citalopram/farmacocinética , Modelos Biológicos , Modelos Estatísticos , Inibidores de Captação de Serotonina/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/sangue , Área Sob a Curva , Disponibilidade Biológica , Biotransformação , Citalopram/administração & dosagem , Citalopram/análogos & derivados , Citalopram/sangue , Simulação por Computador , Modelos Lineares , Masculino , Taxa de Depuração Metabólica , Modelos Animais , Método de Monte Carlo , Dinâmica não Linear , Ratos Sprague-Dawley , Ratos Wistar , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/sangue , Especificidade da Espécie
15.
J Clin Pharm Ther ; 40(6): 672-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26343256

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Genetic variations in drug-metabolizing enzyme genes change drug pharmacokinetics and response. CYP2C19 is a clinically important enzyme that metabolizes citalopram (CIT). The objective of this study was to determine CYP2C19 genetic polymorphisms and to evaluate the impact of these polymorphisms on the metabolism of citalopram in a sample of the Turkish population. We also assessed *17 polymorphism in healthy subjects in this population. METHODS: The CYP2C19 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism method (209 healthy individuals and 50 patients for CIT metabolism), and the plasma concentrations of CIT and demethylcitalopram (DCIT) were quantified by high-performance liquid chromatography. RESULTS AND DISCUSSION: The CYP2C19*1 and *17 allele frequencies for the patient group and the healthy group were 71·0%, 18·0% and 81·1%, 18·9%, respectively. There was no significant difference between the two groups (P > 0·05). The mean plasma concentrations and the mean dose-corrected (C/D) plasma levels of DCIT were significantly higher in patients with the CYP2C19*1/*1 genotype compared to patients with CYP2C19*1/*2 and CYP2C19*2/*2 genotypes (P < 0·05). Furthermore, the mean metabolic ratio (MR, CIT/DCIT) was also significantly higher in the CYP2C19*1/*2 + CYP2C19*2/*2 genotypes (P < 0·05). On the other hand, plasma CIT, DCIT concentrations and M/R value in the CYP2C19*1/*1 genotypes were no different to those of the CYP2C19*1/*17 genotypes (P > 0·05). WHAT IS NEW AND CONCLUSION: Our data suggest that CYP2C19*17 polymorphism does not have a significant effect on CIT metabolism. In contrast CYP2C19*2 polymorphism has a prominent role and is likely to contribute to interindividual variability in CIT metabolism in vivo at therapeutic doses.


Assuntos
Citalopram/metabolismo , Citalopram/uso terapêutico , Citocromo P-450 CYP2C19/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Polimorfismo Genético/genética , Adulto , Idoso , Citalopram/análogos & derivados , Transtorno Depressivo Maior/metabolismo , Relação Dose-Resposta a Droga , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
16.
J Forensic Sci ; 60(5): 1383-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26258895

RESUMO

The body of a 30-year-old woman was found in Como lake at a depth of about 120 meters in her own car after 3 years of immersion. The aim of this study was to evaluate psychoactive drugs as well as alcohol biomarkers in biological matrices. The following analyses were initially performed: GC-MS systematic toxicological analysis on biological fluids and tissues; GC-MS analysis of drugs of abuse on pubic hair; direct ethanol metabolite determination in pubic hair by LC-MS/MS. After 7 years, the samples, that had been stored at -20°C, were re-analyzed and submitted to an LC-MS/MS targeted screening method, using multiple reaction monitoring mode. These analyses detected citalopram (150-3000 ng/mL), desmethylcitalopram (50-2300 ng/mL), clotiapine (20-65 ng/mL), and ethyl glucuronide (97 pg/mg). The methods showed an acceptable reproducibility, and the concentrations of citalopram and desmethylcitalopram calculated through the two analytical techniques did not significantly differ in biological fluids.


Assuntos
Imersão , Mudanças Depois da Morte , Adulto , Antipsicóticos/análise , Bile/química , Química Encefálica , Cromatografia Líquida , Citalopram/análogos & derivados , Citalopram/análise , Dibenzotiazepinas/análise , Feminino , Toxicologia Forense , Cromatografia Gasosa-Espectrometria de Massas , Conteúdo Gastrointestinal/química , Glucuronatos/análise , Cabelo/química , Humanos , Rim/química , Lagos , Pulmão/química , Músculo Esquelético/química , Fatores de Tempo
17.
J Med Chem ; 56(23): 9709-24, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24237160

RESUMO

The serotonin transporter (SERT) is the primary target for antidepressant drugs. The existence of a high affinity primary orthosteric binding site (S1) and a low affinity secondary site (S2) has been described, and their relation to antidepressant pharmacology has been debated. Herein, structural modifications to the N, 4, 5, and 4' positions of (±)citalopram (1) are reported. All of the analogues were SERT-selective and demonstrated that steric bulk was tolerated at the SERT S1 site, including two dimeric ligands (15 and 51). In addition, eight analogues were identified with similar potencies to S-1 for decreasing the dissociation of [(3)H]S-1 from the S1 site via allosteric modulation at S2. Both dimeric compounds had similar affinities for the SERT S1 site (Ki = 19.7 and 30.2 nM, respectively), whereas only the N-substituted analogue, 51, was as effective as S-1 in allosterically modulating the binding of [(3)H]S-1 via S2.


Assuntos
Citalopram/análogos & derivados , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Sítio Alostérico , Animais , Sítios de Ligação , Encéfalo/metabolismo , Células COS , Chlorocebus aethiops , Citalopram/síntese química , Humanos
18.
Pediatr Emerg Care ; 29(9): 998-1001, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24201980

RESUMO

INTRODUCTION: Escitalopram is rarely associated with prolongation of the QTc interval; however, there are no reported cases of QRS complex widening associated with escitalopram overdose. We report a case of a patient who presented with both QRS complex widening and QTc interval prolongation after an escitalopram overdose. CASE: A 16-year-old girl presented to the emergency department after ingestion of escitalopram, tramadol/acetaminophen, and hydrocodone/acetaminophen. Laboratory results were significant for 4-hour acetaminophen 21.1 µg/mL. Serum electrolytes including potassium, magnesium, and calcium were all normal. Initial electrocardiogram (ECG) revealed a widened QRS with an incomplete right bundle branch pattern. After administration of 100-mEq sodium bicarbonate, a repeat ECG revealed narrowing of the QRS complex and a prolonged QTc interval. Magnesium sulfate 2 g intravenous and sodium bicarbonate drip were initiated. A repeat ECG, 1 hour after the second, revealed normalization of the QRS complex and QTc interval. DISCUSSION: Prolongation of the QTc interval is an expected effect of escitalopram. Both escitalopram and citalopram are metabolized to the cardiotoxic metabolite S-didesmethylcitalopram and didesmethylcitalopram, respectively, which have been implicated in numerous cardiac abnormalities including widening of the QRS complex. Although never previously described with escitalopram, this mechanism provides a reasonable explanation for the QRS complex widening and incomplete right bundle branch block that occurred in our patient. CONCLUSIONS: Both QRS complex widening and QTc interval prolongation should be monitored in cases of escitalopram and citalopram overdoses.


Assuntos
Bloqueio de Ramo/induzido quimicamente , Citalopram/envenenamento , Eletrocardiografia/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Canais de Sódio/efeitos dos fármacos , Acetaminofen/envenenamento , Adolescente , Antídotos/administração & dosagem , Antídotos/uso terapêutico , Bradicardia/induzido quimicamente , Bradicardia/tratamento farmacológico , Bloqueio de Ramo/sangue , Bloqueio de Ramo/tratamento farmacológico , Bloqueio de Ramo/fisiopatologia , Citalopram/análogos & derivados , Citalopram/sangue , Citalopram/farmacocinética , Citalopram/farmacologia , Citalopram/toxicidade , Canais de Potássio de Retificação Tardia/efeitos dos fármacos , Quimioterapia Combinada , Emergências , Feminino , Humanos , Hidrocodona/envenenamento , Síndrome do QT Longo/induzido quimicamente , Sulfato de Magnésio/administração & dosagem , Sulfato de Magnésio/uso terapêutico , Bicarbonato de Sódio/administração & dosagem , Bicarbonato de Sódio/uso terapêutico , Tentativa de Suicídio , Síncope Vasovagal/induzido quimicamente , Tramadol/envenenamento
19.
Talanta ; 116: 448-53, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24148428

RESUMO

This paper reports the application of a chiral imprinted polymer (CIP)-coated stir bar for the selective extraction of (+)-(S)-citalopram (SCIT) and its main metabolites, (+)-(S)-desmethylcitalopram (SDCIT) and (+)-(S)-didesmethylcitalopram (SDDCIT), from urine samples. The developed device has been demonstrated to be capable of selectively extracting the three target analytes from urine samples without saturating the imprinted sites. A CIP-coated stir bar sorptive extraction procedure (CIP-SBSE) is proposed for the isolation of SCIT, SDCIT and SDDCIT followed by their subsequent analysis using liquid chromatography ion trap mass spectrometry (LC-ITMS). Deuterated SCIT-d6 was used as an internal standard. The method was validated using a standard procedure, which revealed that a quantification of 5 ng mL(-1) was obtained in urine samples and that the accuracy and precision were within the established values while no matrix effect was observed.


Assuntos
Antidepressivos de Segunda Geração/urina , Citalopram/análogos & derivados , Citalopram/urina , Polímeros/química , Extração em Fase Sólida/normas , Adsorção , Cromatografia Líquida , Humanos , Impressão Molecular/métodos , Padrões de Referência , Sensibilidade e Especificidade , Extração em Fase Sólida/métodos , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo , Espectrometria de Massas em Tandem
20.
Fetal Pediatr Pathol ; 32(5): 362-6, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23438790

RESUMO

Late gestational exposure to citalopram, may be associated with a neonatal toxicity syndrome with immediate onset at birth or soon after birth and sometimes may be mistaken for neonatal withdrawal syndrome. A 3860 g infant was delivered at 40 weeks gestation. The mother had been taking citalopram 20 mg/day until the day of delivery. Fifteen minutes after birth, the baby became hypertonic. Neonatal serotonin toxicity due to citalopram seems the most likely mechanism, though an important differential diagnosis is a citalopram withdrawal syndrome. We suggest the hypothesis that neonatal withdrawal syndrome may follow citalopram serotonin toxicity.


Assuntos
Citalopram/efeitos adversos , Síndrome de Abstinência Neonatal/diagnóstico , Complicações na Gravidez/tratamento farmacológico , Inibidores de Captação de Serotonina/efeitos adversos , Citalopram/análogos & derivados , Citalopram/sangue , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/tratamento farmacológico , Diagnóstico Diferencial , Feminino , Meia-Vida , Humanos , Recém-Nascido , Masculino , Síndrome de Abstinência Neonatal/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Inibidores de Captação de Serotonina/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA