RESUMO
Citalopram (CIT) is one of the most consumed antidepressants and frequently detected in aquatic environments worldwide. Conventional wastewater treatment cannot remove this neuronal active pharmaceutical efficiently. Past studies showed that moving bed biofilm reactors (MBBRs) can degrade CIT but the exact transformation pathways and toxicity reduction remained unclear. In this study, the effects of substrate stimulation on CIT transformation in an MBBR were systematically investigated. The results showed that a co-metabolic stimulation by acetate increased the transformation rate by 54 % and 24 % at high (300 µg/L) and environmental concentration (1.8 µg/L) of CIT, respectively. Conversely, the complex substrates in raw wastewater reduced the reaction rates by 44 %, suggesting a competitive inhibition on the enzymatic sites. The substrate stimulation changed the enantiomeric fraction (EF) of CIT from racemic (EF=0.5) to 0.60 at the high CIT concentrations, while those at lower concentrations resulted in an EF of 0.33, indicating that probably different enantioselective enzymes degraded CIT at high concentrations than at low concentrations, i.e., the presence of 300 µg/L CIT was possibly sufficient to induce the synthesis of different enantioselective enzymes, than those originally present. Through non-target and target analysis, in total 19 transformation products (TPs) including 7 TPs that were hitherto not mentioned in the literature were identified. Among these were quaternary amines, alkenes and conjugate TPs. The major transformation pathways were a) nitrile hydrolysis (up to 43 %), b) amide hydrolysis, and c) N-oxidation. Dosing acetate up-regulated significantly the amide hydrolysis, N-oxidation and conjugation pathways but inhibited the N-demethylation and α-carbon hydroxylation pathways. The in-silico toxicity assessment of CIT and its TPs suggested the overall eco-toxic potential of TPs was reduced by MBBR. Furthermore, the degradation under carbon-limited (famine) conditions favored the formation of the more toxic carboxamide, N-desmethyl and alkene TPs, while carbon-rich conditions, promoted the production of the less toxic carboxylic acid, N-oxide and ester TPs. Therefore, this study demonstrated that a) the co-metabolic stimulation of CIT metabolization by dosing a simple carbon source or b) inhibition of CIT metabolization by complex substrates; c) substrate stimulation made a difference on CIT transformation rates, enantiomeric profiles, pathways and toxic potentials. Overall, a simple-carbon co-metabolic stimulated MBBR was an efficient up-regulation strategy to minimize hazardous CIT and CIT-TPs as much as possible.
Assuntos
Citalopram , Poluentes Químicos da Água , Citalopram/análise , Biofilmes , Estereoisomerismo , Poluentes Químicos da Água/análise , Reatores Biológicos , Águas Residuárias , Antidepressivos , Acetatos , Amidas , CarbonoRESUMO
Food aspiration is one of the major health risks for elderly people in nursing homes which could lead to death. Moreover, misconducts in pharmacotherapy may represent a potential risk of adverse drug reactions. It is reported here the toxicological evaluation of a combined death by food aspiration and acute escitalopram intoxication of a psychiatric subject, occurred in a nursing home. An 89-year-old man, suffering from dysphagia and Alzheimer's, was resident in a nursing home. He was fed with a liquid diet administered directly in mouth using a syringe. The man was also being treated with escitalopram 10 mg tablet. One evening, after receiving the meal in the usual way, the man complained of sudden illness. Carried to the emergency room, the man died about 3 h later with a diagnosis of cardiogenic shock subsequentially to ab ingestis. The histological findings revealed the presence of exogenous material, probably food, up to the finest bronchial branches. The toxicological examination revealed the presence of escitalopram and its main metabolite, desmethylcitalopram: in the blood 1972 ng/ml and 285 ng/ml, in the brain 4657 ng/g and 1025 ng/g, in the gastric content 2317 ng/g and 423 ng/g, in the lung 21,771 ng/g and 468 ng/g, respectively. The bad practice of the nurses to dissolve the escitalopram tablet in the liquefied food and to administer the therapy with a syringe directly into the mouth emerged thanks this investigation. Following food aspiration, escitalopram was absorbed by inhalation route, reaching high concentrations in blood and tissues. The death occurred due to a combined mechanism between food aspiration and the escitalopram toxic action.
Assuntos
Citalopram , Casas de Saúde , Aspiração Respiratória , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Citalopram/análise , Citalopram/intoxicação , Citalopram/análogos & derivados , Masculino , Idoso de 80 Anos ou mais , Inibidores Seletivos de Recaptação de Serotonina/intoxicação , Inibidores Seletivos de Recaptação de Serotonina/análise , Encéfalo/patologia , Conteúdo Gastrointestinal/química , Pulmão/patologia , Transtornos de Deglutição/induzido quimicamente , Doença de AlzheimerRESUMO
The occurrence of pharmaceuticals in the aquatic environment is a global water quality challenge for several reasons, such as deleterious effects on ecological and human health, antibiotic resistance development, and endocrine-disrupting effects on aquatic organisms. To optimize their removal from the water cycle, understanding the processes during biological wastewater treatment is crucial. Time-of-flight secondary ion mass spectrometry imaging was successfully applied to investigate and analyze the distribution of pharmaceuticals as well as endogenous molecules in the complex biological matrix of biofilms for wastewater treatment. Several compounds and their localization were identified in the biofilm section, including citalopram, ketoconazole, ketoconazole transformation products, and sertraline. The images revealed the pharmaceuticals gathered in distinct sites of the biofilm matrix. While citalopram penetrated the biofilm deeply, sertraline remained confined in its outer layer. Both pharmaceuticals seemed to mainly colocalize with phosphocholine lipids. Ketoconazole concentrated in small areas with high signal intensity. The approach outlined here presents a powerful strategy for visualizing the chemical composition of biofilms for wastewater treatment and demonstrates its promising utility for elucidating the mechanisms behind pharmaceutical and antimicrobial removal in biological wastewater treatment.
Assuntos
Eliminação de Resíduos Líquidos , Poluentes Químicos da Água , Humanos , Eliminação de Resíduos Líquidos/métodos , Citalopram/análise , Citalopram/farmacologia , Cetoconazol/análise , Cetoconazol/farmacologia , Sertralina/análise , Sertralina/farmacologia , Espectrometria de Massa de Íon Secundário , Poluentes Químicos da Água/análise , Águas Residuárias , Biofilmes , Preparações FarmacêuticasRESUMO
Hair analysis can provide information regarding previous drug intake and use patterns, as the drugs consumed are incorporated into the hair. Therefore, reference values for drugs in hair are valuable in forensic investigations, especially when evaluating drug intake and assessing drug tolerance. The aim of the study was to determine concentrations of citalopram, escitalopram, and their primary metabolites in hair segments from deceased individuals with mental illness. Concentrations in up to six months prior to death were evaluated and compared with the estimated daily doses. Hair samples collected from 47 deceased individuals, were segmented in one to six 1 cm segments, and extracted overnight in medium. The concentrations in hair were quantified via ultra-high-performance liquid chromatography-tandem mass spectrometry. Following this quantification, the extracts were reanalyzed qualitatively using a chiral method to distinguish between citalopram and escitalopram intake. We found hair concentrations (10-90 percentile (perc.)) of citalopram from 0.12 to 67 ng/mg with a median of 8.2 ng/mg (N = 40 individuals, n = 182 segments) and of escitalopram from 0.027 to 7.0 ng/mg with a median of 3.9 ng/mg (N = 4, n = 23). The metabolite-to-drug ratios in hair (10-90 perc.) of citalopram were 0.091-0.57 with a median of 0.30 (N = 39) and of escitalopram were 0.053-0.63 with a median of 0.41 (N = 3). No correlations were found between concentrations in the hair and the estimated daily dose. However, our results indicate higher concentrations in dark hair compared to light hair, given the estimated doses, and thus an influence of hair color on the results. A significant positive correlation was found between the concentration of citalopram in the proximal segment and the blood concentrations. The median R/S-ratio of citalopram in hair was 1.5 and was similar to previously reported ratios in blood. In the present study, we report concentrations of citalopram and escitalopram in postmortem hair and their relation to an estimated daily dose and thus contribute valuable information in forensic investigations.
Assuntos
Citalopram , Escitalopram , Cromatografia Líquida de Alta Pressão/métodos , Citalopram/análise , Citalopram/metabolismo , Cabelo/química , Humanos , Inibidores Seletivos de Recaptação de Serotonina/análise , Espectrometria de Massas em Tandem/métodosRESUMO
A highly sensitive liquid chromatographic method with UV detection has been developed for simultaneous determination of citalopram, levocetirizine and loratadine in bulk drug, pharmaceutical formulation and human serum at 230nm employing 80:20 v/v methanol-water as mobile phase with pH3.5, adjusting flow rate of 1.0mL.min-1. Separation was achieved on Shimadzu Shim-pack CLC-ODS (M) 25M column within the linear range of 0.4-12.5, 0.8-25 and 0.8-25µg.mL-1 with R2 >0.998 and detection limit 7.75, 3.35 and 10.26ng.mL-1respectively. ICH guidelines were followed for validation showing 0.22-1.76, 0.06-1.83 and 0.22-2.11% RSD. The recovery of analytes in tablets and serum was found to be in acceptable range. The method was fruitfully employed for the determination of studied analyte in pharmaceutical formulation and human serum.
Assuntos
Cetirizina/análise , Cromatografia Líquida de Alta Pressão/métodos , Citalopram/análise , Loratadina/análise , Cetirizina/sangue , Citalopram/sangue , Humanos , Loratadina/sangue , Reprodutibilidade dos TestesRESUMO
A new analyte separation and preconcentration method for the trace determination of antidepressant drugs, Fluoxetine (FLU) and Citalopram (CIT) in urine and wastewaters, was developed based on HPLC-DAD analysis after magnetic solid phase extraction (MSPE). In the proposed method, FLU and CIT were retained on the newly synthetized magnetic sorbent (Fe3O4@PPy-GO) in the presence of buffer (pH 10.0) and then were desorbed into a lower volume of acetonitrile prior to the chromatographic determinations. Before HPLC analysis, all samples were filtered through a 0.45 µm PTFE filter. Experimental parameters such as interaction time, desorption solvent and volume, and pH were studied and optimized in order to establish the detection limit, linearity, enrichment factor and other analytical figures of merit under optimum operation conditions. In the developed method, FLU and CIT were analyzed by diode array detector at the corresponding maximum wavelengths of 227 and 238 nm, respectively, by using an isocratic elution of 60% pH 3.0 buffer, 30% acetonitrile, and 10% methanol. By using the optimum conditions, limit of detections for FLU and CIT were 1.58 and 1.43 ng mL-1, respectively, while the limit of quantifications was 4.82 and 4.71 ng mL-1, respectively. Relative standard deviations (RSD%) for triplicate analyses of model solutions containing 100 ng mL-1 target molecules were found to be less than 5.0 %. Finally, the method was successfully applied to urine (both simulated and real healthy human) and wastewater samples, and quantitative results were obtained in recovery experiments.
Assuntos
Antidepressivos/análise , Cromatografia Líquida/métodos , Citalopram/análise , Fluoxetina/análise , Espectrofotometria Ultravioleta/métodos , Águas Residuárias/química , Poluentes Químicos da Água/análise , Antidepressivos/urina , Citalopram/urina , Fluoxetina/urina , Humanos , Limite de Detecção , Extração em Fase Sólida/métodos , Solventes/química , Poluentes Químicos da Água/urinaRESUMO
Application of capillary electrophoresis (CE) has become a rapidly growing analytical technique for the estimation of drugs in pharmaceutical dosage forms and biological fluids. In this study, an effective and sensitive method was developed for the determination of escitalopram oxalate (ESC-OX) by CE with diode-array detection at 200 nm. The separation was achieved by a fused silica capillary with 40 cm effective length (48.5 cm total, 75 µm i.d.). The background electrolyte was composed of 15 mM phosphate buffer (pH 2.5). The applied potential was 22.5 kV, and the samples were injected at 50 mbar pressure for 10 s. Metoprolol was used as an internal standard (IS). The migration time under these optimum conditions was 6.51 ± 0.07 and 6.73 ± 0.08 min for ESC-OX and IS, respectively, with total run time 7 min. The method was validated for linearity, precision, accuracy, specificity and sensitivity. The limit of detection was calculated as 3.85 and 5.07 ng mL-1 for standard and urine samples, respectively. The developed method was employed successfully for the determination of ESC-OX in different pharmaceutical dosage forms and spiked human urine after simple liquid-liquid extraction with good recovery.
Assuntos
Citalopram/urina , Eletroforese Capilar/métodos , Citalopram/análise , Citalopram/química , Formas de Dosagem , Humanos , Limite de Detecção , Modelos Lineares , Metoprolol , Reprodutibilidade dos TestesRESUMO
Recent state-of-the-art methods developed for the analysis of polar xenobiotics from different types of biological matrices usually employ liquid chromatography with mass spectrometry. However, there are limitations when a small amount of sample mass is available. For example, individual benthic invertebrates or fish tissue samples often weigh less than 100 mg (e.g., brain, liver) but are necessary to understand environmental fate and bioaccumulation dynamics. We developed ultra-fast methods based on a direct sample introduction technique. This included coupling laser diode thermal desorption with atmospheric pressure chemical ionization mass spectrometry (LDTD-APCI-MS). We then quantitated a common selective serotonin reuptake inhibitor (citalopram) in brain tissues of individual juvenile fish after in vivo exposure to environmentally relevant concentration. Two mass spectrometric methods based on low (LDTD-APCI-triple quadrupole (QqQ)-MS/MS) and high (LDTD-APCI-high-resolution product scan (HRPS)) resolutions were developed and evaluated. Individual instrument conditions were optimized to achieve an accurate and robust analytical method with minimum sample preparation requirements. We achieved very good recovery (97-108%) across the range of 1-100 ng g-1 for LDTD-APCI-HRPS. LDTD-APCI-QqQ-MS/MS showed poorer performance due to interferences from the matrix at the lowest concentration level. LDTD-APCI ionization was successfully validated for analysis of non-filtered sample extracts. Evaluation of final methods was performed for a set of real fish brain samples, including comparison of LDTD-APCI-HRPS with a previously validated LC-heated electrospray ionization-HRPS method. This new LDTD-APCI-HRPS method avoids the chromatographic step and provides important benefits such as analysis of limited sample masses, lower total sample volume (typically µL), and reduction in analysis time per sample run to a few seconds. Graphical abstract.
Assuntos
Antidepressivos de Segunda Geração/análise , Química Encefálica , Citalopram/análise , Oncorhynchus mykiss , Inibidores Seletivos de Recaptação de Serotonina/análise , Poluentes Químicos da Água/análise , Animais , Lasers Semicondutores , Oncorhynchus mykiss/metabolismo , Alimentos Marinhos/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
Citalopram (CIT) is a highly selective serotonin reuptake inhibitor (SSRI) frequently used in the treatment of major depressive disorders. It has a chiral centre in its structure and is used in therapy both as a racemic mixture (R,S-CIT) and a pure enantiomer (S-CIT). The differences between the pharmacokinetic and pharmacological profiles of the two enantiomers are well established. Consequently, the development of new efficient chiral analysis methods for their enantiomeric separation is a topic of great actuality. CIT metabolism is stereoselective as it is metabolized in chiral active metabolites, which retain considerable SSRI activity and contribute to the pharmacological effect. Chiral analytical methods are employed for the determination of enantiomeric ratio in pharmaceutical preparations and for monitoring the enantiomer levels in biological samples for therapeutic and toxicologic purposes. The current study reviews the published literature for the chiral analysis of CIT and its metabolites based on chromatographic and electrophoretic methods coupled with UV, fluorescence and mass spectrometry detectors.
Assuntos
Citalopram/análise , Citalopram/metabolismo , Antidepressivos de Segunda Geração/análise , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Eletroforese Capilar/métodos , Humanos , Inibidores Seletivos de Recaptação de Serotonina/análise , Estereoisomerismo , Espectrometria de Massas em Tandem/métodosRESUMO
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/análiseRESUMO
The present study involved segmental testing of hair in two clinical cases with known dosage histories. Hair analysis confirmed the first patient's exposure to the prescribed sertraline and citalopram for several months. Citalopram was generally distributed along the hair shaft in accordance with the drug ingestion period. By contrast, "false" positive results were observed for sertraline in distal hair segments, corresponding to a period of no sertraline exposure, which may indicate incorporation from sweat or sebum, which transport the drugs along the hair surface. The second patient received various drugs during her treatment for brain cancer. Metoclopramide, morphine, oxazepam, paracetamol, sumatriptan, tramadol, and zopiclone, which had been part of the therapy, were all detected in the proximal hair segment. The results of these two cases indicated that results-especially concerning the time of drug intake-must be interpreted with caution and allow for the possibility of incorporation from sweat or sebum.
Assuntos
Analgésicos/análise , Cabelo/química , Hipnóticos e Sedativos/análise , Inibidores Seletivos de Recaptação de Serotonina/análise , Vasoconstritores/análise , Acetaminofen/análise , Adulto , Antieméticos/análise , Compostos Azabicíclicos/análise , Citalopram/análise , Feminino , Toxicologia Forense , Cabelo/crescimento & desenvolvimento , Humanos , Metoclopramida/análise , Morfina/análise , Oxazepam/análise , Piperazinas/análise , Sertralina/análise , Sumatriptana/análise , Tramadol/análiseRESUMO
In this paper, two spiral structure CILs, 1-butyl-3-methylimidazolium(T-4)-bis[(2S)-2-(hydroxy-κO)-3-methyl-butanoato-κO]borate(BMIm+BLHvB-) and 1-butyl-3-methylimidazolium (T-4)-bis[(αS)-α-(hydroxy-κO)-4-methyl-benzeneacetato-κO]borate (BMIm+BSMB-)were applied to evaluate their potential synergistic effect with dextrin for CE enantiomeric separation. The established dextrin-based synergistic system with CILs as additives showed good separation performance towards four tested drugs, including duloxetine, ketoconazole, sulconazole and citalopram. It was also observed that significantly improved separation and selectivity for tested analytes were achieved in CILs/dextrin synergistic system compared to single dextrin system. Primary parameters, such as the concentration of CIL, dextrin concentration, buffer pH and applied voltage, were systematically investigated to optimize the enantiomeric separation with BMIm+BLHvB-/dextrin as model system. Finally, the method of Statistical Product and Service Solutions (SPSS) was exploited to further elucidate the influence of experimental parameters on the synergistic effect.
Assuntos
Dextrinas/química , Líquidos Iônicos/química , Citalopram/análise , Citalopram/química , Cloridrato de Duloxetina/análise , Cloridrato de Duloxetina/química , Eletroforese Capilar/métodos , Imidazóis/análise , Imidazóis/química , Cetoconazol/análise , Cetoconazol/química , EstereoisomerismoRESUMO
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 , ComprimidosRESUMO
Recreational use of the potent synthetic opioid 3,4- dichloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide (U-47700) is rising, accompanied by increasingly frequent cases of serious intoxication. This article reports a case of near-fatal U-47700 intoxication. A man was found unconscious (with drug powder residues). After 40 h in hospital (including 12 h of supported ventilation), he recovered and was discharged. Liquid chromatography/high-resolution mass spectrometry (LC/HRMS) or gas chromatography/mass spectrometry (GC/MS) were used to detect and quantify substances in powders, serum and urine. Powders contained U-47700 and two synthetic cannabinoids. Serum and urine were positive for U-47700 (351.0 ng/mL), citalopram (Assuntos
Benzamidas/efeitos adversos
, Overdose de Drogas
, Drogas Ilícitas/efeitos adversos
, Adulto
, Benzamidas/análise
, Benzodiazepinas/análise
, Cromatografia Líquida
, Citalopram/análise
, República Tcheca
, Toxicologia Forense
, Cromatografia Gasosa-Espectrometria de Massas
, Humanos
, Drogas Ilícitas/análise
, Masculino
, Espectrometria de Massas
, Midazolam/análise
, Detecção do Abuso de Substâncias
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 Seletivos de Recaptação de Serotonina/análise , Inibidores Seletivos de Recaptação 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 JovemRESUMO
Serotonin-specific reuptake inhibitors (SSRIs) are generally considered safe drugs but fatal adverse effects do sometimes occur, often as a consequence of interactions with other serotonin active drugs. Polypharmacy is usually a problem that the elderly encounter, but it can also have dire consequences for young people, especially when an underlying heart condition is present. Thus, failure to diagnose heart disease and the use of contraindicated medications can be a lethal combination, irrespective of age. Here we present a case of a young adult suffering from bipolar disorder who used a combination of two SSRIs (citalopram and fluoxetine) and a monoamine oxidase inhibitor (MAO; moclobemide) with tragic consequences. The deceased also suffered from undiagnosed hypertrophic cardiomyopathy and was carrier of a genotype that may have predisposed him to increased sensitivity to SSRIs. The apparent difficulty in establishing the manner of death in this case is also discussed.
Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Citalopram/intoxicação , Fluoxetina/intoxicação , Variantes Farmacogenômicos , Inibidores Seletivos de Recaptação de Serotonina/intoxicação , Adulto , Transtorno Bipolar/tratamento farmacológico , Citalopram/análise , Fluoxetina/análise , Genótipo , Heterozigoto , Humanos , Masculino , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores Seletivos de Recaptação de Serotonina/análiseRESUMO
MS Binding Assays represent a label-free alternative to radioligand binding assays. In this study, we present an LC-ESI-MS/MS method for the quantification of (R,R)-4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-ol [(R,R)-D-84, (R,R)-1], (S,S)-reboxetine [(S,S)-2], and (S)-citalopram [(S)-3] employed as highly selective nonlabeled reporter ligands in MS Binding Assays addressing the dopamine [DAT, (R,R)-D-84], norepinephrine [NET, (S,S)-reboxetine] and serotonin transporter [SERT, (S)-citalopram], respectively. The developed LC-ESI-MS/MS method uses a pentafluorphenyl stationary phase in combination with a mobile phase composed of acetonitrile and ammonium formate buffer for chromatography and a triple quadrupole mass spectrometer in the multiple reaction monitoring mode for mass spectrometric detection. Quantification is based on deuterated derivatives of all three analytes serving as internal standards. The established LC-ESI-MS/MS method enables fast, robust, selective and highly sensitive quantification of all three reporter ligands in a single chromatographic run. The method was validated according to the Center for Drug Evaluation and Research (CDER) guideline for bioanalytical method validation regarding selectivity, accuracy, precision, calibration curve and sensitivity. Finally, filtration-based MS Binding Assays were performed for all three monoamine transporters based on this LC-ESI-MS/MS quantification method as read out. The affinities determined in saturation experiments for (R,R)-D-84 toward hDAT, for (S,S)-reboxetine toward hNET, and for (S)-citalopram toward hSERT, respectively, were in good accordance with results from literature, clearly demonstrating that the established MS Binding Assays have the potential to be an efficient alternative to radioligand binding assays widely used for this purpose so far.
Assuntos
Compostos Benzidrílicos/análise , Cromatografia Líquida/métodos , Citalopram/análise , Morfolinas/análise , Piperidinas/análise , Simportadores/metabolismo , Animais , Compostos Benzidrílicos/metabolismo , Citalopram/metabolismo , Humanos , Morfolinas/metabolismo , Piperidinas/metabolismo , Ligação Proteica , Reboxetina , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
A bare composite graphite-polyurethane electrode (EGPU) and two other modified with graphene (EGPU-GR) and functionalized multi-walled carbon nanotubes (EGPU-CNTs) were prepared and compared regarding their voltammetric response to escitalopran (EST). The modifiers were characterized by Raman spectroscopy and the resulting electrode materials by contact angle measurements with a hydrophilicity character in the ascending order for the composites: GPU > GPU-GR > GPU-CNTs and scanning electron microscopy (SEM). The electroactive areas of the EGPU, EGPU-GR, and EGPU-CNTs were 0.065, 0.080, and 0.092cm2, respectively, calculated from the chronocoulometry using K3[Fe(CN)6] as a probe and the Cottrell equation. The cyclic voltammograms obtained for EST indicated irreversible electrochemical behavior, with an anodic peak at ca. +0.80V (νs. SCE). These measurements were carried out with the three electrodes, and comparison of the analytical responses led to the EGPU-GR electrode being selected for use in the subsequent experiments. Under optimal conditions, square wave and differential pulse voltammetry at EGPU-GR presented linear dynamic ranges between 1.5 × 10-6 and 1.2 × 10-5mol L-1, with a detection limit of 2.5 × 10-7molL-1 (SWV) and 1.5 × 10-6 and 1.2 × 10-5molL-1, with a detection limit of 3.2 × 10-7molL-1 (DPV) for EST. The proposed method was applied for the quantification of EST in synthetic urine and cerebrospinal fluid samples, offering advantages including simplicity of fabrication, no requirement for analyte preconcentration and surface renewal, fast response, and selectivity.
Assuntos
Citalopram/análise , Eletroquímica/instrumentação , Grafite/química , Nanotubos de Carbono/química , Poliuretanos/química , Citalopram/líquido cefalorraquidiano , Citalopram/química , Citalopram/urina , Eletrodos , Limite de DetecçãoRESUMO
The sorption of 3 pharmaceuticals, which may exist in 4 different forms depending on the solution pH (irbesartan in cationic, neutral and anionic, fexofenadine in cationic, zwitter-ionic and anionic, and citalopram cationic and neutral), in seven different soils was studied. The measured sorption isotherms were described by Freundlich equations, and the sorption coefficients, KF (for the fixed n exponent for each compound), were related to the soil properties to derive relationships for estimating the sorption coefficients from the soil properties (i.e., pedotransfer rules). The largest sorption was obtained for citalopram (average KF value for nâ¯=â¯1 was 1838â¯cm3â¯g-1) followed by fexofenadine (KFâ¯=â¯35.1 cm3/n µg1-1/n g-1, nâ¯=â¯1.19) and irbesartan (KFâ¯=â¯3.96 cm3/n µg1-1/n g-1, nâ¯=â¯1.10). The behavior of citalopram (CIT) in soils was different than the behaviors of irbesartan (IRB) and fexofenadine (FEX). Different trends were documented according to the correlation coefficients between the KF values for different compounds (RIRB,FEXâ¯=â¯0.895, p-value<0.01; RIRB,CITâ¯=â¯-0.835, p-value<0.05; RFEX,CITâ¯=â¯-0.759, p-value<0.05) and by the reverse relationships between the KF values and soil properties in the pedotransfer functions. While the KF value for citalopram was positively related to base cation saturation (BCS) or sorption complex saturation (SCS) and negatively correlated to the organic carbon content (Cox), the KF values of irbesartan and fexofenadine were negatively related to BCS, SCS or the clay content and positively related to Cox. The best estimates were obtained by combining BCS and Cox for citalopram (R2â¯=â¯93.4), SCS and Cox for irbesartan (R2â¯=â¯96.3), and clay content and Cox for fexofenadine (R2â¯=â¯82.9).
Assuntos
Compostos de Bifenilo/metabolismo , Citalopram/metabolismo , Poluentes do Solo/análise , Poluentes do Solo/metabolismo , Terfenadina/análogos & derivados , Tetrazóis/metabolismo , Adsorção/fisiologia , Agricultura , Silicatos de Alumínio/química , Compostos de Bifenilo/análise , Citalopram/análise , Argila , Irbesartana , Solo/química , Terfenadina/análise , Terfenadina/metabolismo , Tetrazóis/análise , Águas Residuárias/análise , Águas Residuárias/químicaRESUMO
Two new simple and selective assay methods have been presented for the analysis of Escitalopram Oxalate (ESC) and L-Methylfolate (L-MF) in pharmaceutical formulations. The ultraviolet (UV)-Spectrophotometric simultaneous equation method was based on the measurement of absorbance at 238 nm (Êmax of ESC) and 284 nm (Êmax of L-MF) in methanol. The assay was linear over the concentration ranges 0.5-12.0 µg/mL for ESC and 0.5-9.0 µg/mL for L-MF. The quantitation limits for ESC and L-MF were found to be 0.912 and 0.667 µg/mL; while the detection limits were 0.301 and 0.220 µg/mL for ESC and L-MF, respectively. The second method involved isocratic reversed-phase liquid chromatography using a mobile phase composed of methanol-0.02 M phosphate buffer (pH 5.5) (75:25, v/v), Hypersil BDS-C18 Column (5 µm, 250 mm × 4.6 mm i.d.) with detection at 270 nm. The linearity ranges were found to be 3.0-30.0 and 0.75-22.5 µg/mL for ESC and L-MF, respectively. The limits of detection were found to be 1.065 and 1.160 µg/mL for ESC and L-MF, respectively. The limits of quantitation were found to be 3.226 and 3.515 µg/mL for ESC and L-MF, respectively. The proposed methods were successfully applied to the determination of commercially available tablets with a high percentage of recovery, good accuracy and precision.