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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.
Biomed Chromatogr ; 34(1): e4730, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31652353

RESUMO

LC separation of biologically and pharmaceutically important enantiomers (from racemic or non-racemic mixtures) remains a subject of importance. The present review article deals with the liquid chromatographic enantioseparation of chiral selective serotonin reuptake inhibitors (SSRIs), namely citalopram, paroxetine, sertraline and fluoxetine. It is now known that the enantiomers of numerous psychotropic drugs exhibit distinct pharmacodynamics, pharmacokinetic patterns and receptor binding properties, and psychiatric patients are frequently taking more than one medication. Therefore, monitoring of the levels of these analytes in biological fluids is important to determine the levels of enantiomer concentrations; the present paper may be helpful in understanding the present state of available methods (along with a critical discussion of applicability of the methods) and in developing the new ones for this purpose. Different approaches using LC discussed herein may be applied for determining the enantiomeric composition (and enantiomeric purity) of SSRIs and numerous other racemic drugs, of current/future pharmaceutical importance and utility, using simple separation methods, instrumentation, inexpensive reagents and potentially significant analytical approaches. The contents cover the essential data to understand the various separation techniques and associated issues, if any, with documented examples.


Assuntos
Cromatografia Líquida/métodos , Inibidores de Captação de Serotonina , Animais , Humanos , Ratos , Inibidores de Captação de Serotonina/análise , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/química , Estereoisomerismo
3.
Biomed Chromatogr ; 34(3): e4760, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31758582

RESUMO

Depression is now the second largest public health burden throughout the world. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have replaced older antidepressants to become first-line medications to treat this disease with increased remission rates and markedly decreased incidence of severe adverse events. Traditional and modern bioanalytical strategies for SSRI and SNRI determination are being continuously improved. There has also been a recent increase in the use of unconventional sample preparation methods. This review critically evaluates the development of SSRI and SNRI liquid chromatographic analytical methods published between 2014 and mid-2019, with special attention to novel sample preparation methods.


Assuntos
Cromatografia Líquida/métodos , Inibidores de Captação de Serotonina , Inibidores da Recaptação de Serotonina e Norepinefrina , Humanos , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/química , Inibidores de Captação de Serotonina/urina , Inibidores da Recaptação de Serotonina e Norepinefrina/sangue , Inibidores da Recaptação de Serotonina e Norepinefrina/química , Inibidores da Recaptação de Serotonina e Norepinefrina/urina
4.
BMC Nephrol ; 20(1): 395, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664940

RESUMO

BACKGROUND: Major Depressive Disorder (MDD) can lead to adverse cardiovascular outcomes in patients with chronic kidney disease (CKD). Although one of the proposed mechanisms is heightened platelet activation, effects of MDD and its treatment with a selective serotonin reuptake inhibitor (SSRI) on platelet function in patients with CKD remain unclear. METHODS: In a pre-specified analysis, changes from baseline to 12 weeks in whole blood platelet aggregation (WBPA) and plasma levels of E-selectin and P-selectin on treatment with sertraline vs. placebo were investigated in 175 patients with CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m2) and MDD (MDD+/CKD+) in a randomized, double-blind trial. Correlations between severity of depressive symptoms and platelet function were also analyzed. In order to investigate whether differences in platelet function were due to presence of CKD or MDD, we compared a subgroup of 49 MDD+/CKD+ patients with eGFR < 30 ml/min/1.73m2 to 43 non-depressed CKD controls (28 CKD with eGFR < 30 ml/min/1.73m2 [MDD-/CKD+] and 15 individuals with eGFR ≥90 ml/min/1.73m2 [MDD-/CKD-]. RESULTS: In MDD+/CKD+ individuals, there were no significant correlations between severity of depressive symptoms and platelet function, and no significant changes in platelet function after 12 weeks of treatment with sertraline vs. placebo. There were no significant differences in platelet function among MDD+/CKD+ patients and controls without MDD except in WBPA to 10 µM ADP (P = 0.03). WBPA to ADP was lower in the MDD-/CKD- group (8.0 Ω [5.0 Ω, 11.0 Ω]) as compared to the MDD-/CKD+ group (12.5 Ω [8.0 Ω, 14.5 Ω]), P = 0.01, and the MDD+/CKD+ group (11.0 Ω [8.0 Ω, 15.0 Ω]), P < 0.01. CONCLUSIONS: Heightened ADP-induced platelet aggregability was observed in CKD patients compared to controls with normal kidney function, regardless of presence of comorbid MDD, and treatment with sertraline did not affect platelet function. These findings suggest that increased platelet activation may not be a major contributory underlying mechanism by which depression may lead to worse cardiovascular outcomes in patients with CKD. Future studies should include positive MDD controls without CKD to confirm our findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier numbers: CAST Study: NCT00946998 (Recruitment Status: Completed. First Posted: July 27, 2009. Results First Posted: January 30, 2018). WiCKDonASA Study: NCT01768637 (Recruitment Status: Completed. First Posted: January 15, 2013. Results First Posted: April 19, 2019).


Assuntos
Plaquetas/efeitos dos fármacos , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Insuficiência Renal Crônica/sangue , Inibidores de Captação de Serotonina/uso terapêutico , Sertralina/uso terapêutico , Ácido Araquidônico/sangue , Plaquetas/fisiologia , Transtorno Depressivo Maior/complicações , Método Duplo-Cego , Selectina E/sangue , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Selectina-P/sangue , Placebos/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/fisiologia , Agregação Plaquetária , Insuficiência Renal Crônica/complicações , Inibidores de Captação de Serotonina/sangue , Sertralina/sangue , Fatores de Tempo
5.
Bioanalysis ; 11(13): 1243-1254, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31397579

RESUMO

Aim: Hypidone hydrochloride (YL-0919) was a novel combined selective serotonin reuptake inhibitor and 5-hydroxytryptamine receptor agonist for treatment of major depressive disorder. Quantitation of YL-0919 in plasma samples was critical for evaluation of its pharmacokinetics in clinical studies. Methodology & results: An ultra HPLC-MS/MS method has been developed and validated. Plasma samples were extracted by SPE method and then chromatographed on an Acquity BEH C18 column. Detection was performed on an API-5500 tandem mass spectrometer using positive ESI. Conclusion: A sensitive and robust method was developed and validated for quantitative analysis of YL-0919 in human plasma samples for the first time. And this novel method was successfully applied to investigate pharmacokinetic profiles of YL-0919 in Chinese healthy subjects.


Assuntos
Cromatografia Líquida de Alta Pressão , Piperidinas/sangue , Piridonas/sangue , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão/normas , Meia-Vida , Humanos , Limite de Detecção , Piperidinas/isolamento & purificação , Piperidinas/normas , Piridonas/isolamento & purificação , Piridonas/normas , Controle de Qualidade , Reprodutibilidade dos Testes , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/isolamento & purificação , Inibidores de Captação de Serotonina/normas , Extração em Fase Sólida , Espectrometria de Massas em Tandem/normas
6.
Clin Ther ; 41(9): 1755-1766, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31371035

RESUMO

PURPOSE: To date, the available data on the relationship between the use of selective serotonin reuptake inhibitors (SSRIs) or the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine and postpartum hemorrhage (PPH) are conflicting and have not been extensively investigated, especially in terms of plasma drug concentrations. We performed data mining of antidepressant-induced PPH reported to the US Food and Drug Administration's Adverse Event Reporting System database, to assess the strength of the potential association between antidepressant pharmacotherapy and PPH in pregnant women. Concurrently, we carried out a descriptive observational population (pregnant women) analysis of the correlation between the plasma concentrations of SSRIs/SNRIs used during pregnancy and the extent of bleeding at delivery. METHODS: A disproportionality analysis of individual case study reports of PPH associated with SSRIs or venlafaxine in pregnant women was performed. Reporting odds ratio was used as a measure of disproportionality analysis. Pregnant women treated with an SSRI or SNRI (venlafaxine) for depressive or anxiety disorder and who consented to plasma drug concentration monitoring at the time of delivery were recruited. Plasma drug concentration assay was performed according to validated LC-MS/MS. Based on plasma drug concentrations, patients were classified into 1 of 2 groups, in therapeutic range or below therapeutic range for the drug administered, in accordance with the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie guideline, and correlations with blood loss were identified, with PPH defined as a blood loss of >500 mL. FINDINGS: Only 43 Individual Case Safety Reports (ICSRs) reported at least one SSRIs or venlafaxine as suspect drug in 14 years (database analyses). Forty-three women were enrolled in the study population (observational study). In 24 patients (55.8%) the plasma drug concentration was below the therapeutic threshold. Unexpectedly, the mean blood loss in the below-range group was significantly higher than that in the in-range group. PPH occurred in 30% of women: in 9.3% and in 20.7% of patients in the in-range and below-range groups, respectively. IMPLICATIONS: Although preliminary, these data indicate a rather good tolerability profile of SSRIs/SNRIs regarding postpartum bleeding. Moreover, they suggest that keeping the plasma levels of SSRIs/SNRIs low as a precautionary measure does not reduce postpartum bleeding, which was higher in the below-range group. The findings from this study suggest that the use of therapeutic drug monitoring in pregnancy, a period in which multiple variables affect drug metabolism, may allow for better treatment customization, with subsequent advantages in terms of tolerability and efficacy of treatment.


Assuntos
Antidepressivos/uso terapêutico , Hemorragia Pós-Parto/epidemiologia , Inibidores de Captação de Serotonina/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Adolescente , Adulto , Antidepressivos/sangue , Bases de Dados Factuais , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Período Pós-Parto , Gravidez , Inibidores de Captação de Serotonina/sangue , Inibidores da Recaptação de Serotonina e Norepinefrina/sangue , Adulto Jovem
7.
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
8.
Drug Test Anal ; 11(3): 461-471, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30207090

RESUMO

Synthetic cathinones continue to proliferate in clandestine drug markets worldwide. N-ethylnorpentylone (also known as N-ethylpentylone or ephylone) is a popular emergent cathinone, yet little information is available about its toxicology and pharmacology. Here we characterize the analytical quantification, clinical presentation, and pharmacological mechanism of action for N-ethylnorpentylone. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to quantify N-ethylnorpentylone in blood obtained from human cases. Clinical features exhibited by the intoxicated individuals are described. The activity of N-ethylnorpentylone at plasma membrane transporters for dopamine (DAT), norepinephrine (NET) and 5-HT (SERT) was assessed using in vitro assays measuring uptake inhibition and evoked release of [3 H] neurotransmitters in rat brain synaptosomes. Our LC-MS/MS method assayed N-ethylnorpentylone concentrations with limits of detection and quantification of 1 and 5 ng/mL, respectively. Quantitation was linear from 5 to 500 ng/mL, and the method displayed specificity and reproducibility. Circulating concentrations of N-ethylnorpentylone ranged from 7 to 170 ng/mL in clinical cases, and the associated symptoms included palpitations, tachycardia, agitation, hallucinations, coma and death. N-Ethylnorpentylone was a potent inhibitor at DAT (IC50  = 37 nM), NET (IC50  = 105 nM) and SERT (IC50  = 383 nM) but displayed no transporter releasing activity. We present a validated method for quantifying N-ethylnorpentylone in human case work. The drug is a psychomotor stimulant capable of inducing serious cardiovascular and neurological side-effects which can be fatal. In vitro findings indicate that N-ethylnorpentylone exerts its effects by potent blockade of DAT and NET, thereby elevating extracellular levels of dopamine and norepinephrine in the brain and periphery.


Assuntos
Benzodioxóis/sangue , Benzodioxóis/farmacologia , Butilaminas/sangue , Butilaminas/farmacologia , Adolescente , Adulto , Animais , Benzodioxóis/toxicidade , Butilaminas/toxicidade , Estimulantes do Sistema Nervoso Central/sangue , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Cromatografia Líquida , Inibidores da Captação de Dopamina/sangue , Inibidores da Captação de Dopamina/farmacologia , Feminino , Humanos , Limite de Detecção , Masculino , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Ratos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/farmacologia , Sinaptossomos/metabolismo , Espectrometria de Massas em Tandem , Adulto Jovem
9.
Drug Test Anal ; 11(4): 601-609, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30328685

RESUMO

The misuse of psychotropic drugs intended for medical treatment represents a recent worldwide public health concern. Quenchbody (Q-body) is a novel fluoroimmunosensor that can detect an antigen immediately without additional reagents or washing steps. Here, we describe creating Q-bodies for the detection of the antidepressant fluvoxamine (FLV) and determining optimal conditions to achieve the highest fluorescence intensity (FI). We prepared five Q-bodies with the fluorophore labeled at either the N- or C- terminus and with different linker lengths. Fluorescence was measurable within minutes, indicating the interaction of Q-bodies with FLV. The normalized FI (FI ratio) of the N-terminus labeled Q-body increased approximately 1.5-fold upon FLV addition; Q-bodies labeled at the C-terminus did not significantly increase FI. Among the fluorescence dyes used in this study, Rhodamine 6G labeled Q-body showed the best FI ratio. EC50 values of the N-terminus labeled Q-bodies were similar (23.2-224nM) regardless of linker length or labeling dye. We examined whether the Q-body could be applicable to serum matrix instead of phosphate-buffered saline. The intact serum interfered strongly with the Q-body fluorescence. However, the FI ratios of the Q-body for FLV-spiked serum filtrate, for which proteins were removed by filtration, showed a dose-dependency for detecting FLV levels. Deproteinization, which does not interfere with Q-body fluorescence measurements, is likely necessary to detect serum FLV with high sensitivity. This study demonstrates the potential of Q-body probes as a tool towards developing creative immunoassay applications.


Assuntos
Antidepressivos de Segunda Geração/sangue , Técnicas Biossensoriais/métodos , Corantes Fluorescentes/química , Fluvoxamina/sangue , Imunoconjugados/química , Rodaminas/química , Antidepressivos de Segunda Geração/análise , Monitoramento de Medicamentos/métodos , Fluvoxamina/análise , Humanos , Inibidores de Captação de Serotonina/análise , Inibidores de Captação de Serotonina/sangue
10.
Z Kinder Jugendpsychiatr Psychother ; 47(2): 168-170, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30185094

RESUMO

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


Assuntos
Citalopram/administração & dosagem , Citalopram/envenenamento , Overdose de Drogas , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/envenenamento , Tentativa de Suicídio , Adolescente , Citalopram/sangue , Depressão , Testes Diagnósticos de Rotina , Feminino , Humanos , Inibidores de Captação de Serotonina/sangue
11.
Physiol Res ; 67(Suppl 3): S525-S530, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30484679

RESUMO

The paper presents the results of our effort to reveal objective parameters for evaluation of the spa treatment for patients with anxiety-depressive disorders. The study was based on our previous experience with neuroactive steroids and neurosteroids, which play a crucial role in the psychological well-being of patients by maintaining balance of the organism. A total number of 94 steroids were determinated in a group of 70 female patients diagnosed with anxiety-depressive disorders. Patients underwent a month spa treatment while maintaining unchanged medication dosing with SSRI (selective serotonin reuptake inhibitors). The other investigated factors contributing to improving the health of treated subjects were amino-acid homocysteine and serotonin. The blood samples were collected at the beginning and the end of the spa treatment. Serotonin in all patients increased by a relative 23 % (results given as relative differences in percent), while homocysteine decreased by 17.1 %. Statistically significant increases were found in 21 steroids, which indicate activation of the adrenal cortex. It can be assumed, that the overall improvement in the mental condition of patients, which was proved by questionnaire from Knobloch and Hausner, the increase in immune suppressive substances and anti-autoimmune responses, will maintain for a longer time after the spa treatment.


Assuntos
Transtornos de Ansiedade/sangue , Transtorno Depressivo/sangue , Dietoterapia/tendências , Hormônios/sangue , Massagem/tendências , Terapia de Relaxamento/tendências , Transtornos de Ansiedade/terapia , Transtorno Depressivo/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/uso terapêutico , Resultado do Tratamento
12.
Biol Pharm Bull ; 41(11): 1727-1731, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30381673

RESUMO

Duloxetine is a serotonin/noradrenaline reuptake inhibitor that is used as an antidepressant. However, it is known to cause constipation as a side effect. Magnesium compounds, such as magnesium oxide and magnesium hydroxide aqueous solution, are often combined with duloxetine to ameliorate the constipation caused by duloxetine. However, there is concern that these magnesium compounds might alter the effects of duloxetine via physicochemical interactions. In this study, we attempted to clarify the interactions that take place between duloxetine and magnesium oxide using in vivo and in vitro experiments. We evaluated the influence of magnesium oxide on in vitro duloxetine concentrations using HPLC. In addition, we examined the in vivo antidepressant-like effects and serum concentrations of duloxetine in rats. In the in vitro experiment, the duloxetine concentration was significantly decreased by co-treatment with magnesium oxide. In the in vivo experiment, the antidepressant-like effects of duloxetine were not affected by the combined oral administration of magnesium oxide and a duloxetine formulation although the serum duloxetine level was significantly decreased. However, the antidepressant-like effects of a duloxetine reagent were significantly attenuated by the co-administration of magnesium oxide. These results suggest that duloxetine and magnesium oxide directly interact and that such interactions affect the absorption and antidepressant-like effects of duloxetine.


Assuntos
Antidepressivos/farmacocinética , Depressão/tratamento farmacológico , Interações Medicamentosas , Cloridrato de Duloxetina/farmacocinética , Óxido de Magnésio/efeitos adversos , Inibidores de Captação de Serotonina/farmacocinética , Animais , Antidepressivos/efeitos adversos , Antidepressivos/sangue , Antidepressivos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Constipação Intestinal/tratamento farmacológico , Depressão/sangue , Cloridrato de Duloxetina/sangue , Cloridrato de Duloxetina/farmacologia , Cloridrato de Duloxetina/uso terapêutico , Óxido de Magnésio/uso terapêutico , Masculino , Norepinefrina/sangue , Ratos Wistar , Serotonina/sangue , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/farmacologia , Inibidores de Captação de Serotonina/uso terapêutico , Natação , Tiofenos
13.
Nutrients ; 10(8)2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30081500

RESUMO

Animal studies using tests and models have demonstrated that magnesium exerts an antidepressant effect. The literature contains few studies in humans involving attempts to augment antidepressant therapy with magnesium ions. The purpose of our study was to assess the efficacy and safety of antidepressant treatment, in combination with magnesium ions. A total of 37 participants with recurrent depressive disorder who developed a depressive episode were included in this study. As part of this double-blind study, treatment with the antidepressant fluoxetine was accompanied with either magnesium ions (120 mg/day as magnesium aspartate) or placebo. During an 8-week treatment period, each patient was monitored for any clinical abnormalities. Moreover, serum fluoxetine and magnesium levels were measured, and pharmaco-electroencephalography was performed. The fluoxetine + magnesium and fluoxetine + placebo groups showed no significant differences in either Hamilton Depression Rating Scale (HDRS) scores or serum magnesium levels at any stage of treatment. Multivariate statistical analysis of the whole investigated group showed that the following parameters increased the odds of effective treatment: lower baseline HDRS scores, female gender, smoking, and treatment augmentation with magnesium. The parameters that increased the odds of remission were lower baseline HDRS scores, shorter history of disease, the presence of antidepressant-induced changes in the pharmaco-EEG profile at 6 h after treatment, and the fact of receiving treatment augmented with magnesium ions. The limitation of this study is a small sample size.


Assuntos
Afeto/efeitos dos fármacos , Antidepressivos de Segunda Geração/administração & dosagem , Ácido Aspártico/administração & dosagem , Transtorno Depressivo/tratamento farmacológico , Suplementos Nutricionais , Fluoxetina/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Adulto , Idoso , Antidepressivos de Segunda Geração/sangue , Ácido Aspártico/sangue , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/fisiopatologia , Método Duplo-Cego , Feminino , Fluoxetina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Polônia , Indução de Remissão , Inibidores de Captação de Serotonina/sangue , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
Spectrochim Acta A Mol Biomol Spectrosc ; 205: 292-297, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30029192

RESUMO

Women are the most ones who susceptible to a common syndrome called fibromyalgia syndrome, up to 90% of all people with fibromyalgia are women. It affects mainly muscles and soft tissue and cause for them muscle pain, sleep problems and painful tender points. Milnacipran is acting as a serotonin-norepinephrine reuptake inhibitor (SNRI) therefore, it is recommended for the treatment of this syndrome. The widespread use of this compound in our market requires the development and validation of a simple, sensitive, cheap, fast and reproducible spectrofluorimetric method for the assay of milnacipran hydrochloride in its pure state, pharmaceutical tablets and spiked human urine and plasma. In the current work ninhydrin and phenylacetaldehyde in Teorell and Stenhagen buffer (pH 7) reacts with the amino moiety of milnacipran through a sensitive condensation reaction resulting in formation of a fluorescent product, which exhibits its fluorescence emission intensity at 465 nm after excitation at 390 nm. It is observed that, in the concentration range 0.5 to 3.0 µgmL-1, the constructed calibration curve was linear with a good correlation coefficient (0.9998). The condensation reaction was successfully applied for the assay of the studied drug in Avermilan® tablets, spiked human urine and plasma without interference from the components of the sample matrix with average percentage recoveries of 101.73 ±â€¯0.56 and 100.55 ±â€¯0.64 for urine and plasma, respectively.


Assuntos
Milnaciprano/sangue , Milnaciprano/urina , Ninidrina/química , Espectrometria de Fluorescência/métodos , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/urina , Comprimidos
15.
Accid Anal Prev ; 107: 86-91, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28806612

RESUMO

Selective Serotonin Reuptake Inhibitors (SSRI) were a disqualifying medication for U.S. civil pilots before April 5, 2010. After this date, a Federal Aviation Administration policy was created that allowed airmen, on select SSRIs, a pathway to hold a valid medical certificate. The purpose of this study was to provide a detailed look at SSRIs in the U.S. pilot population since the inception of this new policy. We examined the toxicology results from fatally injured airmen in addition to outcomes concerning pilots who are participating in the program. This study examined data from the Civil Aerospace Medical Institute's Bioaeronautical Sciences Research Laboratory in conjunction with the Medical Analysis Tracking Registry and the Document Imaging and Workflow System. A count-based regression model quantified the relationships between positive SSRI findings with additional factors of interest. These factors included pilot rating, ethanol, and first generation antihistamines. There were 1484 fatally injured airmen over the six year study period, of which 44-tested positive for an SSRI. First-generation antihistamines were statistically associated with positive findings of SSRIs.


Assuntos
Acidentes Aeronáuticos/mortalidade , Pilotos/estatística & dados numéricos , Inibidores de Captação de Serotonina/uso terapêutico , Adulto , Idoso , Bases de Dados Factuais , Etanol/sangue , Feminino , Antagonistas dos Receptores Histamínicos/sangue , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pilotos/legislação & jurisprudência , Distribuição de Poisson , Medição de Risco , Inibidores de Captação de Serotonina/sangue , Estados Unidos , Adulto Jovem
16.
Prog Neuropsychopharmacol Biol Psychiatry ; 79(Pt B): 213-219, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28663113

RESUMO

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


Assuntos
Líquido Amniótico/metabolismo , Citalopram/farmacocinética , Monitoramento de Medicamentos , Sangue Fetal/metabolismo , Complicações na Gravidez/tratamento farmacológico , Inibidores de Captação de Serotonina/farmacocinética , Adulto , Citalopram/sangue , Citalopram/uso terapêutico , Cordocentese , Relação Dose-Resposta a Droga , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Complicações na Gravidez/metabolismo , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/uso terapêutico , Adulto Jovem
17.
PLoS One ; 12(7): e0181082, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28708853

RESUMO

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


Assuntos
Antidepressivos/sangue , Monitoramento de Medicamentos , Inibidores de Captação de Serotonina/sangue , Cloridrato de Venlafaxina/sangue , Adulto , Antidepressivos/uso terapêutico , Citalopram/sangue , Citalopram/uso terapêutico , Bases de Dados Factuais , Transtorno Depressivo/tratamento farmacológico , Feminino , Fluvoxamina/sangue , Fluvoxamina/uso terapêutico , Humanos , Noruega , Paroxetina/sangue , Paroxetina/uso terapêutico , Gravidez , Terceiro Trimestre da Gravidez , Inibidores de Captação de Serotonina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico
18.
Behav Brain Res ; 332: 172-179, 2017 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-28587819

RESUMO

Deficits in neuronal inhibition via gamma-aminobutyric acid (GABA) type A receptors (GABAA-Rs) are implicated in the pathophysiology of major depressive disorder and the therapeutic effects of current antidepressant treatments, however, the relevant GABAA-R subtype as defined by its alpha subunit is still unknown. We previously reported anxiety- and depressive-like behavior in alpha2+/- and alpha2-/- mice, respectively (Vollenweider, 2011). We sought to determine whether this phenotype could be reversed by chronic antidepressant treatment. Adult male mice received 4 or 8mg/kg fluoxetine or 53mg/kg desipramine in their drinking water for four weeks before undergoing behavioral testing. In the novelty suppressed feeding test, desipramine had anxiolytic-like effects reducing the latencies to bite and to eat the pellet in both wild-type and alpha2+/- mice. Surprisingly, 4mg/kg fluoxetine had anxiogenic-like effects in alpha2+/- mice increasing latency to bite and to eat while 8mg/kg fluoxetine increased the latency to eat in both wild-type and alpha2+/- mice. In the forced swim and tail suspension tests, chronic desipramine treatment increased latency to immobility in wild-type and alpha2-/- mice. In contrast, chronic fluoxetine treatment increased immobility in alpha2-/- mice in both tasks while generally having no effect in wild-type mice. These findings suggest that in preclinical paradigms of anxiety and behavioral despair the antidepressant-like effects of desipramine are independent of alpha2-containing GABAA-Rs, while a reduction in alpha2 expression leads to an increased sensitivity to anxiogenic- and prodepressant-like effects with chronic fluoxetine treatment, pointing to a potential role of alpha2-containing GABAA-Rs in the response to serotonin-selective antidepressants.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Antidepressivos/farmacologia , Desipramina/farmacologia , Fluoxetina/farmacologia , Receptores de GABA-A/deficiência , Inibidores de Captação de Serotonina/farmacologia , Inibidores da Captação Adrenérgica/sangue , Animais , Antidepressivos/sangue , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Desipramina/sangue , Relação Dose-Resposta a Droga , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Fluoxetina/análogos & derivados , Fluoxetina/sangue , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Fenótipo , Receptores de GABA-A/genética , Inibidores de Captação de Serotonina/sangue
19.
Clin Neuropharmacol ; 40(4): 177-179, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28622213

RESUMO

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed among the general population. Despite their benign side effect profile, these drugs can cause significant adverse effects in elderly patients, including severe hyponatremia. We report 1 case of SSRI-induced hyponatremia and review therapeutic alternatives. CASE: We present an 81-year-old male patient treated with sertraline and furosemide who presented with a recent-onset symptomatic hyponatremia. Low sodium levels persisted for more than 1 week after furosemide had been discontinued. Sertraline was then replaced with a nonserotonergic antidepressant (bupropion), leading to a full recovery. CONCLUSIONS: Although SSRIs are the first treatment option for elderly depressed patients, they should be prescribed cautiously in this population because of the risk of potentially severe adverse effects such as hyponatremia. Particularly vulnerable patients could benefit from being prescribed nonserotonergic antidepressants from the start.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Bupropiona/uso terapêutico , Depressão/tratamento farmacológico , Hiponatremia/induzido quimicamente , Hiponatremia/diagnóstico , Inibidores de Captação de Serotonina/efeitos adversos , Idoso de 80 Anos ou mais , Depressão/sangue , Depressão/diagnóstico , Humanos , Hiponatremia/sangue , Masculino , Inibidores de Captação de Serotonina/sangue
20.
PLoS One ; 12(6): e0179927, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28644875

RESUMO

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


Assuntos
Gânglios da Base/efeitos dos fármacos , Citalopram/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Administração Intravenosa , Administração Oral , Animais , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/metabolismo , Benzilaminas , Mapeamento Encefálico , Radioisótopos de Carbono , Citalopram/sangue , Cães , Esquema de Medicação , Feminino , Imagem por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Inibidores de Captação de Serotonina/sangue
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