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1.
Ann Neurol ; 89(2): 199-211, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33159466

RESUMO

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin-associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called "transcriptome reversal" for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene-expression signatures associated with disease states. ANN NEUROL 2021;89:199-211.


Assuntos
Regulação da Expressão Gênica/genética , Células-Tronco Neurais/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Neurônios/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anticonvulsivantes/farmacologia , Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Carbamazepina/farmacologia , Simulação por Computador , Descoberta de Drogas , Epirizol/farmacologia , Perfilação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas , Células MCF-7 , Camundongos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Células-Tronco Neurais/metabolismo , Transtornos do Neurodesenvolvimento/genética , Neurônios/metabolismo , Células PC-3 , Perfenazina/farmacologia , Cultura Primária de Células , RNA-Seq , Risperidona/farmacologia , Análise de Célula Única , Trazodona/farmacologia , Trimipramina/farmacologia
2.
J Mater Chem B ; 9(2): 471-478, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33289771

RESUMO

A novel molecularly imprinted polymer (MIP)-electrochemiluminescence (MIP-ECL) sensor based on CeO2NP-RGO/Ru(bpy)32+-MIP-chitosan was introduced for the ultrasensitive and ultraselective detection of trimipramine (TRI). TRI-MIP was synthesized via the precipitation polymerization process. A nanocomposite of reduced graphene oxide decorated with ceria (CeO2NP-RGO) was synthesized through a facile sonochemical process. CeO2NP-RGO was utilized for modifying the surface of an electrode which consequently led to an excellent electrical conductivity, enhanced electrochemical and ECL characteristics of Ru(bpy)32+. Electrochemical and ECL behaviors of the MIP-ECL sensor were evaluated. Accordingly, the ECL intensity was significantly enhanced via TRI molecule adsorption on the MIP composite film. The prepared MIP-ECL sensor demonstrated high sensitivity and selectivity as well as good reproducibility and stability for TRI determination under the applied optimal conditions. The assays response for TRI concentration was linear in the range of 0.2-100 pM with a 0.995 correlation coefficient. The limit of detection (LOD) was as small as 0.025 pM (S/N = 3). The recoveries between 91-107% for human serum (RSDs < 4.1%) and 94-104.6% for human urine (RSDs < 3.4%) approve that the MIP-ECL sensor can be used for precise detection of TRI in complex biological matrices. Ultimately, this sensor was utilized successfully for the analysis of TRI in human serum and urine samples without any special pretreatment.


Assuntos
Antidepressivos Tricíclicos/uso terapêutico , Quitosana/metabolismo , Técnicas Eletroquímicas/métodos , Polímeros Molecularmente Impressos/química , Trimipramina/uso terapêutico , Antidepressivos Tricíclicos/farmacologia , Humanos , Trimipramina/farmacologia
3.
Int J Mol Sci ; 20(21)2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671916

RESUMO

We developed a pipeline for the discovery of transcriptomics-derived disease-modifying therapies and used it to validate treatments in vitro and in vivo that could be repurposed for TBI treatment. Desmethylclomipramine, ionomycin, sirolimus and trimipramine, identified by in silico LINCS analysis as candidate treatments modulating the TBI-induced transcriptomics networks, were tested in neuron-BV2 microglial co-cultures, using tumour necrosis factor α as a monitoring biomarker for neuroinflammation, nitrite for nitric oxide-mediated neurotoxicity and microtubule associated protein 2-based immunostaining for neuronal survival. Based on (a) therapeutic time window in silico, (b) blood-brain barrier penetration and water solubility, (c) anti-inflammatory and neuroprotective effects in vitro (p < 0.05) and (d) target engagement of Nrf2 target genes (p < 0.05), desmethylclomipramine was validated in a lateral fluid-percussion model of TBI in rats. Despite the favourable in silico and in vitro outcomes, in vivo assessment of clomipramine, which metabolizes to desmethylclomipramine, failed to demonstrate favourable effects on motor and memory tests. In fact, clomipramine treatment worsened the composite neuroscore (p < 0.05). Weight loss (p < 0.05) and prolonged upregulation of plasma cytokines (p < 0.05) may have contributed to the worsened somatomotor outcome. Our pipeline provides a rational stepwise procedure for evaluating favourable and unfavourable effects of systems-biology discovered compounds that modulate post-TBI transcriptomics.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Doença , Biologia de Sistemas/métodos , Animais , Anti-Inflamatórios/farmacologia , Biomarcadores , Linhagem Celular , Clomipramina/análogos & derivados , Clomipramina/metabolismo , Clomipramina/farmacologia , Técnicas de Cocultura , Citocinas/sangue , Expressão Gênica , Técnicas In Vitro , Ionomicina/farmacologia , Aprendizado de Máquina , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Nitritos/metabolismo , Ratos , Sirolimo/farmacologia , Transcriptoma , Trimipramina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
4.
Int Clin Psychopharmacol ; 34(5): 241-246, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31094902

RESUMO

OBJECTIVE: The aim of this study was to ensure patients' safety and to enhance treatment efficacy, knowledge about pharmacokinetic interactions even in complex clinical situations of polypharmacy is invaluable. This study is to uncover the potential of pharmacokinetic interactions between venlafaxine and trimipramine in a naturalistic sample. METHODS: Out of a therapeutic drug monitoring database with plasma concentrations of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV), we considered two groups of patients receiving venlafaxine without known cytochrome P450 confounding medications, taking solely venlafaxine: V0 (n = 905), and a group of patients co-medicated with trimipramine, VTRIM (n = 33). For VEN, ODV and active moiety (sum of VEN + ODV) plasma concentrations and dose-adjusted concentrations as well as ODV/VEN ratios were compared between groups using the Mann-Whitney U test with a significance level of 0.05. RESULTS: Patients co-medicated with trimipramine had higher plasma concentrations of VEN (183.0 vs. 72.0, +154%, P = 0.002) and AM (324.0 vs. 267.5, +21%, P = 0.005) and higher dose adjusted plasma concentrations than patients in the control group (P = 0.001 and P = 0.003). No differences were found for ODV and C/D ODV (P < 0.05 for both comparisons). The metabolite to parent ratio, ODV/VEN, was significantly lower in the VTRIM group (1.15 vs. 2.37, P = 0.012). CONCLUSION: Findings suggest inhibitory effects of trimipramine on venlafaxine pharmacokinetics most likely via an inhibition of CYP 2D6 or by saturated enzyme capacity. The lack of in vitro data hampers the understanding of the exact mechanisms. Clinicians should be aware of drug-drug interactions when combining these agents. Therapeutic drug monitoring helps to ensure treatment efficacy and patients' safety.


Assuntos
Succinato de Desvenlafaxina/sangue , Trimipramina/farmacologia , Cloridrato de Venlafaxina/sangue , Adulto , Succinato de Desvenlafaxina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trimipramina/sangue , Cloridrato de Venlafaxina/farmacocinética
5.
Talanta ; 199: 329-335, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30952267

RESUMO

Nowadays, developing new methods for the effective extraction/separation of drugs (present at trace levels) from complicated matrices (as biological fluids) is certainly a great challenge for many operators. In this regard, green-based agarose gel electromembrane extraction (G-EME) was for the first time combined with dispersive liquid-liquid microextraction (DLLME) toward G-EME/DLLME methodology (i.e., tandem extraction approach). Two basic drugs such as trimipramine (TRI) and clomipramine (CLO) extracted from the urine samples, were used as model compounds. Regarding method workflow, analytes were extracted from the 5 mL sample, through a synthesized agarose gel membrane, to the 700 µL aqueous acceptor phase under the optimized conditions (pH of acceptor phase: 2.0; pH of gel membrane: 2.0; pH of donor phase: 4.0, voltage value: 30 V, and extraction time: 25 min). In the next step, acceptor solution was poured to a conic vial and mixed with 100 µL alkaline solution (NaOH, 1 M). Afterwards, DLLME procedure took place again at optimal conditions, i.e., extraction solvent was carbon tetrachloride (10 µL), and dispersive solvent was acetone (100 µL). Ultimately, gas chromatography (GC) was applied for the detection and quantification of drugs. Such G-EME/DLLME configuration has brought two main advantages. Firstly, interferences such as proteins and other large biological molecules were eliminated from biological fluids via G-EME. Further, high enrichment factors (EFs of 260-370 refer to extraction recoveries of 52-74%) were obtained using DLLME with acceptable detection limits (1.0-3.0 ng mL-1). Finally, the suggested approach was successfully utilized to determine drugs at trace levels in urine samples.


Assuntos
Clomipramina/urina , Microextração em Fase Líquida/métodos , Sefarose , Trimipramina/urina , Cromatografia Gasosa , Géis/síntese química , Géis/química , Humanos , Concentração de Íons de Hidrogênio , Sefarose/síntese química , Sefarose/química
6.
Biosens Bioelectron ; 111: 27-33, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29631160

RESUMO

A novel carbon nanocomposite paste electrode was prepared and used as a voltammetric sensor for ultratrace determination of trimipramine (TRI) which currently used for the treatment of psychiatric disorders. For this aim, nanoparticles of molecularly imprinted polymer (MIP), synthesized by precipitation polymerization method, and multi-walled carbon nanotubes (MWCNTs) were embedded in a nanocomposite paste electrode. The nanocomposite mixing style demonstrated a significant influence on the final electrode performance. The sensor exhibited linear response range of 1.0 × 10-10-2.5 × 10-8 mol L-1 and very high sensitivity of 2131 µA µâ€¯mol L-1. The lower detection limit of the sensor was calculated to be 4.5 × 10-11 mol L-1 (S/N = 3). This sensor was applied successfully for highly selective determination of TRI in pharmaceutical formulations, urine and serum samples without applying any sample pretreatment.


Assuntos
Antidepressivos Tricíclicos/sangue , Antidepressivos Tricíclicos/urina , Técnicas Biossensoriais/métodos , Impressão Molecular/métodos , Polímeros/química , Trimipramina/sangue , Trimipramina/urina , Antidepressivos Tricíclicos/análise , Técnicas Biossensoriais/instrumentação , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Eletrodos , Humanos , Limite de Detecção , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Nanotubos de Carbono/química , Nanotubos de Carbono/ultraestrutura , Polimerização , Comprimidos , Trimipramina/análise
7.
Mater Sci Eng C Mater Biol Appl ; 76: 153-160, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28482512

RESUMO

Electrochemical oxidation of trimipramine in the absence and presence of 1,3 dimethyl barbituric acid as a nucleophile in aqueous solution has been studied using cyclic voltammetry and controlled-potential coulometry electrolysis. Voltammetric studies of electro-oxidation of trimipramine were realized in a range of pH1.0 to 8.0 in the absence and presence of 1,3 dimethyl barbituric acid. Based on the obtained electrochemical results, dimerization is the main reaction of electro-oxidation of trimipramine in the absence of nucleophile. The voltammetric data indicate that the 1,3 dimethyl barbituric acid participation in Michael addition reaction with the oxidized dimeric form of trimipramine via an ECEC electrochemical mechanisms. On the other hand the results indicate existence of a catalytic (EC') electrochemical mechanism in parallel with ECEC electrochemical mechanism. This method provides a facile and one-pot procedure for the synthesis of new dibenzazepine derivative. Finally, a possible mechanism is proposed for the electrode process, on the basis of the present and previous investigations. The product has been characterized by IR, 1H NMR, 13CNMR and MS methods.


Assuntos
Dibenzazepinas/química , Catálise , Eletrodos , Oxirredução , Trimipramina
8.
Water Res ; 108: 197-211, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27855951

RESUMO

Trimipramine (TMP) is an antidepressant drug used for the treatment of a variety of depressive states and other psychiatric disorders. It has been already detected in the aquatic environment. Currently, no further knowledge is available on fate and effects of TMP in the aquatic environment. Therefore, we studied the biodegradability of TMP and of its photolysis transformation products (PTPs) generated by irradiation with polychromatic UV light in aqueous solution. Different conditions including initial drug concentration, pH, and temperature were applied during TMP photolysis. Subsequently, the time courses of TMP and dissolved organic carbon (DOC) concentrations were monitored throughout the whole photo-degradation process. Then, high-resolution mass spectrometry was used to identify and elucidate the structures of the resulting PTPs. After that, the two standardized biodegradation tests, Closed Bottle test (CBT; OECD 301 D) and Manometric Respirometry test (MRT; OECD 301 F), were performed for TMP and its photolytic mixtures to assess the biodegradability of TMP and its PTPs. Finally, the toxicity of TMP and its photolytic mixtures was predicted using different quantitative structure activity relationship (QSAR) software. It was found that after 128 min of UV-irradiation, 91.8% of TMP at the initial concentration of 100 mg L-1 was eliminated with only 23.9% removal in the DOC. So, it can be pointed out that more than 65% of the degraded TMP is transformed to new non-mineralized PTPs. 14 new PTPs were detected in TMP's photolytic mixtures. Their supposed structures indicate that the proposed photo-transformation pathway is mainly by hydroxylation. The statistical analysis confirms that the differences in the degradation rates of TMP as a function of concentration, pH, and temperature are statistically significant in most cases investigated here. In biodegradation testing, TMP and its PTPs are classified as not readily biodegradable, while LC-MS analysis revealed some PTPs to be eliminated more than TMP itself. Results from QSAR analysis confirmed that some of the PTPs could be biodegradable, and revealed that some of the non-biodegradable PTPs may be human and/or eco-toxic, posing a risk to the environment. Our findings show that TMP under UV-irradiation could lead to the formation of some more easily biodegradable PTPs and some others toxic and non-biodegradable PTPs. Therefore, further studies should be conducted regarding the fate and effects of TMP and its PTPs elucidated in this study on human health and on the environment.


Assuntos
Teratógenos , Trimipramina , Humanos , Concentração de Íons de Hidrogênio , Fotólise , Temperatura , Poluentes Químicos da Água/química
9.
Electrophoresis ; 37(2): 339-46, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26462723

RESUMO

Electromembrane extraction (EME) of model analytes was carried out using a virtually rotating supported liquid membrane (SLM). The virtual (nonmechanical) rotating of the SLM was achieved using a novel electrode assembly including a central electrode immersed inside the lumen of the SLM and five counter electrodes surrounding the SLM. A particular electronic circuit was designed to distribute the potential among five counter electrodes in a rotating pattern. The effect of the experimental parameters on the recovery of the extraction was investigated for verapamil (VPL), trimipramine (TRP), and clomipramine (CLP) as the model analytes and 2-ethyl hexanol as the SLM solvent. The results showed that the recovery of the extraction is a function of the angular velocity of the virtual rotation. The best results were obtained at an angular velocity of 1.83 RadS(-1) (or a rotation frequency of 0.29 Hz).The optimization of the parameters gave higher recoveries up to 50% greater than those of a conventional EME method. The rotating also allowed the extraction to be carried out at shorter time (15 min) and lower voltage (200 V) with respect to the conventional extraction. The model analytes were successfully extracted from wastewater and human urine samples with recoveries ranging from 38 to 85%. The RSD of the determinations was in the range of 12.6 to 14.8%.


Assuntos
Fracionamento Químico/instrumentação , Clomipramina/isolamento & purificação , Técnicas Eletroquímicas/instrumentação , Membranas Artificiais , Trimipramina/isolamento & purificação , Verapamil/isolamento & purificação , Antiarrítmicos/isolamento & purificação , Antiarrítmicos/urina , Antidepressivos Tricíclicos/isolamento & purificação , Antidepressivos Tricíclicos/urina , Clomipramina/urina , Eletrodos , Desenho de Equipamento , Humanos , Limite de Detecção , Rotação , Trimipramina/urina , Urinálise/instrumentação , Verapamil/urina , Águas Residuárias/análise , Poluentes Químicos da Água/isolamento & purificação , Poluentes Químicos da Água/urina , Purificação da Água/instrumentação
10.
J Pharm Biomed Anal ; 100: 271-278, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25178259

RESUMO

Dispersive liquid-liquid microextraction (DLLME) coupled with high performance liquid chromatography by ultraviolet detection (HPLC-UV) as a fast and inexpensive technique was applied to the determination of imipramine and trimipramine in urine samples. Response surface methodology (RSM) was used for multivariate optimization of the effects of seven different parameters influencing the extraction efficiency of the proposed method. Under optimized experimental conditions, the enrichment factors and extraction recoveries were between 161.7-186.7 and 97-112%, respectively. The linear range and limit of detection for both analytes found to be 5-100ng mL(-1) and 0.6ng mL(-1), respectively. The relative standard deviations for 5ng mL(-1) of the drugs in urine samples were in the range of 5.1-6.1 (n=5). The developed method was successfully applied to real urine sample analyses.


Assuntos
Antidepressivos Tricíclicos/urina , Cromatografia Líquida de Alta Pressão , Imipramina/urina , Microextração em Fase Líquida , Modelos Estatísticos , Trimipramina/urina , Antidepressivos Tricíclicos/farmacocinética , Calibragem , Cromatografia Líquida de Alta Pressão/normas , Humanos , Imipramina/farmacocinética , Limite de Detecção , Modelos Lineares , Microextração em Fase Líquida/normas , Masculino , Análise Multivariada , Padrões de Referência , Reprodutibilidade dos Testes , Solventes/química , Espectrofotometria Ultravioleta , Trimipramina/farmacocinética
11.
Clin Toxicol (Phila) ; 52(6): 629-34, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24844578

RESUMO

CONTEXT: Seizures during intoxications with pharmaceuticals are a well-known complication. However, only a few studies report on drugs commonly involved and calculate the seizure potential of these drugs. OBJECTIVES: To identify the pharmaceutical drugs most commonly associated with seizures after single-agent overdose, the seizure potential of these pharmaceuticals, the age-distribution of the cases with seizures and the ingested doses. METHODS: A retrospective review of acute single-agent exposures to pharmaceuticals reported to the Swiss Toxicological Information Centre (STIC) between January 1997 and December 2010 was conducted. Exposures which resulted in at least one seizure were identified. The seizure potential of a pharmaceutical was calculated by dividing the number of cases with seizures by the number of all cases recorded with that pharmaceutical. Data were analyzed using descriptive statistics. RESULTS: We identified 15,441 single-agent exposures. Seizures occurred in 313 cases. The most prevalent pharmaceuticals were mefenamic acid (51 of the 313 cases), citalopram (34), trimipramine (27), venlafaxine (23), tramadol (15), diphenhydramine (14), amitriptyline (12), carbamazepine (11), maprotiline (10), and quetiapine (10). Antidepressants were involved in 136 cases. Drugs with a high seizure potential were bupropion (31.6%, seizures in 6 of 19 cases, 95% CI: 15.4-50.0%), maprotiline (17.5%, 10/57, 95% CI: 9.8-29.4%), venlafaxine (13.7%, 23/168, 95% CI: 9.3-19.7%), citalopram (13.1%, 34/259, 95% CI: 9.5-17.8%), and mefenamic acid (10.9%, 51/470, 95% CI: 8.4-14.0%). In adolescents (15-19y/o) 23.9% (95% CI: 17.6-31.7%) of the cases involving mefenamic acid resulted in seizures, but only 5.7% (95% CI: 3.3-9.7%) in adults (≥ 20y/o; p < 0.001). For citalopram these numbers were 22.0% (95% CI: 12.8-35.2%) and 10.9% (95% CI: 7.1-16.4%), respectively (p = 0.058). The probability of seizures with mefenamic acid, citalopram, trimipramine, and venlafaxine increased as the ingested dose increased. CONCLUSIONS: Antidepressants were frequently associated with seizures in overdose, but other pharmaceuticals, as mefenamic acid, were also associated with seizures in a considerable number of cases. Bupropion was the pharmaceutical with the highest seizure potential even if overdose with bupropion was uncommon in our sample. Adolescents might be more susceptible to seizures after mefenamic acid overdose than adults. "Part of this work is already published as a conference abstract for the XXXIV International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 27-30 May 2014, Brussels, Belgium." Abstract 8, Clin Toxicol 2014;52(4):298.


Assuntos
Overdose de Drogas/complicações , Convulsões/induzido quimicamente , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/efeitos adversos , Criança , Pré-Escolar , Citalopram/efeitos adversos , Cicloexanóis/efeitos adversos , Feminino , Humanos , Lactente , Masculino , Ácido Mefenâmico/efeitos adversos , Pessoa de Meia-Idade , Centros de Controle de Intoxicações , Estudos Retrospectivos , Suíça/epidemiologia , Trimipramina/efeitos adversos , Cloridrato de Venlafaxina , Adulto Jovem
12.
Biochem Biophys Res Commun ; 434(4): 710-6, 2013 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-23541943

RESUMO

Human embryonic stem cells (hESCs) and induced pluripotent cells have the potential to provide an unlimited source of tissues for regenerative medicine. For this purpose, development of defined/xeno-free culture systems under feeder-free conditions is essential for the expansion of hESCs. Most defined/xeno-free media for the culture of hESCs contain basic fibroblast growth factor (bFGF). Therefore, bFGF is thought to have an almost essential role for the expansion of hESCs in an undifferentiated state. Here, we report identification of small molecules, some of which were neurotransmitter antagonists (trimipramine and ethopropazine), which promote long-term hESC self-renewal without bFGF in the medium. The hESCs maintained high expression levels of pluripotency markers, had a normal karyotype after 20 passages, and could differentiate into all three germ layers.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células-Tronco Embrionárias/citologia , Compostos Orgânicos/farmacologia , Bibliotecas de Moléculas Pequenas , Animais , Técnicas de Cultura de Células , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Células-Tronco Embrionárias/metabolismo , Citometria de Fluxo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imuno-Histoquímica , Metotrimeprazina/química , Metotrimeprazina/farmacologia , Camundongos , Camundongos SCID , Estrutura Molecular , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Compostos Orgânicos/química , Fenotiazinas/química , Fenotiazinas/farmacologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Prometazina/química , Prometazina/farmacologia , Trimeprazina/química , Trimeprazina/farmacologia , Trimipramina/química , Trimipramina/farmacologia
13.
Analyst ; 138(5): 1395-404, 2013 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-23324861

RESUMO

An Amberlite XAD-2 (XAD2) and titanium dioxide nanoparticles (TNPs) modified glassy carbon paste electrode (XAD2-TNP-GCPE) was developed for the determination of imipramine (IMI), trimipramine (TRI) and desipramine (DES). The electrochemical behavior of these molecules was investigated employing cyclic voltammetry (CV), chronocoulometry (CC), electrochemical impedance spectroscopy (EIS) and adsorptive stripping differential pulse voltammetry (AdSDPV). After optimization of analytical conditions using a XAD2-TNP-GCPE electrode at pH 6.0 phosphate buffer (0.1 M), the peak currents were found to vary linearly with its concentration in the range of 1.30 × 10(-9) to 6.23 × 10(-6) M for IMI, 1.16 × 10(-9) to 6.87 × 10(-6) M for TRI and 1.43 × 10(-9) to 5.68 × 10(-6) M for DES. The detection limits (S/N = 3) of 3.93 × 10(-10), 3.51 × 10(-10) and 4.35 × 10(-10) M were obtained for IMI, TRI and DES respectively using AdSDPV. The prepared modified electrode showed several advantages such as a simple preparation method, high sensitivity, very low detection limits and excellent reproducibility. The proposed method was employed for the determination of IMI, TRI and DES in pharmaceutical formulations, blood serum and urine samples.


Assuntos
Antidepressivos Tricíclicos/análise , Desipramina/análise , Técnicas Eletroquímicas/métodos , Imipramina/análise , Trimipramina/análise , Adsorção , Antidepressivos Tricíclicos/sangue , Antidepressivos Tricíclicos/urina , Carbono/química , Desipramina/sangue , Desipramina/urina , Eletrodos , Humanos , Imipramina/sangue , Imipramina/urina , Limite de Detecção , Nanopartículas/química , Preparações Farmacêuticas/química , Reprodutibilidade dos Testes , Resinas Sintéticas/química , Titânio/química , Trimipramina/sangue , Trimipramina/urina
14.
Br J Clin Pharmacol ; 75(1): 227-35, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22642681

RESUMO

AIMS: To analyze the clinical features of trimipramine poisoning, identify a minimal toxic dose, and the dose bearing a 50% risk of developing a moderate, severe or fatal outcome. METHODS: All acute adult trimipramine monointoxications reported by physicians to the Swiss Toxicological Information Centre between January 1992 and December 2009 were identified. RESULTS: Two hundred and thirty cases (26 confirmed and 204 probable) were analyzed, the mean age was 35.7 years and 74% were females. One hundred and thirty-seven patients showed mild, 54 moderate and 21 severe symptoms. Three cases were fatal due to refractory cardiovascular collapse. Ninety-three per cent of the events were attempted or completed suicides. The most common symptoms were central nervous system depression (79.2%), tachycardia (19.1%) and QT(c) prolongation (13.9%). The severity of poisoning depended significantly on the ingested dose (P < 0.001). The minimal dose for moderate symptoms was 250 mg (median dose 1.2 g) and 850 mg for severe symptoms (median dose 2.7 g). The dose for a 50% risk of developing a moderate, severe or fatal outcome was 5.11 g. In 38 patients early gastrointestinal decontamination was performed. Overall, these patients ingested higher trimipramine doses than the late- or not-decontaminated patients (P = 0.113). The median doses were also higher in the decontaminated group within each severity category except in the fatal cases. CONCLUSIONS: We demonstrated that moderate trimipramine poisoning can already occur after ingestion of doses in the high therapeutic range. Poisoned patients have to be monitored for central nervous system depression, dysrhythmias and QT(c) prolongation. Early decontamination might be beneficial.


Assuntos
Antidepressivos Tricíclicos/envenenamento , Trimipramina/envenenamento , Doença Aguda , Adolescente , Adulto , Idoso , Overdose de Drogas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Cochrane Database Syst Rev ; (9): CD003853, 2012 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-22972065

RESUMO

BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 4, 2006 and previously updated in 2009.Tinnitus is described as the perception of sound or noise in the absence of real acoustic stimulation. It has been compared with chronic pain, and may be associated with depression or depressive symptoms which can affect quality of life and the ability to work. Antidepressant drugs have been used to treat tinnitus in patients with and without depressive symptoms. OBJECTIVES: To assess the effectiveness of antidepressants in the treatment of tinnitus and to ascertain whether any benefit is due to a direct tinnitus effect or a secondary effect due to treatment of concomitant depressive states. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; PsycINFO; CINAHL; Web of Science; BIOSIS; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 5 January 2012. SELECTION CRITERIA: Randomised controlled clinical studies of antidepressant drugs versus placebo in patients with tinnitus. DATA COLLECTION AND ANALYSIS: Two authors critically appraised the retrieved studies and extracted data independently. Where necessary we contacted study authors for further information. MAIN RESULTS: Six trials involving 610 patients were included. Trial quality was generally low. Four of the trials looked at the effect of tricyclic antidepressants on tinnitus, investigating 405 patients. One trial investigated the effect of a selective serotonin reuptake inhibitor (SSRI) in a group of 120 patients. One study investigated trazodone, an atypical antidepressant, versus placebo. Only the trial using the SSRI drug reached the highest quality standard. None of the other included trials met the highest quality standard, due to use of inadequate outcome measures, large drop-out rates or failure to separate the effects on tinnitus from the effects on symptoms of anxiety and depression. All the trials assessing tricyclic antidepressants suggested that there was a slight improvement in tinnitus but these effects may have been attributable to methodological bias. The trial that investigated the SSRI drug found no overall improvement in any of the validated outcome measures that were used in the study although there was possible benefit for a subgroup that received higher doses of the drug. This observation merits further investigation. In the trial investigating trazodone, the results showed an improvement in tinnitus intensity and in quality of life after treatment, but in neither case reached statistical significance. Reports of side effects including sedation, sexual dysfunction and dry mouth were common. AUTHORS' CONCLUSIONS: There is as yet insufficient evidence to say that antidepressant drug therapy improves tinnitus.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Zumbido/tratamento farmacológico , Amitriptilina/uso terapêutico , Humanos , Nortriptilina/uso terapêutico , Paroxetina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Zumbido/psicologia , Trazodona/uso terapêutico , Trimipramina/uso terapêutico
16.
Acta Crystallogr C ; 68(Pt 2): o65-70, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22307256

RESUMO

Polymorph (Ia) of eldoral [5-ethyl-5-(piperidin-1-yl)barbituric acid or 5-ethyl-5-(piperidin-1-yl)-1,3-diazinane-2,4,6-trione], C(11)H(17)N(3)O(3), displays a hydrogen-bonded layer structure parallel to (100). The piperidine N atom and the barbiturate carbonyl group in the 2-position are utilized in N-H···N and N-H···O=C hydrogen bonds, respectively. The structure of polymorph (Ib) contains pseudosymmetry elements. The two independent molecules of (Ib) are connected via N-H···O=C(4/6-position) and N-H···N(piperidine) hydrogen bonds to give a chain structure in the [100] direction. The hydrogen-bonded layers, parallel to (010), formed in the salt diethylammonium 5-ethyl-5-(piperidin-1-yl)barbiturate [or diethylammonium 5-ethyl-2,4,6-trioxo-5-(piperidin-1-yl)-1,3-diazinan-1-ide], C(4)H(12)N(+)·C(11)H(16)N(3)O(3)(-), (II), closely resemble the corresponding hydrogen-bonded structure in polymorph (Ia). Like many other 5,5-disubstituted derivatives of barbituric acid, polymorphs (Ia) and (Ib) contain the R(2)(2)(8) N-H···O=C hydrogen-bond motif. However, the overall hydrogen-bonded chain and layer structures of (Ia) and (Ib) are unique because of the involvement of the hydrogen-bond acceptor function in the piperidine group.


Assuntos
Barbitúricos/química , Piperidinas/química , Compostos de Amônio Quaternário/química , Triazinas/química , Trimipramina/química , Cristalização , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Sais
17.
Electrophoresis ; 33(3): 506-15, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22287179

RESUMO

A sensitive, simple and reproducible method was developed for preconcentration and determination of trimipramine (TPM) enantiomers in biological samples using electromembrane extraction combined with cyclodextrin-modified capillary electrophoresis (CE). During the extraction, TPM enantiomers migrated from a 5 mL sample solution through a thin layer of 2-nitrophenyl octyl ether NPOE immobilized in the pores of a hollow fiber, and into a 20 µL acidic aqueous acceptor phase presented inside the lumen of the fiber. A Box-Behnken design and the response surface methodology (RSM) were used for the optimization of different variables on extraction efficiency. Optimized extraction conditions were: NPOE as supported liquid membrane, inter-electrode distance of 5 mm, stirring rate of 1000 rpm, 51 V potential difference, 34 min as the extraction time, acceptor phase pH 1.0 and donor phase pH 4.5. Then, the extract was analyzed using optimized cyclodextrin (CD)-modified CE method for the separation of TPM enantiomers. Best results were achieved using 100 mM phosphate running buffer (pH 2.0) containing 10 mM α-CD as the chiral selector, applied voltage of 18 kV and 20°C. The range of quantitation for both enantiomers was 20-500 ng/mL. The method was very reproducible so that intra- and interday RSDs (n=6) were <6%. The limits of quantitation and detection for both enantiomers were 20 and 7 ng/mL, respectively. Finally, this method was successfully applied to determine the concentration of TPM enantiomers in plasma and urine samples without any pre-treatment.


Assuntos
Ciclodextrinas/química , Eletroforese Capilar/métodos , Extração Líquido-Líquido/métodos , Trimipramina/análise , Trimipramina/química , Análise de Variância , Humanos , Limite de Detecção , Membranas Artificiais , Reprodutibilidade dos Testes , Cloreto de Sódio , Estereoisomerismo , Trimipramina/sangue , Trimipramina/urina
19.
PLoS One ; 6(9): e24844, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21931860

RESUMO

Prion diseases currently have no effective therapy. These illnesses affect both animal and human populations, and are characterized by the conformational change of a normal self protein PrP(C) (C for cellular) to a pathological and infectious conformer, PrP(Sc) (Sc for scrapie). We used a well characterized tissue culture model of prion infection, where mouse neuroblastoma cells (N2a) were infected with 22L PrP(Sc), to screen compounds for anti-prion activity. In a prior study we designed a library of styryl based, potential imaging compounds which were selected for high affinity binding to Alzheimer's disease ß-amyloid plaques and good blood-brain barrier permeability. In the current study we screened this library for activity in the N2a/22L tissue culture system. We also tested the anti-prion activity of two clinically used drugs, trimipramine and fluphenazine, in the N2a/22L system. These were selected based on their structural similarity to quinacrine, which was previously reported to have anti-prion activity. All the compounds were also screened for toxicity in tissue culture and their ability to disaggregate amyloid fibrils composed of PrP and ß-amyloid synthetic peptides in vitro. Two of the imaging agents, 23I and 59, were found to be both effective at inhibiting prion infection in N2a/22L tissue culture and to be non-toxic. These two compounds, as well as trimipramine and fluphenazine were evaluated in vivo using wild-type CD-1 mice infected peripherally with 139A PrP(Sc). All four agents significantly prolonged the asymptomatic incubation period of prion infection (p<0.0001 log-rank test), as well as significantly reducing the degree of spongiform change, astrocytosis and PrP(Sc) levels in the brains of treated mice. These four compounds can be considered, with further development, as candidates for prion therapy.


Assuntos
Flufenazina/uso terapêutico , Doenças Priônicas/tratamento farmacológico , Trimipramina/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Camundongos , Proteínas PrPC/metabolismo , Proteínas PrPSc/metabolismo , Doenças Priônicas/metabolismo , Príons/metabolismo
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