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1.
Forensic Sci Int ; 324: 110825, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34000617

RESUMO

We report a case in which a tapentadol acute intoxication was suspected as the cause of death of a 39-year-old man: approximately two days after death, cardiac and femoral blood, as well as urine, bile, gastric content and chest hair, were collected during the autopsy. Tapentadol was detected before and after hydrolysis in femoral (530 ng/mL unconjugated and 1570 ng/mL conjugated) and cardiac (680 ng/mL unconjugated and 3440 ng/mL conjugated) blood, and additionally in bile (3200 ng/mL), urine (9300 ng/mL), chest hair (2850 pg/mg) and gastric content. LC-QTOF screening analysis confirmed the presence of five different tapentadol metabolites (tapentadol-O-glucuronide, tapentadol-O-sulfate, N-desmethyltapentadol, N-desmethyltapentadol-glucuronide and N-desmethyltapentadol-O-sulfate), in urine, bile, cardiac and femoral blood. Positivity of body hairs allowed us to conclude that the man had used tapentadol in the last weeks/months. Autopsy and toxicological results (also positive for clotiapine, diazepam and chlordesmethyldiazepam) suggested that tapentadol could have caused, even at low concentrations, a severe respiratory depression, which contributed to the death of the subject. This is one of the few cases in literature where tapentadol was detected in blood, together with its metabolites, and the only one in which the parent drug was identified in hairs.


Assuntos
Analgésicos Opioides/envenenamento , Tapentadol/envenenamento , Adulto , Analgésicos Opioides/análise , Benzodiazepinas/análise , Bile/química , Cromatografia Líquida , Diazepam/análise , Dibenzotiazepinas/análise , Cromatografia Gasosa-Espectrometria de Massas , Conteúdo Gastrointestinal/química , Cabelo/química , Humanos , Masculino , Nordazepam/análogos & derivados , Nordazepam/análise , Prisioneiros , Tapentadol/análise , Tranquilizantes/análise , Ácido Valproico/análise
2.
Clin Neuropharmacol ; 44(4): 123-125, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33811191

RESUMO

OBJECTIVES: A meaningful proportion of patients with obsessive-compulsive disorder (OCD) develop symptoms of bipolar depression (BP-D). In the present investigation, we aimed to determine whether quetiapine is efficacious in OCD patients who despite continuous treatment with a selective serotonin reuptake inhibitor developed an acute episode of BP-D. METHODS: We analyzed 68 charts of Diagnostic and Statistical Manual of Mental Disorders Fifth Edition OCD patients from our outpatient clinic and identified 15 patients who in addition met Diagnostic and Statistical Manual of Mental Disorders Fifth Edition criteria for bipolar II disorder, depressive episode. Eleven (7 men and 4 women, aged 24-54 years) patients for whom quetiapine was added to treat the index episode of BP-D were included. Treatment response was assessed retrospectively and defined as a score of "much improved" or "very much improved" on the Clinical Global Impression-Improvement scale. RESULTS: Quetiapine was added for treatment of BP-D in a dose range of 150 to 400 mg (mean, 273 mg). Eight (73%) of the 11 study patients fulfilled the criterion of response, that is a score of "much improve" (4 patients) and "very much improved" (4 patients) on the Clinical Global Impression-Improvement scale. Notably, quetiapine was associated with additional improvement of OCD symptoms in 6 of 8 study responders. Quetiapine was well tolerated. The most frequently detected side effects were drowsiness (5 patients), constipation (4 patients), and orthostatic hypotension (2 patients). CONCLUSIONS: The revealed beneficial effect of quetiapine addition for acute episode of BP-D in OCD patients maintained on selective serotonin reuptake inhibitor treatment merits further controlled investigation.


Assuntos
Antipsicóticos , Transtorno Bipolar , Transtorno Obsessivo-Compulsivo , Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Dibenzotiazepinas/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Fumarato de Quetiapina/uso terapêutico , Estudos Retrospectivos , Inibidores de Captação de Serotonina/uso terapêutico , Resultado do Tratamento
5.
J Affect Disord ; 276: 696-698, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32871702

RESUMO

BACKGROUND: Melancholic depression may preferentially respond to certain treatments. This study examined the efficacy of extended-release quetiapine monotherapy in patients with melancholic and nonmelancholic major depressive disorder. METHODS: Data from four randomized placebo-controlled trials was pooled. Melancholic features were assessed with baseline depression scale items according to DSM criteria. The outcome measure was response on the Montgomery-Åsberg Depression Rating Scale. Cox regression models predicting response over time with interactions between treatment condition and melancholic status were used to test for treatment effect heterogeneity. RESULTS: The 6-week response rate difference between quetiapine and placebo was roughly 10% greater in the melancholic subgroup, primarily due to a lower placebo response, although the subgroup-treatment interactions did not reach statistical significance. The main effect of quetiapine was significant in every model. LIMITATIONS: The main limitations were the retrospective analysis and the post-hoc designation of melancholic depression based on scale items not designed for that purpose. Results should be considered preliminary and exploratory until replicated. CONCLUSIONS: The lower placebo response rate in the melancholic subgroup is consistent with past research and reinforces the benefit of pharmacotherapy for these patients.


Assuntos
Antipsicóticos , Transtorno Depressivo Maior , Antipsicóticos/uso terapêutico , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Dibenzotiazepinas/uso terapêutico , Método Duplo-Cego , Humanos , Escalas de Graduação Psiquiátrica , Fumarato de Quetiapina/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
6.
Eur J Pharmacol ; 885: 173532, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32882214

RESUMO

Quetiapine, an atypical antipsychotic drug, is used for the treatment of schizophrenia and acute mania. Although a previous report showed that quetiapine blocked hERG potassium current, quetiapine has been considered relatively safe in terms of cardiovascular side effects. In the present study, we used the whole-cell patch-clamp technique to investigate the effect that quetiapine and its major metabolite norquetiapine can exert on human cardiac sodium channels (hNav1.5). The half-maximal inhibitory concentrations of quetiapine and norquetiapine at a holding potential of -90 mV near the resting potential of cardiomyocytes were 30 and 6 µM, respectively. Norquetiapine as well as quetiapine was preferentially bound in the inactivated state of the hNav1.5 channel. Norquetiapine slowed the recovery from inactivation of hNav1.5 and consequently induced strong use-dependent inhibition. Our results indicate that norquetiapine blocks hNav1.5 current in concentration-, state- and use-dependent manners, suggesting that the blockade of hNav1.5 current by norquetiapine may shorten the cardiac action potential duration and reduce the risk of QT interval prolongation induced by the inhibition of hERG potassium currents.


Assuntos
Dibenzotiazepinas/farmacologia , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Potenciais de Ação/efeitos dos fármacos , Células HEK293 , Humanos , Síndrome do QT Longo/prevenção & controle , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Fumarato de Quetiapina/farmacologia
7.
J Anal Toxicol ; 44(8): 915-922, 2020 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-32780823

RESUMO

Antipsychotic drugs (AP) are widely prescribed for the treatment of schizophrenia and psychosis. The pharmacological treatment of schizophrenia is often performed with the simultaneous use of two or more antipsychotic agents to achieve the desired control of psychotic symptoms Available AP include both conventional (typical) and new (atypical) antipsychotic medications. Atypical AP, such as quetiapine, now account for the vast majority of AP prescriptions. In forensic toxicology, AP are of considerable interest because of their potential abuse and their involvement in intoxications and suicides. The authors retrospectively examined AP positive cases detected in samples collected during autopsies performed in the Forensic Clinical and Pathology Service of National Institute of Legal Medicine and Forensic Sciences Centre Branch or in other autopsies carried out in the central region of Portugal, between January 2016 and December 2018. A quantitative liquid chromatography-tandem mass spectrometry assay was developed for the simultaneous determination of 16 AP (amisulpride, aripiprazole, chlorpromazine, clozapine, cyamemazine, fluphenazine, haloperidol, levomepromazine, melperone, olanzapine, paliperidone, promethazine, quetiapine, risperidone, sulpiride and ziprasidone) in blood samples of postmortem cases. The Laboratory of Forensic Chemistry and Toxicology received 3,588 requests for toxicological analysis: 1,413 cases were positive for drugs from which 351 (24.8%) cases were positive for AP, 60.1% from male individuals and 39.9% from female. Quetiapine was the most prevalent AP (36.5%) followed by olanzapine (20.8%). During this period, there were 25 postmortem cases with AP blood concentrations above therapeutic range, in which 36% of those are in agreement with the information received (psychological history or acute intoxication suspicion) and the manner of death was suicide. Our results point that antipsychotics are an increasingly prevalent class of drugs. AP must be measured not only in toxic concentrations but also in therapeutic levels in postmortem cases; therefore, it is important to come up with a sensitive method to cover the low therapeutic range in which AP are usually present.


Assuntos
Antipsicóticos/sangue , Detecção do Abuso de Substâncias/métodos , Adulto , Amissulprida/sangue , Aripiprazol/sangue , Benzodiazepinas/sangue , Cromatografia Líquida , Clozapina/sangue , Dibenzotiazepinas/sangue , Feminino , Toxicologia Forense , Humanos , Masculino , Olanzapina/sangue , Palmitato de Paliperidona/sangue , Piperazinas/sangue , Fumarato de Quetiapina/sangue , Estudos Retrospectivos , Risperidona/sangue , Esquizofrenia/tratamento farmacológico , Suicídio , Sulpirida/sangue , Espectrometria de Massas em Tandem , Tiazóis/sangue
8.
J Clin Psychopharmacol ; 40(2): 167-179, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32134852

RESUMO

PURPOSE/BACKGROUND: The aim of the study was to estimate and rank the risk for the discontinuation due to adverse events (DAEs), 7% or more weight gain (WG), and somnolence during the acute and maintenance treatment of bipolar disorder with a mood stabilizer or an antipsychotic monotherapy. METHODS/PROCEDURES: The search of MEDLINE, EMBASE, PsycINFO, and clinicaltrials.gov from the inception to December 31, 2018, provided 32 studies in mania, 16 in bipolar depression, and 13 in maintenance. Data of DAEs, WG, and somnolence from each study were extracted. The risk for these variables of an active treatment relative to placebo was estimated with a number needed to harm (NNH) as a single study and pooled sample. FINDINGS/RESULTS: For DAEs, pooled NNH ranged from 19 with carbamazepine to -21 with quetiapine-XR in mania, 11 with quetiapine-IR 600 mg/d to -37 with olanzapine/fluoxetine combination in bipolar depression, and 5 with lithium to -8 with asenapine in maintenance. For WG, pooled NNH ranged from 9 with olanzapine to -78 with aripiprazole in mania, 5 with olanzapine to -112 with lithium in bipolar depression, and 4 with olanzapine to 126 with asenapine in maintenance. For somnolence, pooled NNH was from 5 with carbamazepine to 23 with cariprazine in mania, 3 with quetiapine-XR 300 mg/d to 79 with lurasidone in bipolar depression, and 11 with olanzapine to -49 with aripiprazole in maintenance. IMPLICATIONS/CONCLUSIONS: All medications studied in bipolar disorder were relatively well tolerated during different phases of treatment; however, the risk for short- and long-term WG and somnolence varied widely among included psychotropics.


Assuntos
Antipsicóticos/efeitos adversos , Transtorno Bipolar/tratamento farmacológico , Aripiprazol , Benzodiazepinas , Carbamazepina , Ensaios Clínicos como Assunto , Dibenzotiazepinas , Método Duplo-Cego , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fluoxetina , Humanos , Lítio , Cloridrato de Lurasidona , Olanzapina , Piperazinas , Fumarato de Quetiapina , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Forensic Sci Int ; 307: 110108, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31877542

RESUMO

Quetiapine is an atypical antipsychotic drug, frequently found in post-mortem samples. The quantitative determination of active metabolites may help in the interpretation of the potential toxic effects of the parent drug and its role in death. A fully validated LC-MS/MS method was developed for the identification and quantification of quetiapine and two main metabolites (N-desalkylquetiapine and 7-hydroxyquetiapine) in blood, biological fluids and tissues. Then, the distribution of analytes in different matrices was evaluated. LODs of 0.9, 0.3 and 0.3ng/mL were calculated for quetiapine, N-desalkylquetiapine and 7-hydroxyquetiapine respectively; while a LOQ at the concentration of 10.0ng/mL was defined for the three analytes. 13 post-mortem positive real cases have been included in the experiment. The results revealed that quetiapine and N-desalkylquetiapine might undergo a significant post-mortem redistribution, while 7-hydroxyquetiapine is less affected by this factor. N-desalkylquetiapine could be found in blood in relatively high concentrations in comparison to those of quetiapine; therefore, it should be always advisable to measure both the analytes. The analysis of tissues could provide additional data on potential intoxication with quetiapine.


Assuntos
Antipsicóticos/farmacocinética , Mudanças Depois da Morte , Fumarato de Quetiapina/farmacocinética , Tecido Adiposo/química , Adulto , Idoso , Bile/química , Química Encefálica , Cromatografia Líquida , Dibenzotiazepinas/farmacocinética , Feminino , Toxicologia Forense , Humanos , Rim/química , Limite de Detecção , Fígado/química , Pulmão/química , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/química , Baço/química , Espectrometria de Massas em Tandem , Distribuição Tecidual , Adulto Jovem
10.
Artigo em Russo | MEDLINE | ID: mdl-31626219

RESUMO

AIM: The randomized comparative study of aripiprazole and quetiapine in the treatment of patients with 'dual diagnosis' of schizophrenia and drug addiction. MATERIAL AND METHODS: Intra-group analysis of dependent variables on the scales PANSS, BPRS, VAS, SACS showed significant differences in the dinamics of the therapy in all groups. A comparative randomized study included 90 men admitted to an inpatient addiction unit. Of these, 54 (60%) had a previously established psychiatric diagnosis and 36 patients (40%) did not have an established psychiatric diagnosis. They were randomized into 3 groups of 30 patients each: group 1 received aripiprazole at a dose of up to 20 mg/day, group 2 received quetiapine at a dose of up to 600 mg/day and group 3 (controls) was treated with haloperidol at a dose of up to 30 mg/day. Treatment duration was 21 days. The efficacy of aripiprazole and quetiapine was evaluated with PANSS, BPRS, VAS and SACS on 10th, 14th and 21st day (visits 2-4). Drug safety was evaluated by recording adverse events or side-effects. RESULTS AND CONCLUSION: An analysis of independent variables showed significant differences between aripiprazole and haloperidol in PANSS and BPRS scores at visit 4, in VAS scores at visit 3, and in SACS scores at visit 2. An intergroup analysis of independent variables showed significant differences between quetiapine and haloperidol in PANSS, VAS and SACS scores at visit 4 and between aripiprazole and quetiapine in VAS and SACS scores. According to the results of the correlation analisys it has been concluded that presenting features of schizophrenia are closely correlated with drug addiction (craving).


Assuntos
Antipsicóticos , Aripiprazol , Fumarato de Quetiapina , Esquizofrenia , Transtornos Relacionados ao Uso de Substâncias , Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Diagnóstico Duplo (Psiquiatria) , Dibenzotiazepinas , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Fumarato de Quetiapina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Resultado do Tratamento
11.
J Clin Psychopharmacol ; 39(4): 312-317, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205192

RESUMO

PURPOSE/BACKGROUND: Quetiapine is a relatively new atypical antipsychotic with fewer adverse effects. It is increasingly prescribed to patients. The purpose of this study was to describe the cases of poisoning observed at the western France Poison Control Centre and identify potential risk factors that increase the severity of the cases. METHODS: This was a retrospective study of self-poisoning with quetiapine as reported by the western France Poison Control Centre between 2007 and 2017. RESULTS: There were 372 cases of quetiapine poisoning. Circumstances are known in 367 of 372 cases. There were 75 cases of null severity (grade 0), 133 cases of mild severity (grade 1), 85 cases of moderate severity (grade 2), and 79 cases of high severity (grade 3). Five deaths were listed in this series. The most commonly observed symptoms were neurological and cardiovascular in nature (drowsiness, coma, tachycardia, hypotension). Of these cases, 79.8% included voluntary ingestions. Among 302 cases with coagents, the most common coagents were benzodiazepines (56%), other psychotropic drugs (41%), and antidepressants (37%). An evaluated ingested dose 1500 mg or greater and 2 or more coagents increase the risk of severe poisoning. In particular, concomitant ingestion of benzodiazepines and antidepressants with quetiapine was associated with high severity (odds ratio, 2.478 [confidence interval, 1.3-4.723]; odds ratio, 1.820 [confidence interval, 1.010-3.316]). CONCLUSIONS: Quetiapine may lead to severe poisoning for which there is currently no specific treatment. Patients and practitioners should be aware of this when quetiapine is prescribed, particularly when used in combination with other medications, and in order to deal with cases of poisoning.


Assuntos
Antipsicóticos/envenenamento , Dibenzotiazepinas/envenenamento , Fumarato de Quetiapina/envenenamento , Adulto , Antipsicóticos/uso terapêutico , Coma/induzido quimicamente , Dibenzotiazepinas/uso terapêutico , Overdose de Drogas/mortalidade , Feminino , França , Humanos , Hipotensão/induzido quimicamente , Masculino , Centros de Controle de Intoxicações , Fumarato de Quetiapina/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Taquicardia/induzido quimicamente
12.
Forensic Sci Int ; 301: 341-349, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31202147

RESUMO

A rapid, sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination and quantification of 12 psychotropic drugs and metabolites in hair was developed and validated. After freeze grinding with methanol, the supernatant was determined by LC-MS/MS using an Allure PFPPropyl column (100 × 2.1 mm, 5 µm) with a gradient elution of acetonitrile and 10 mmol/L ammonium acetate with 0.1% formic acid, and in the subsequent analysis using multiple reaction monitoring (MRM) mode, two ion transitions were monitored for each analyte. The limits of detection ranged from 0.002 to 0.05 ng/mg, and the limits of quantitation were in the range of 0.005-0.1 ng/mg. Good linearity (r > 0.995) was observed for all analytes over the linear range. Acceptable intraday and interday precision (RSD ≤ 20%) and accuracy (85.3%-112.9%) were achieved. This method of detection was applied to the analysis of guinea pig hair roots after a single dose of quetiapine. Quetiapine and 7-hydroxyquetiapine were both detected in guinea pig hair roots from 5 min post administration. The concentration of quetiapine (10.3-1733.8 ng/mg) was much higher than that of 7-hydroxyquetiapine (0.1-40.6 ng/mg) in the hair roots of guinea pigs, and higher concentrations of quetiapine and 7-hydroxyquetiapine occurred in black hair root than in that of white and brown. The animal experiment demonstrated that hair roots may be a good specimen for proving acute quetiapine poisoning when other biological matrices are not available.


Assuntos
Cabelo/química , Psicotrópicos/análise , Animais , Cromatografia Líquida , Dibenzotiazepinas/análise , Toxicologia Forense , Cobaias , Limite de Detecção , Modelos Animais , Envenenamento/diagnóstico , Fumarato de Quetiapina/análise , Detecção do Abuso de Substâncias/métodos , Espectrometria de Massas em Tandem
14.
Psychiatr Danub ; 30(Suppl 7): 415-417, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30439816

RESUMO

BACKGROUND: Neuroleptic malignant syndrome (NMS), which is linked to the use of antipsychotic medication, is a potentially lethal neurological emergency. The interest of our study is that NMS induced by the use of clotiapine has never previously been described. SUBJECTS AND METHODS: We present the case of a 61-year old man whose sleep disorders were treated with clotiapine 40 mg/day. After 7 days of taking 40 mg clotiapine, the patient presented with a deterioration of his general health which had gradually taken hold, with altered consciousness accompanied by generalised muscle rigidity and hypersalivation. Laboratory blood tests revealed elevated levels of Creatine Phosphokinase (CPK) at 812 U/l. The patient was diagnosed with NMS and treated accordingly. RESULTS: The mechanism that underlies the appearance of NMS remains largely unknown. Clotiapine is a second-generation antipsychotic, first released onto the market in the 1970s, and is available in a few countries, including Belgium. NMS is treated as a medical emergency due to the possibility of morbidity and death. The first step in the treatment of NMS consists in withholding the agent suspected of provoking the symptoms. CONCLUSIONS: NMS is difficult to diagnose due to a great variability in clinical presentations and the absence of specific tests and laboratory results. The use of clotiapine in treating sleep disorders can provoke NMS as a life-threatening side-effect. To our knowledge, this is the first time a case of clotiapine-induced NMS has been published.


Assuntos
Antipsicóticos , Dibenzotiazepinas , Síndrome Maligna Neuroléptica , Transtornos do Sono-Vigília , Antipsicóticos/efeitos adversos , Bélgica , Dibenzotiazepinas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Maligna Neuroléptica/etiologia , Transtornos do Sono-Vigília/tratamento farmacológico
15.
Drug Des Devel Ther ; 12: 711-719, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29670329

RESUMO

Background: Norquetiapine (N-desalkyl quetiapine, NQ) is an active metabolite of quetiapine with stable pharmacokinetic and pharmacological properties. However, its short half-life is a drawback for clinical applications, and long-acting formulations are required. Purpose: The objectives of this study were to prepare improved entrapment efficiency NQ freebase microspheres by the solvent evaporation method with poly(d,l-lactic-co-glycolic acid) (PLGA) as a release modulator and to evaluate their physicochemical and in vitro/in vivo release properties. Methods: NQ freebase PLGA (1:5 w/w) formulations were prepared by the oil-in-water (o/w) emulsion-solvent evaporation method. A solution of the drug and PLGA in 9:1 v/v dichloromethane:ethanol was mixed with 0.2% polyvinyl alcohol and homogenized at 2,800 rpm. The emulsion was stirred for 3 h to dilute and evaporate the solvent. After that, the resulting product was freeze-dried. Drug-loading capacity was measured by the validated RP-HPLC method. The surface morphology of the microspheres was observed by scanning electron microscopy (SEM), and the physicochemical properties were evaluated by differential scanning calorimetry, powder X-ray diffraction, and Fourier-transform infrared spectroscopy particle size distribution. The in vitro dissolution test was performed using a rotary shaking bath at 37°C, with constant shaking at 50 rpm in sink condition. Results: The NQ freebase microspheres prepared by o/w emulsion-solvent evaporation showed over 30% efficiency. NQ was confirmed to be amorphous in the microspheres by powder X-ray diffraction and differential scanning calorimetry. Special chemical interaction in the microspheres was not observed by FT-IR. The in vitro dissolution test demonstrated that the prepared microspheres' release properties were maintained for more than 20 days. The in vivo test also confirmed that the particles' long acting properties were maintained. Therefore, good in vitro-in vivo correlation was established. Conclusion: In this study, NQ freebase-PLGA microspheres showed potential for the treatment of schizophrenia for long-periods.


Assuntos
Dibenzotiazepinas/farmacocinética , Ácido Láctico/farmacocinética , Microesferas , Ácido Poliglicólico/farmacocinética , Animais , Dibenzotiazepinas/administração & dosagem , Dibenzotiazepinas/química , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Tamanho da Partícula , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície
16.
Neurosci Lett ; 664: 66-73, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29133173

RESUMO

Quetiapine is an atypical antipsychotic drug that is widely used for the treatment of schizophrenia. It is mainly metabolized by a cytochrome P450 system in the liver. Norquetiapine is a major active metabolite in humans with a pharmacological profile that differs distinctly from that of quetiapine. We used the whole-cell patch-clamp technique to investigate the effects of norquetiapine on hERG channels that are stably expressed in HEK cells. Quetiapine and norquetiapine inhibited the hERG tail currents at -50mV in a concentration-dependent manner with IC50 values of 8.3 and 10.8µM, respectively, which suggested equal potency. The block of hERG currents by norquetiapine was voltage-dependent with a steep increase over a range of voltages for channel activation. However, at more depolarized potentials where the channels were fully activated, the block by norquetiapine was voltage-independent. The steady-state inactivation curve of the hERG currents was shifted to the hyperpolarizing direction in the presence of norquetiapine. Norquetiapine did not produce a use-dependent block. A fast application of norquetiapine inhibited the hERG current elicited by a 5s depolarizing pulse to +60mV, which fully inactivated the hERG currents, suggesting an inactivated-state block. During a repolarizing pulse wherein the hERG current was slowly deactivated, albeit remaining in an open state, a fast application of norquetiapine rapidly and reversibly inhibited the open state of the hERG current. Our results indicated that quetiapine and norquetiapine had equal potency in inhibiting hERG tail currents. Norquetiapine inhibited the hERG current by preferentially interacting with the open and/or inactivated states of the channels.


Assuntos
Clonagem Molecular , Dibenzotiazepinas/farmacologia , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/fisiologia , Fumarato de Quetiapina/farmacologia , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Dibenzotiazepinas/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Fumarato de Quetiapina/metabolismo
17.
Int J Neuropsychopharmacol ; 21(2): 108-113, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29016993

RESUMO

Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy. Methods: In this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7. Results: Norepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L. Conclusion: These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.


Assuntos
Inibidores da Captação Adrenérgica , Antidepressivos/farmacocinética , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Dibenzotiazepinas/sangue , Hipotálamo/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/efeitos dos fármacos , Tomografia por Emissão de Pósitrons/métodos , Fumarato de Quetiapina/farmacocinética , Reboxetina , Adulto , Antidepressivos/administração & dosagem , Transtorno Bipolar/diagnóstico por imagem , Preparações de Ação Retardada , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Humanos , Hipotálamo/diagnóstico por imagem , Locus Cerúleo/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Fumarato de Quetiapina/administração & dosagem , Adulto Jovem
18.
Psychopharmacology (Berl) ; 235(1): 245-255, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29075885

RESUMO

INTRODUCTION: The use of second-generation antipsychotics (SGA) has been associated with metabolic changes. However, there are differences in the metabolic profile between SGAs. We have previously observed that ziprasidone had a more benign early metabolic profile compared to aripiprazole and quetiapine. However, a long-term follow-up is preferred to detect clinically relevant impairment in metabolic parameters. We aimed to compare the effect of aripiprazole, ziprasidone, and quetiapine on metabolic measures in first-episode non-affective psychosis patients after 1 year of treatment. MATERIAL AND METHODS: One hundred and sixty-five drug-naïve patients, suffering from a first episode of non-affective psychosis, were randomly assigned to receive quetiapine, ziprasidone, or aripiprazole. Weight and glycemic/lipid parameters were recorded at baseline and after 1 year of treatment. RESULTS: After 1 year of antipsychotic treatment, we found significant increments in weight, BMI, total cholesterol, LDL-cholesterol, triglycerides, and the triglyceride/HDL index in the sample as a whole. These changes produced a significant rise in the percentage of patients with obesity, hypercholesterolemia, and hypertriglyceridemia. However, when comparing the differential effect of each antipsychotic medication, we found no significant differences in any of the metabolic parameters between antipsychotics groups after 1 year of treatment. CONCLUSION: We concluded that the antipsychotics studied present similar metabolic profiles. However, the primary exposure to SGAs during the first year of psychosis was associated with significant increases in weight and metabolic parameters, leading to increments in obesity, hypertriglyceridemia, and hypercholesterolemia.


Assuntos
Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Piperazinas/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Fumarato de Quetiapina/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacologia , Aripiprazol/efeitos adversos , Aripiprazol/farmacologia , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Colesterol/metabolismo , Dibenzotiazepinas/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Transtornos Psicóticos/metabolismo , Fumarato de Quetiapina/efeitos adversos , Fumarato de Quetiapina/farmacologia , Quinolonas/uso terapêutico , Tiazóis/efeitos adversos , Tiazóis/farmacologia , Triglicerídeos/metabolismo , Adulto Jovem
19.
Cochrane Database Syst Rev ; 8: CD008559, 2017 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-28791693

RESUMO

BACKGROUND: This is an update of the original Cochrane Review, last published in 2012 (Loy 2012). Children and youths with disruptive behaviour disorders may present to health services, where they may be treated with atypical antipsychotics. There is increasing usage of atypical antipsychotics in the treatment of disruptive behaviour disorders. OBJECTIVES: To evaluate the effect and safety of atypical antipsychotics, compared to placebo, for treating disruptive behaviour disorders in children and youths. The aim was to evaluate each drug separately rather than the class effect, on the grounds that each atypical antipsychotic has different pharmacologic binding profile (Stahl 2013) and that this is clinically more useful. SEARCH METHODS: In January 2017, we searched CENTRAL, MEDLINE, Embase, five other databases and two trials registers. SELECTION CRITERIA: Randomised controlled trials of atypical antipsychotics versus placebo in children and youths aged up to and including 18 years, with a diagnosis of disruptive behaviour disorders, including comorbid ADHD. The primary outcomes were aggression, conduct problems and adverse events (i.e. weight gain/changes and metabolic parameters). The secondary outcomes were general functioning, noncompliance, other adverse events, social functioning, family functioning, parent satisfaction and school functioning. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors (JL and KS) independently collected, evaluated and extracted data. We used the GRADE approach to assess the quality of the evidence. We performed meta-analyses for each of our primary outcomes, except for metabolic parameters, due to inadequate outcome data. MAIN RESULTS: We included 10 trials (spanning 2000 to 2014), involving a total of 896 children and youths aged five to 18 years. Bar two trials, all came from an outpatient setting. Eight trials assessed risperidone, one assessed quetiapine and one assessed ziprasidone. Nine trials assessed acute efficacy (over four to 10 weeks); one of which combined treatment with stimulant medication and parent training. One trial was a six-month maintenance trial assessing symptom recurrence.The quality of the evidence ranged from low to moderate. Nine studies had some degree of pharmaceutical support/funding. Primary outcomesUsing the mean difference (MD), we combined data from three studies (238 participants) in a meta-analysis of aggression, as assessed using the Aberrant Behaviour Checklist (ABC) ‒ Irritability subscale. We found that youths treated with risperidone show reduced aggression compared to youths treated with placebo (MD -6.49, 95% confidence interval (CI) -8.79 to -4.19; low-quality evidence). Using the standardised mean difference (SMD), we pooled data from two risperidone trials (190 participants), which used different scales: the Overt Aggression Scale ‒ Modified (OAS-M) Scale and the Antisocial Behaviour Scale (ABS); as the ABS had two subscales that could not be combined (reactive and proactive aggression), we performed two separate analyses. When we combined the ABS Reactive subscale and the OAS-M, the SMD was -1.30 in favour of risperidone (95% CI -2.21 to -0.40, moderate-quality evidence). When we combined the ABS Proactive subscale and OAS-M, the SMD was -1.12 (95% CI -2.30 to 0.06, moderate-quality evidence), suggesting uncertainty about the estimate of effect, as the confidence intervals overlapped the null value. In summary, there was some evidence that aggression could be reduced by risperidone. Data were lacking on other atypical antipsychotics, like quetiapine and ziprasidone, with regard to their effects on aggression.We pooled data from two risperidone trials (225 participants) in a meta-analysis of conduct problems, as assessed using the Nisonger Child Behaviour Rating Form ‒ Conduct Problem subscale (NCBRF-CP). This yielded a final mean score that was 8.61 points lower in the risperidone group compared to the placebo group (95% CI -11.49 to -5.74; moderate-quality evidence).We investigated the effect on weight by performing two meta-analyses. We wanted to distinguish between the effects of antipsychotic medication only and the combined effect with stimulants, since the latter can have a counteracting effect on weight gain due to appetite suppression. Pooling two trials with risperidone only (138 participants), we found that participants on risperidone gained 2.37 kilograms (kg) more (95% CI 0.26 to 4.49; moderate-quality evidence) than those on placebo. When we added a trial where all participants received a combination of risperidone and stimulants, we found that those on the combined treatment gained 2.14 kg more (95% CI 1.04 to 3.23; 3 studies; 305 participants; low-quality evidence) than those on placebo. Secondary outcomesOut of the 10 included trials, three examined general functioning, social functioning and parent satisfaction. No trials examined family or school functioning. Data on non-compliance/attrition rate and other adverse events were available from all 10 trials. AUTHORS' CONCLUSIONS: There is some evidence that in the short term risperidone may reduce aggression and conduct problems in children and youths with disruptive behaviour disorders There is also evidence that this intervention is associated with significant weight gain.For aggression, the difference in scores of 6.49 points on the ABC ‒ Irritability subscale (range 0 to 45) may be clinically significant. It is challenging to interpret the clinical significance of the differential findings on two different ABS subscales as it may be difficult to distinguish between reactive and proactive aggression in clinical practice. For conduct problems, the difference in scores of 8.61 points on the NCBRF-CP (range 0 to 48) is likely to be clinically significant. Weight gain remains a concern.Caution is required in interpreting the results due to the limitations of current evidence and the small number of high-quality trials. There is a lack of evidence to support the use of quetiapine, ziprasidone or any other atypical antipsychotic for disruptive behaviour disorders in children and youths and no evidence for children under five years of age. It is uncertain to what degree the efficacy found in clinical trials will translate into real-life clinical practice. Given the effectiveness of parent-training interventions in the management of these disorders, and the somewhat equivocal evidence on the efficacy of medication, it is important not to use medication alone. This is consistent with current clinical guidelines.


Assuntos
Agressão/efeitos dos fármacos , Antipsicóticos/uso terapêutico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/tratamento farmacológico , Dibenzotiazepinas/uso terapêutico , Piperazinas/uso terapêutico , Fumarato de Quetiapina/uso terapêutico , Risperidona/uso terapêutico , Tiazóis/uso terapêutico , Adolescente , Antipsicóticos/efeitos adversos , Transtornos de Ansiedade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Criança , Pré-Escolar , Transtorno da Conduta/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Dibenzotiazepinas/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Risperidona/efeitos adversos , Ganho de Peso
20.
Cochrane Database Syst Rev ; 4: CD011810, 2017 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-28387925

RESUMO

BACKGROUND: Schizophrenia is a chronic, disabling and severe mental disorder, characterised by disturbance in perception, thought, language, affect and motor behaviour. Chlorpromazine and clotiapine are among antipsychotic drugs used for the treatment of people with schizophrenia. OBJECTIVES: To determine the clinical effects, safety and cost-effectiveness of chlorpromazine compared with clotiapine for adults with schizophrenia. SEARCH METHODS: We searched Cochrane Schizophrenia's Trials Register (last update search 16/01/2016), which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO and clinical trials registries. There are no language, date, document type, or publication status limitations for inclusion of records in the Register. SELECTION CRITERIA: All randomised clinical trials focusing on chlorpromazine versus clotiapine for schizophrenia. We included trials meeting our selection criteria and reporting useable data. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effects model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. MAIN RESULTS: We have included four studies, published between 1974 and 2003, randomising 276 people with schizophrenia to receive either chlorpromazine or clotiapine. The studies were poor at concealing allocation of treatment and blinding of outcome assessment. Our main outcomes of interest were clinically important change in global and mental state, specific change in negative symptoms, incidence of movement disorder (dyskinesia), leaving the study early for any reason, and costs. All reported data were short-term (under six months' follow-up).The trials did not report data for the important outcomes of clinically important change in global or mental state, or cost of care. Improvement in mental state was reported using the Positive and Negative Syndrome Scale (PANSS). When chlorpromazine was compared with clotiapine the average improvement scores for mental state using the PANSS total was higher in the clotiapine group (1 RCT, N = 31, MD 11.50 95% CI 9.42 to 13.58, very low-quality evidence). The average change scores on the PANSS negative sub-scale were similar between treatment groups (1 RCT, N = 21, MD -0.97 95% CI -2.76 to 0.82, very low-quality evidence). There was no clear difference in incidence of dyskinesia (1 RCT, N = 68, RR 3.00 95% CI 0.13 to 71.15, very low-quality evidence). Similar numbers of participants left the study early from each treatment group (3 RCTs, N = 158, RR 0.68 95% CI 0.24 to 1.88, very low-quality evidence). AUTHORS' CONCLUSIONS: Clinically important changes in global and mental state were not reported. Only one trial reported the average change in overall mental state; results favour clotiapine but these limited data are very difficult to trust due to methodological limitations of the study. The comparative effectiveness of chlorpromazine compared to clotiapine on change in global state remains unanswered. Results in this review suggest chlorpromazine and clotiapine cause similar adverse effects, although again, the quality of evidence for this is poor, making firm conclusions difficult.


Assuntos
Antipsicóticos/uso terapêutico , Clorpromazina/uso terapêutico , Dibenzotiazepinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/efeitos adversos , Clorpromazina/efeitos adversos , Dibenzotiazepinas/efeitos adversos , Discinesia Induzida por Medicamentos/epidemiologia , Humanos , Análise de Intenção de Tratamento , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco
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