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1.
Artigo em Inglês | MEDLINE | ID: mdl-38104432

RESUMO

A new efficient ZnO-Al2O3 nanocomposite (ZANC) was synthesized to form solid-phase microextraction (SPME) fiber. The prepared fiber was used for trace determination of benzodiazepines by gas chromatography-flame ionization detector in urine samples. The effective parameters on the extraction process including extraction time, salt percentage, desorption time and sample pH were optimized by a factorial design method. The method was evaluated at the optimum conditions and limits of detection (LODs) were calculated 20 µg/L for diazepam and oxazepam. The method repeatability for oxazepam and diazepam (50 µg/L, n = 4) was calculated at 8.8 % and 6.4 %. Also, the method reproducibility was obtained, 7.45 % and 6.61 % for oxazepam and diazepam (50 µg/L, n = 4). Also, fiber-to-fiber relative standard deviation (RSDs%) for the target analytes were less than 15.5 %. The method linearity is within the range of 62-500 µg/L for diazepam and oxazepam. The ZANC-SPME fiber showed a good lifetime (60 times) with high chemical stability. The high thermal stability of ZANC-SPME fiber was attained at 280 °C. The extraction results of poly dimethylsiloxan/divinyl benzene (PDMS/DVB) fiber were compared by ZANC-SPME fiber. Therefore, the method is proposed as a suitable technique for benzodiazepines detection in the urine sample.


Assuntos
Nanocompostos , Óxido de Zinco , Diazepam , Oxazepam , Microextração em Fase Sólida/métodos , Reprodutibilidade dos Testes , Benzodiazepinas
2.
Int J Mol Sci ; 24(19)2023 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-37834226

RESUMO

In this study, atomistic simulations were carried out to study the difference in the adsorption process between two similar molecules, diazepam and oxazepam, on Na+-montmorillonite. Kinetic and XRD measurements showed a contrasting adsorption mechanism of these two molecules, differing only by the presence/absence of methyl and hydroxyl groups, with a larger adsorption amount and intercalation for the oxazepam. The structural characterization of these molecules was investigated through DFT calculations and showed the vicinity of hydroxyl and carbonyl groups for only the chair conformation of oxazepam compared to the boat conformation. Classical molecular dynamics simulations of diazepam and the two forms of oxazepam on the external surface of Na+-montmorillonite highlighted the better coordination of the oxazepam-chair conformation, compared to its boat counterpart and diazepam. This has been confirmed through DFT calculations, from which a coordination energy that is greater by 10 kcal·mol-1 is observed. This strongly suggests that the experimentally observed intercalation of oxazepam occurs only in the chair form because of the strong coordination with the Na+ cation present in the Na-Mt interlayer. Classical MD simulations of the intercalated oxazepam chair molecule in the Na-Mt interlayer allowed the evaluation of the interlayer spacing d001, which was in very good agreement with the experimental XRD measurement.


Assuntos
Bentonita , Oxazepam , Argila , Bentonita/química , Adsorção , Diazepam
3.
Ugeskr Laeger ; 184(23)2022 06 06.
Artigo em Dinamarquês | MEDLINE | ID: mdl-35703059

RESUMO

In this case report we describe a life-threatening episode of delirium in a 51-year-old man. The condition was triggered by an abrupt withdrawal of benzodiazepines. The patient had been taking multiple sedatives for several years but a large proportion of the drugs were not available in Denmark. His general practitioner substituted and prescribed oxazepam and zolpidem for ten days. Afterwards the patient did not have access to benzodiazepines and developed a severe benzodiazepine withdrawal delirium. He was treated with diazepam and olanzapine with gradual dose reduction.


Assuntos
Delirium por Abstinência Alcoólica , Delírio , Síndrome de Abstinência a Substâncias , Delirium por Abstinência Alcoólica/tratamento farmacológico , Benzodiazepinas/efeitos adversos , Delírio/induzido quimicamente , Delírio/tratamento farmacológico , Diazepam/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Oxazepam/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/etiologia
4.
Sci Total Environ ; 836: 155643, 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-35513148

RESUMO

Soil Aquifer Treatment (SAT) can provide supplementary treatment of trace organic compounds (TrOCs) such as pharmaceutical and industrial compounds present in Secondary Treated Wastewater (STWW). Concern on presence of unregulated TrOCs in natural systems has raised recently as well as the interest in SAT systems for remediation. The present study quantifies, at the field scale over35 m of lateral groundwater flow, the effectiveness of the Agon-Coutainville SAT system (Manche, Normandy, France) for TrOCs removal by sorption and biodegradation through monitoring of seven TrOCs (oxazepam, carbamazepine, benzotriazole, tolyltriazole, caffein, paracetamol, ibuprofen) and major inorganic compounds as intrinsic tracers in STWW and groundwater during a 34-day STWW infiltration experiment during operational use of the SAT. Cationic exchanges and mixing between groundwater and STWW during the experiment were highlighted by major ions and geochemical simulations. Due to the low thickness of the unsaturated zone, a 1D analytical solution of the advection-dispersion equation (ADE) was applied on chloride data. Chloride was used as conservative intrinsic tracer to calibrate the horizontal flow and transport parameters such as the aquifer dispersion coefficient (D) and the average pore water velocity (ν) allowing estimation of the groundwater residence time. Transport and attenuation of the TrOCs were simulated assuming first-order degradation constant (µ) and linear retardation coefficient (R), calibrated to simulate the observed temporal changes in the breakthrough of TrOCs. Sorption was found to play a role in the transport of TrOCs, notably for oxazepam with a higher linear retardation coefficient value of 2.2, whereas no significant differences of retardation were observed for carbamazepine, tolyltriazole, benzotriazole (1.37, 1.35, 1.36 respectively). Estimated first order degradation rate constants, between 0.03d-1 for carbamazepine and 0.09d-1 for tolyltriazole, were generally high compared to the literature, possibly due to favourable redox conditions and important microbial activities within the system. This study provides evidence of the efficiency of the Agon-Coutainville SAT system for the removal of TrOCs.


Assuntos
Água Subterrânea , Poluentes Químicos da Água , Carbamazepina , Cloretos , Felodipino , Água Subterrânea/química , Compostos Orgânicos , Oxazepam , Solo/química , Águas Residuárias/análise , Poluentes Químicos da Água/análise
5.
J Anal Toxicol ; 46(8): 899-904, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-35640884

RESUMO

A rapid, simple extraction method followed by qualitative screening using liquid chromatography-tandem mass spectrometry (LC-MS-MS) for drugs in oral fluid is presented. The decision points were selected to be at, or lower, than those recommended as Tier I compounds by the National Safety Council's Alcohol, Drugs and Impairment Division for toxicological investigation of driving under the influence of drug (DUID) cases and were also at, or lower, than those recommended by Substance Abuse and Mental Health Service Administration and the Department of Transportation for Federal workplace drug testing programs. The method included 30 drugs: delta-9-tetrahydrocannabinol, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, cocaine, benzoylecgonine, carisoprodol, meprobamate, zolpidem, alprazolam, clonazepam, 7-aminoclonazepam, diazepam, nordiazepam, lorazepam, oxazepam, temazepam, codeine, morphine, 6-acetylmorphine, buprenorphine, fentanyl, hydrocodone, hydromorphone, oxycodone, oxymorphone, methadone, tramadol and phencyclidine. Phencyclidine was included because it is in the Federal workplace program even though it is considered a Tier II drug for DUID cases. A liquid-liquid extraction method using isopropanol, hexane and ethyl acetate to extract drugs from the oral fluid-buffer mix collected in a Quantisal™ device, followed by LC-MS-MS screening, was developed and validated according to ANSI/ASB 2019 Standard Practices for Method Validation in Forensic Toxicology. Interference studies, limit of detection, precision at the decision point, ionization suppression/enhancement and processed sample stability were determined for each drug. The method was successfully applied to proficiency specimens and routine samples received in the laboratory.


Assuntos
3,4-Metilenodioxianfetamina , Buprenorfina , Carisoprodol , Cocaína , Meprobamato , Metanfetamina , N-Metil-3,4-Metilenodioxianfetamina , Tramadol , 2-Propanol , Alprazolam , Anfetaminas , Clonazepam , Codeína , Dronabinol , Fentanila , Hexanos , Hidrocodona , Hidromorfona , Lorazepam , Metadona , Derivados da Morfina , Nordazepam , Oxazepam , Oxicodona , Oximorfona , Preparações Farmacêuticas/análise , Fenciclidina , Espectrometria de Massas em Tandem , Temazepam , Zolpidem
6.
J Addict Med ; 16(4): e274-e277, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34954745

RESUMO

ABSTRACT: Patients suffering from substance use disorder, including for instance benzodiazepines, may have comorbidity with attention deficit hyperactivity disorder (ADHD). Centrally acting stimulants play an important role in the treatment of ADHD. Before such treatment can be initiated, withdrawal of benzodiazepines may be necessary. Urine testing is the preferred method for monitoring adherence in benzodiazepine withdrawal, but there is a lack of studies reporting detection time. Here, we report a case of a 30-year-old woman with substance use disorder and ADHD who had detectable metabolites of diazepam 79 days after withdrawal. To our knowledge, no cases with detection time equivalent to this have previously been published. This case report serves as an example that clinicians may need to consider interindividual pharmacokinetic characteristics when interpreting the results of urine drug tests, and that a positive urine test may still be consistent with abstinence from a certain drug. In the current case, a high body mass index and a genetic polymorphism gave a reasonable explanation for the prolonged detection of diazepam metabolites.


Assuntos
Síndrome de Abstinência a Substâncias , Transtornos Relacionados ao Uso de Substâncias , Adulto , Benzodiazepinas/efeitos adversos , Diazepam/efeitos adversos , Diazepam/farmacocinética , Feminino , Humanos , Oxazepam/efeitos adversos , Síndrome de Abstinência a Substâncias/diagnóstico , Síndrome de Abstinência a Substâncias/etiologia , Transtornos Relacionados ao Uso de Substâncias/complicações
7.
Anal Bioanal Chem ; 414(1): 451-463, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33751162

RESUMO

Oxazepam, one of the most frequently prescribed anxiolytic drugs, is not completely removed from wastewater with conventional treatment processes. It can thus be found at trace levels in environmental water, with human urine constituting the major source of contamination. This study focused on the development and characterization of molecularly imprinted polymers (MIPs) for the selective solid-phase extraction of oxazepam at trace levels from environmental water and human urine samples. Two MIPs were synthesized, and their selectivity in pure organic and aqueous media were assayed. After optimizing the extraction procedure adapted to a large sample volume to reach a high enrichment factor, the most promising MIP was applied to the selective extraction of oxazepam from environmental water. Extraction recoveries of 83 ± 12, 92 ± 4 and 89 ± 10% were obtained using the MIP for tap, mineral and river water, respectively, while a recovery close to 40% was obtained on the corresponding non-imprinted polymer (NIP). Thanks to the high enrichment factors, a limit of quantification (LOQ) of 4.5 ng L-1 was obtained for river water. A selective extraction procedure was also developed for urine samples and gave rise to extraction recoveries close to 95% for the MIP and only 23% for the NIP. Using the MIP, a LOQ of 357 ng L-1 was obtained for oxazepam in urine. The use of the MIP also helped to limit the matrix effects encountered for the quantification of oxazepam in environmental samples and in human urine samples after extraction on an Oasis HLB sorbent.


Assuntos
Impressão Molecular , Cromatografia Líquida de Alta Pressão , Humanos , Impressão Molecular/métodos , Polímeros Molecularmente Impressos , Oxazepam , Polímeros , Extração em Fase Sólida/métodos
8.
J Anal Toxicol ; 46(1): e16-e20, 2022 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33180140

RESUMO

Drug-facilitated sexual assault (DFSA) cases are pretty common in forensic toxicology. In this case report, a 56-year-old female tourist claimed to have been sexually assaulted by five men after having had a drug-spiked alcoholic drink. Urine samples were collected at 38, 44 and 45 h after the alleged rape. After 7 months, hair strands (28 cm in length) were also sampled to perform the segmental hair testing. The urine samples and decontaminated hair segments were tested for different groups of basic, acidic and neutral substances (γ-hydroxybutyrate or GHB, Z-drugs, barbiturates, benzodiazepines, hypnotics, antipsychotics and drugs of abuse). Gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry methods were applied for the qualitative and quantitative analyses. Toxicological analyses performed on the urine samples showed inconclusive findings. Zolpidem, flunitrazepam and oxazepam were detected in the hair segments corresponding to the time frame of the alleged assault. The endogenous levels of GHB were detected along the hair shaft. No drugs were detected in the proximal and distal hair segments or in washing solutions. This DFSA case demonstrated that the segmental toxicological analysis of hair, even when performed 7 months after the sexual assault, can provide evidence consistent with a single exposure to psychoactive drugs, at the time of the offense.


Assuntos
Preparações Farmacêuticas , Delitos Sexuais , Feminino , Flunitrazepam , Toxicologia Forense , Humanos , Masculino , Pessoa de Meia-Idade , Oxazepam , Detecção do Abuso de Substâncias , Zolpidem
9.
Molecules ; 26(21)2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34770758

RESUMO

Partially and exhaustively methylated ß-cyclodextrins [(2-methyl)-ß-CD (MCD), heptakis-(2,6-di-O-methyl)-ß-CD (DIMEB), and heptakis-(2,3,6-tri-O-methyl)-ß-CD (TRIMEB)] have been compared in the hydrolysis and enantiodiscrimination of benzodiazepine derivative (R)- or (S)-oxazepam hemisuccinate (OXEMIS), using nuclear magnetic resonance (NMR) spectroscopy as an investigation tool. After 6 h, MCD induced an 11% hydrolysis of OXEMIS, remarkably lower in comparison with underivatized ß-CD (48%), whereas no hydrolysis was detected in the presence of DIMEB or TRIMEB after 24 h. DIMEB showed greater ability to differentiate OXEMIS enantiomers in comparison to TRIMEB, by contrast MCD did not produce any splitting of racemic OXEMIS resonances. Both enantiomers of OXEMIS underwent deep inclusion of their phenyl pendant into cyclodextrins cavities from their wider rims, but tighter complexes were formed by DIMEB with respect to TRIMEB.


Assuntos
Espectroscopia de Ressonância Magnética , Oxazepam/análogos & derivados , beta-Ciclodextrinas/química , Hidrólise , Metilação , Modelos Moleculares , Estrutura Molecular , Oxazepam/química
10.
Ecotoxicology ; 30(9): 1880-1892, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34379245

RESUMO

Psychoactive drugs have emerged as contaminants over the last few decades. These drugs are frequently prescribed and poorly eliminated by wastewater treatment plants, and many are present at non-negligible concentrations in surface waters. Several studies have investigated the non-target organism toxicity of one such drug, oxazepam, a benzodiazepine anxiolytic frequently detected in rivers. However, very little is known about the impact of this drug on reproduction. We investigated the effects of environmentally relevant concentrations of oxazepam on Radix balthica, a freshwater gastropod widespread in Europe. We identified the reproductive organs of Radix balthica. We then exposed this gastropod to oxazepam for two months and assessed several reproductive parameters, from reproductive organ status to behavioral parameters. We found that adults exposed to 10 µg/L oxazepam display an increase in the density of spermatozoa, and that adults exposed to 0.8 µg/L oxazepam displayed a decrease in the number of eggs per egg mass over time. By contrast, oxazepam had no effect on shell length, the size of male reproductive organs or social interactions. Finally, a locomotor activity analysis showed the distance covered over time decreased in all conditions of exposure to oxazepam, potentially reflecting a disturbance of exploratory activity. These results shed light on the effects of oxazepam on the reproduction of a non-target freshwater mollusk.


Assuntos
Ansiolíticos , Gastrópodes , Poluentes Químicos da Água , Animais , Ansiolíticos/toxicidade , Benzodiazepinas/toxicidade , Água Doce , Masculino , Oxazepam/toxicidade , Estudos Prospectivos , Reprodução , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
11.
PLoS One ; 16(4): e0249065, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33886568

RESUMO

BACKGROUND: Cognitive reappraisal is a strategy for emotional regulation, important in the context of anxiety disorders. It is not known whether anxiolytic effects of benzodiazepines affect cognitive reappraisal. AIMS: We aimed to investigate the effect of 25 mg oxazepam on cognitive reappraisal. METHODS: In a preliminary investigation, 33 healthy male volunteers were randomised to oxazepam or placebo, and then underwent an experiment where they were asked to use cognitive reappraisal to upregulate or downregulate their emotional response to images with negative or neutral emotional valence. We recorded unpleasantness ratings, skin conductance, superciliary corrugator muscle activity, and heart rate. Participants completed rating scales measuring empathy (Interpersonal Reactivity Index, IRI), anxiety (State-Trait Anxiety Inventory, STAI), alexithymia (Toronto Alexithymia Scale-20, TAS-20), and psychopathy (Psychopathy Personality Inventory-Revised, PPI-R). RESULTS: Upregulation to negative-valence images in the cognitive reappraisal task caused increased unpleasantness ratings, corrugator activity, and heart rate compared to downregulation. Upregulation to both negative- and neutral-valence images caused increased skin conductance responses. Oxazepam caused lower unpleasantness ratings to negative-valence stimuli, but did not interact with reappraisal instruction on any outcome. Self-rated trait empathy was associated with stronger responses to negative-valence stimuli, whereas self-rated psychopathic traits were associated with weaker responses to negative-valence stimuli. CONCLUSIONS: While 25 mg oxazepam caused lower unpleasantness ratings in response to negative-valence images, we did not observe an effect of 25 mg oxazepam on cognitive reappraisal.


Assuntos
Ansiolíticos/efeitos adversos , Cognição/efeitos dos fármacos , Regulação Emocional/efeitos dos fármacos , Oxazepam/efeitos adversos , Adolescente , Adulto , Ansiolíticos/farmacologia , Humanos , Masculino , Oxazepam/farmacologia , Percepção Visual
12.
Ecotoxicol Environ Saf ; 217: 112246, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33901781

RESUMO

It is generally expected that biotransformation and excretion of pharmaceuticals occurs similarly in fish and mammals, despite significant physiological differences. Here, we exposed European perch (Perca fluviatilis) to the benzodiazepine drug temazepam at a nominal concentration of 2 µg L-1 for 10 days. We collected samples of blood plasma, muscle, and brain in a time-dependent manner to assess its bioconcentration, biotransformation, and elimination over another 10 days of depuration in clean water. We observed rapid pharmacokinetics of temazepam during both the exposure and depuration periods. The steady state was reached within 24 h of exposure in most individuals, as was complete elimination of temazepam from tissues during depuration. Further, the biologically active metabolite oxazepam was produced via fish biotransformation, and accumulated significantly throughout the exposure period. In contrast to human patients, where a negligible amount of oxazepam is created by temazepam biotransformation, we observed a continuous increase of oxazepam concentrations in all fish tissues throughout exposure. Indeed, oxazepam accumulated more than its parent compound, did not reach a steady state during the exposure period, and was not completely eliminated even after 10 days of depuration, highlighting the importance of considering environmental hazards posed by pharmaceutical metabolites.


Assuntos
Hipnóticos e Sedativos/toxicidade , Percas/fisiologia , Temazepam/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biotransformação , Hipnóticos e Sedativos/metabolismo , Oxazepam/metabolismo , Percas/metabolismo , Temazepam/metabolismo , Poluentes Químicos da Água/metabolismo
13.
Environ Sci Technol ; 55(6): 3624-3633, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33663207

RESUMO

A current theory in environmental science states that dissolved anxiolytics (oxazepam) from wastewater effluents can reduce anti-predator behavior in fish with potentially negative impacts on prey fish populations. Here, we hypothesize that European perch (Perca fluviatilis) populations being exposed to oxazepam in situ show reduced anti-predator behavior, which has previously been observed for exposed isolated fish in laboratory studies. We tested our hypothesis by exposing a whole-lake ecosystem, containing both perch (prey) and northern pike (Esox lucius; predator), to oxazepam while tracking fish behavior before and after exposure in the exposed lake as well as in an unexposed nearby lake (control). Oxazepam concentrations in the exposed lake ranged between 11 and 24 µg L-1, which is >200 times higher than concentrations reported for European rivers. In contrast to our hypothesis, we did not observe an oxazepam-induced reduction in anti-predator behavior, inferred from perch swimming activity, distance to predators, distance to conspecifics, home-range size, and habitat use. In fact, exposure to oxazepam instead stimulated anti-predator behavior (decreased activity, decreased distance to conspecifics, and increased littoral habitat use) when using behavior in the control lake as a reference. Shoal dynamics and temperature changes may have masked modest reductions in anti-predator behavior due to oxazepam. Although we cannot fully resolve the mechanism(s) behind our observations, our results indicate that the effects of oxazepam on perch behavior in a familiar natural ecosystem are negligible in comparison to the effects of other environmental conditions.


Assuntos
Percas , Animais , Ecossistema , Esocidae , Lagos , Oxazepam
14.
J Steroid Biochem Mol Biol ; 205: 105765, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32991989

RESUMO

The aim of this project was to investigate the endocrine disrupting effects of three γ-aminobutyric acid type A receptor (GABAAR) agonists, diazepam (DZ), oxazepam (OX) and alprazolam (AL) using the steroidogenic in vitro H295R cell line assay, a recombinant CYP17A1 assay, qPCR analysis and computational modelling. Similar effects for DZ and OX on the steroidogenesis were observed in the H295R experiment at therapeutically relevant concentrations. Progestagens and corticosteroids were increased up to 10 fold and androgens were decreased indicating CYP17A1 lyase inhibition. For DZ the inhibition on both the hydroxylase and lyase was confirmed by the recombinant CYP17A1 assay, whereas OX did not appear to directly affect the recombinant CYP17A1 enzyme. Androgens were decreased when exposing the H295R cells to AL, indicating a CYP17A1 lyase inhibition. However, this was not confirmed by the recombinant CYP17A1 assay but a down-regulation in gene expression was observed for StAR and CYP17A1. The present study showed that the three investigated benzodiazepines (BZDs) are rather potent endocrine disruptors in vitro, exerting endocrine effects close the therapeutic Cmax. Both direct and indirect effects on steroidogenesis were observed, but molecular modelling indicated no direct interactions between the heme group in the steroidogenic CYP enzymes and the unique diazepin structure. In contrast, physicochemical properties such as high log P, structure and molecular weight similar to that of steroids appeared to influence the endocrine disrupting abilities of the investigated pharmaceuticals in vitro. Docking of the three BZDs in CYP17A1 and CYP21A2 confirmed that shape complementarity and hydrophobic effects seem to determine the binding modes.


Assuntos
Benzodiazepinas/química , Disruptores Endócrinos/química , Esteroide 17-alfa-Hidroxilase/química , Esteroide 21-Hidroxilase/química , Esteroides/biossíntese , Corticosteroides/química , Corticosteroides/farmacologia , Glândulas Suprarrenais/efeitos dos fármacos , Alprazolam/química , Alprazolam/farmacologia , Androgênios/genética , Benzodiazepinas/farmacologia , Diazepam/química , Diazepam/farmacologia , Disruptores Endócrinos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Oxazepam/química , Oxazepam/farmacologia , Receptores Androgênicos/química , Receptores Androgênicos/genética , Receptores de GABA-A/química , Receptores de GABA-A/genética , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 21-Hidroxilase/antagonistas & inibidores , Esteroide 21-Hidroxilase/genética , Esteroides/química
15.
J Anal Toxicol ; 44(9): 985-992, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-32453428

RESUMO

A procedure based on gas chromatography-mass spectrometry was developed for the analysis of benzodiazepines (nordiazepam, oxazepam, lormetazepam, lorazepam, clonazepam, bromazepam and alprazolam) in postmortem human ribs. Powdered bone samples, including marrow remains inside, with the internal standard diazepam-d5 were subjected to enzymatic hydrolysis with 100 µL of ß-glucoronidase and were incubated in sodium hydroxide for 1 h in a 70°C oven. Samples underwent liquid phase extraction and ethyl acetate was used as eluent. Chromatography was performed on a fused silica capillary column and the selected-ion-monitoring mode was used for analytes determination. The method was validated in the range 0.1-0.5 ng/mg (depending on the benzodiazepine) to 100 ng/mg with average values of recovery, matrix effect and process efficiency ranged from 83.2 to 94.3%, from 97.3 to 102.1% and from 80.5 to 91.2%, respectively. The intra- and inter-day accuracy was <15%. The procedure was tested in rib specimens obtained during routine autopsies from 20 cases where these benzodiazepines were found in blood. Benzodiazepines were detected in the combined bone and marrow samples in 60% of cases. Lorazepam was detected in bone in the range of 0.3-0.7 ng/mg, nordiazepam at 1.3-4.2 ng/mg and oxazepam at 1.1-1.2 ng/mg. To our knowledge, this protocol for the simultaneous analysis of these benzodiazepines is the first performed and validated using human ribs.


Assuntos
Benzodiazepinas/análise , Toxicologia Forense/métodos , Cromatografia Gasosa-Espectrometria de Massas , Alprazolam , Autopsia , Cromatografia Líquida , Clonazepam , Diazepam , Humanos , Extração Líquido-Líquido , Lorazepam/análogos & derivados , Nordazepam , Oxazepam , Espectrometria de Massas em Tandem
16.
Aquat Toxicol ; 230: 105694, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33316747

RESUMO

Psychotropics, especially benzodiazepines, are commonly prescribed worldwide. Poorly eliminated at wastewater treatment plants, they belong to a group of emerging contaminants. Due to their interaction with the GABAA receptor, they may affect the function of the nervous system of non-target organisms, such as aquatic organisms. The toxicity of oxazepam, a very frequently detected benzodiazepine in continental freshwater, has been largely studied in aquatic vertebrates over the last decade. However, its effects on freshwater non-vertebrates have received much less attention. We aimed to evaluate the long-term effects of oxazepam on the juvenile stage of a freshwater gastropod widespread in Europe, Radix balthica. Juveniles were exposed for a month to environmentally-relevant concentrations of oxazepam found in rivers (0.8 µg/L) and effluents (10 µg/L). Three main physiological functions were studied: feeding, growth, and locomotion. Additionally, gene expression analysis was performed to provide insights into toxicity mechanisms. There was a strong short-term activation of the feeding rate at low concentration, whereas the high dose resulted in long-term inhibition of food intake. A significant decrease in mortality rate was observed in juveniles exposed to the lowest dose. Shell growth and locomotor activity did not appear to be affected by oxazepam. Transcriptomic analysis revealed global over-expression of genes involved in the nervous regulation of the feeding, digestive, and locomotion systems after oxazepam exposure. The molecular analysis also revealed a possible interference of animal manipulation with the molecular effects induced by oxazepam exposure. Overall, these results improve our understanding of the effects of the psychoactive drug oxazepam on an aquatic mollusc gastropod.


Assuntos
Organismos Aquáticos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Gastrópodes/efeitos dos fármacos , Oxazepam/toxicidade , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Organismos Aquáticos/genética , Organismos Aquáticos/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Gastrópodes/genética , Gastrópodes/crescimento & desenvolvimento , Atividade Motora/efeitos dos fármacos , Oxazepam/análise , Rios/química , Poluentes Químicos da Água/análise
17.
Ther Drug Monit ; 43(2): 143-145, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337586

RESUMO

ABSTRACT: The authors present here a case of a pharmacobezoar after drug overdose, diagnosed using multiple blood samples for TDM. This grand round highlights the importance of a dialog between a clinician and a TDM consultant for the optimal care of a patient.


Assuntos
Bezoares , Overdose de Drogas , Oxazepam/envenenamento , Cloridrato de Venlafaxina/envenenamento , Bezoares/diagnóstico , Overdose de Drogas/diagnóstico , Humanos , Visitas com Preceptor
18.
Cochrane Database Syst Rev ; 12: CD009861, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33319916

RESUMO

BACKGROUND: Anxiety in relation to surgery is a well-known problem. Melatonin offers an alternative treatment to benzodiazepines for ameliorating this condition in the preoperative and postoperative periods. OBJECTIVES: To assess the effects of melatonin on preoperative and postoperative anxiety compared to placebo or benzodiazepines. SEARCH METHODS: We searched the following databases on 10 July 2020: CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science. For ongoing trials and protocols, we searched clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform. SELECTION CRITERIA: We included randomized, placebo-controlled or standard treatment-controlled (or both) studies that evaluated the effects of preoperatively administered melatonin on preoperative or postoperative anxiety. We included adult patients of both sexes (15 to 90 years of age) undergoing any kind of surgical procedure for which it was necessary to use general, regional, or topical anaesthesia. DATA COLLECTION AND ANALYSIS: One review author conducted data extraction in duplicate. Data extracted included information about study design, country of origin, number of participants and demographic details, type of surgery, type of anaesthesia, intervention and dosing regimens, preoperative anxiety outcome measures, and postoperative anxiety outcome measures. MAIN RESULTS: We included 27 randomized controlled trials (RCTs), involving 2319 participants, that assessed melatonin for treating preoperative anxiety, postoperative anxiety, or both. Twenty-four studies compared melatonin with placebo. Eleven studies compared melatonin to a benzodiazepine (seven studies with midazolam, three studies with alprazolam, and one study with oxazepam). Other comparators in a small number of studies were gabapentin, clonidine, and pregabalin. No studies were judged to be at low risk of bias for all domains. Most studies were judged to be at unclear risk of bias overall. Eight studies were judged to be at high risk of bias in one or more domain, and thus, to be at high risk of bias overall. Melatonin versus placebo Melatonin probably results in a reduction in preoperative anxiety measured by a visual analogue scale (VAS, 0 to 100 mm) compared to placebo (mean difference (MD) -11.69, 95% confidence interval (CI) -13.80 to -9.59; 18 studies, 1264 participants; moderate-certainty evidence), based on a meta-analysis of 18 studies. Melatonin may reduce immediate postoperative anxiety measured on a 0 to 100 mm VAS compared to placebo (MD -5.04, 95% CI -9.52 to -0.55; 7 studies, 524 participants; low-certainty evidence), and may reduce delayed postoperative anxiety measured six hours after surgery using the State-Trait Anxiety Inventory (STAI) (MD -5.31, 95% CI -8.78 to -1.84; 2 studies; 73 participants; low-certainty evidence). Melatonin versus benzodiazepines (midazolam and alprazolam) Melatonin probably results in little or no difference in preoperative anxiety measured on a 0 to 100 mm VAS (MD 0.78, 95% CI -2.02 to 3.58; 7 studies, 409 participants; moderate-certainty evidence) and there may be little or no difference in immediate postoperative anxiety (MD -2.12, 95% CI -4.61 to 0.36; 3 studies, 176 participants; low-certainty evidence). Adverse events Fourteen studies did not report on adverse events. Six studies specifically reported that no side effects were observed, and the remaining seven studies reported cases of nausea, sleepiness, dizziness, and headache; however, no serious adverse events were reported. Eleven studies measured psychomotor and cognitive function, or both, and in general, these studies found that benzodiazepines impaired psychomotor and cognitive function more than placebo and melatonin. Fourteen studies evaluated sedation and generally found that benzodiazepine caused the highest degree of sedation, but melatonin also showed sedative properties compared to placebo. Several studies did not report on adverse events; therefore, it is not possible to conclude with certainty, from the data on adverse effects collected in this review, that melatonin is better tolerated than benzodiazepines. AUTHORS' CONCLUSIONS: When compared with placebo, melatonin given as premedication (as tablets or sublingually) probably reduces preoperative anxiety in adults (measured 50 to 120 minutes after administration), which is potentially clinically relevant. The effect of melatonin on postoperative anxiety compared to placebo (measured in the recovery room and six hours after surgery) was also evident but was much smaller, and the clinical relevance of this finding is uncertain. There was little or no difference in anxiety when melatonin was compared with benzodiazepines. Thus, melatonin may have a similar effect to benzodiazepines in reducing preoperative and postoperative anxiety in adults.


ANTECEDENTES: La ansiedad relacionada con la cirugía es un problema conocido. La melatonina ofrece un tratamiento alternativo a las benzodiazepinas para mejorar esta afección en los períodos pre y posoperatorio. OBJETIVOS: Evaluar los efectos de la melatonina en la ansiedad pre y posoperatoria en comparación con el placebo o las benzodiazepinas. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las siguientes bases de datos el 10 de julio de 2020: CENTRAL, MEDLINE, Embase, CINAHL y Web of Science. Para los ensayos y protocolos en curso, se buscó en clinicaltrials.gov y en la Plataforma de registros internacionales de ensayos clínicos de la Organización Mundial de la Salud (OMS). CRITERIOS DE SELECCIÓN: Estudios aleatorizados controlados con placebo o controlados con tratamiento estándar, o ambos, que evaluaron los efectos de la melatonina administrada de forma preoperatoria para la ansiedad preoperatoria o posoperatoria. Se incluyeron pacientes adultos de ambos sexos (15 a 90 años de edad) a los que se les realizó cualquier clase de procedimiento quirúrgico donde fue necesario utilizar anestesia general, regional o tópica. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Un autor de la revisión realizó la extracción de los datos por duplicado. Los datos que se extrajeron incluyeron información acerca del diseño del estudio, el país de origen, el número de participantes y los detalles demográficos, el tipo de cirugía, el tipo de anestesia, la intervención y el régimen de dosis, medidas de desenlace de ansiedad preoperatoria y medidas de desenlace de ansiedad posoperatoria. RESULTADOS PRINCIPALES: Se incluyeron 27 ensayos controlados aleatorizados (ECA), con 2319 participantes, que evaluaron la melatonina para el tratamiento de la ansiedad preoperatoria, la ansiedad posoperatoria o ambas. Veinticuatro estudios compararon la melatonina con el placebo. Once estudios compararon la melatonina con una benzodiazepina (siete estudios con midazolam, tres estudios con alprazolam y un estudio con oxazepam). Otros comparadores en un escaso número de estudios fueron la gabapentina, la clonidina y la pregabalina. No se consideró que ningún estudio tuviera un riesgo bajo de sesgo en todos los dominios. La mayoría de los estudios se consideraron con riesgo incierto de sesgo en general. Se consideró que ocho estudios tenían un alto riesgo de sesgo en uno o más dominios y, por lo tanto, un alto riesgo de sesgo en general. Melatonina versus placebo La melatonina probablemente da lugar a una reducción de la ansiedad preoperatoria medida por una escala visual analógica (EVA, 0 a 100 mm) en comparación con el placebo (diferencia de medias [DM] ­11,69; intervalo de confianza [IC] del 95%: ­13,80 a ­9,59; 18 estudios, 1264 participantes; evidencia de certeza moderada), sobre la base de un metanálisis de 18 estudios. La melatonina podría reducir la ansiedad posoperatoria inmediata medida en una EVA de 0 a 100 mm en comparación con el placebo (DM ­5,04; IC del 95%: ­9,52 a ­0,55; siete estudios, 524 participantes; evidencia de certeza baja), y podría reducir la ansiedad posoperatoria tardía medida seis horas después de la cirugía mediante el State­Trait Anxiety Inventory (STAI) (DM ­5,31; IC del 95%: ­8,78 a ­1,84; dos estudios; 73 participantes; evidencia de certeza baja). Melatonina versus benzodiazepinas (midazolam y alprazolam) La melatonina probablemente da lugar a poca o ninguna diferencia en la ansiedad preoperatoria medida en una EVA de 0 a 100 mm (DM 0,78; IC del 95%: ­2,02 a 3,58; siete estudios, 409 participantes; evidencia de certeza moderada) y podría haber poca o ninguna diferencia en la ansiedad posoperatoria inmediata (DM ­2,12; IC del 95%: ­4,61 a 0,36; tres estudios, 176 participantes; evidencia de certeza baja). Eventos adversos Catorce estudios no informaron sobre los eventos adversos. Seis estudios informaron específicamente que no se observaron efectos secundarios y los siete estudios restantes informaron casos de náuseas, somnolencia, mareos y cefalea; sin embargo, no se informaron eventos adversos graves. Once estudios midieron la función psicomotora y cognitiva, o ambas, y en general, estos estudios encontraron que las benzodiazepinas deterioraron la función psicomotora y cognitiva más que el placebo y la melatonina. Catorce estudios evaluaron la sedación y en general encontraron que la benzodiazepina causaba el mayor grado de sedación, pero la melatonina también mostró propiedades sedantes en comparación con el placebo. Varios estudios no informaron sobre los efectos adversos; por lo tanto, no es posible concluir con certeza, a partir de los datos sobre los efectos adversos obtenidos en esta revisión, que la melatonina se tolera mejor que las benzodiazepinas. CONCLUSIONES DE LOS AUTORES: Cuando se compara con el placebo, la melatonina administrada como premedicación (en forma de comprimidos o sublingual) probablemente reduce la ansiedad preoperatoria en los adultos (medida entre 50 y 120 minutos después de la administración), lo que es potencialmente relevante desde el punto de vista clínico. El efecto de la melatonina sobre la ansiedad posoperatoria en comparación con el placebo (medido en la sala de recuperación y seis horas después de la cirugía) también fue evidente, pero fue mucho menor, y la relevancia clínica de este hallazgo no está clara. Hubo poca o ninguna diferencia en la ansiedad cuando la melatonina se comparó con las benzodiazepinas. Por lo tanto, la melatonina puede tener un efecto similar al de las benzodiazepinas en la reducción de la ansiedad pre y posoperatoria en los adultos.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Melatonina/uso terapêutico , Procedimentos Cirúrgicos Operatórios/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alprazolam/uso terapêutico , Ansiolíticos/efeitos adversos , Viés , Clonidina/uso terapêutico , Esquema de Medicação , Humanos , Melatonina/efeitos adversos , Midazolam/uso terapêutico , Pessoa de Meia-Idade , Oxazepam/uso terapêutico , Cuidados Pós-Operatórios , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/psicologia , Cuidados Pré-Operatórios , Viés de Publicação , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
AAPS J ; 22(6): 128, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033903

RESUMO

Physiologically based pharmacokinetic (PBPK) modeling is less well established for substrates of UDP-glucuronosyltransferases (UGT) than for cytochrome P450 (CYP) metabolized drugs and more verification of simulations is necessary to increase confidence. To address specific challenges of UGT substrates, we developed PBPK models for four drugs cleared majorly via glucuronidation (lorazepam, oxazepam, naloxone, and zidovudine). In vitro to in vivo scaling of intrinsic clearance generated with co-cultured human hepatocytes was applied for hepatic metabolism and extra-hepatic clearance was extrapolated based on relative expression of UGT isoforms in the liver, kidney, and intestine. Non-metabolic clearance and the contributions of individual UGT isoforms to glucuronidation were based on in vitro and in vivo studies taken from the literature and simulations were verified and evaluated with a broad set of clinical pharmacokinetic data. Model evaluation showed systemic clearance predictions within 1.5-fold for all drugs and all simulated parameters were within 2-fold of observed. However, during the verification step, top-down model fitting was necessary to adjust for under-prediction of zidovudine VSS and renal clearance and over estimation of intestinal first pass for lorazepam, oxazepam, and zidovudine. The impact of UGT2B15 polymorphisms on the pharmacokinetics of oxazepam and lorazepam was simulated and glucuronide metabolites were also simulated for all four drugs. To increase confidence in predicting extra-hepatic clearance, improvement of enzyme phenotyping for UGT substrates and more quantitative tissue expression levels of UGT enzymes are both needed. Prediction of glucuronide disposition is also challenging when active transport processes play a major role.


Assuntos
Glucuronosiltransferase/metabolismo , Taxa de Depuração Metabólica/fisiologia , Modelos Biológicos , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Idoso , Técnicas de Cultura de Células , Células Cultivadas , Técnicas de Cocultura , Conjuntos de Dados como Assunto , Feminino , Glucuronídeos/metabolismo , Hepatócitos , Humanos , Intestinos/enzimologia , Rim/enzimologia , Fígado/enzimologia , Lorazepam/farmacocinética , Masculino , Microssomos Hepáticos , Pessoa de Meia-Idade , Naloxona/farmacocinética , Oxazepam/farmacocinética , Adulto Jovem , Zidovudina/farmacocinética
20.
Am J Psychiatry ; 177(6): 497-505, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32252539

RESUMO

OBJECTIVE: Benzodiazepines and Z-drugs are two of the most prescribed agents worldwide. However, because of their cognitive side effects, the question of their influence on the risk of dementia has been raised. The authors examined the association of benzodiazepines, Z-drugs, and other anxiolytics with incident dementia in patients with affective disorders. METHODS: The authors conducted a cohort and nested case-control study of 235,465 patients over age 20 who were identified in the Danish National Patient Registry as having had a first-time hospital contact for an affective disorder between 1996 and 2015. From the Danish National Prescription Registry, information was obtained on all prescriptions for benzodiazepines, Z-drugs, and other anxiolytics, and patients were followed for incident dementia (defined by hospital discharge diagnosis or acetylcholinesterase inhibitor use). Cox proportional hazards and conditional logistic regression models were used to calculate hazard ratios and odds ratios with adjustment for sociodemographic and clinical variables. RESULTS: A total of 75.9% (N=171,287) of patients had any use of benzodiazepines or Z-drugs, and during the median follow-up of 6.1 years (interquartile range, 2.7-11), 9,776 (4.2%) patients were diagnosed with dementia. Any use of benzodiazepines or Z-drugs showed no association with dementia after multiple adjustments in either the cohort analysis or a nested case-control design. In the cohort analysis, the number of prescriptions and the cumulated dose of benzodiazepines or Z-drugs at baseline were not associated with dementia. In the nested case-control study, where prescriptions were counted from 1995 until 2 years before the index date, there was a slightly higher odds ratio of dementia in patients with the lowest use of benzodiazepines or Z-drugs (odds ratio=1.08, 95% CI=1.01, 1.15) compared with no lifetime use. However, patients with the highest use had the lowest odds of developing dementia (odds ratio=0.83, 95% CI=0.77, 0.88). CONCLUSIONS: This large cohort study did not reveal associations between use of benzodiazepines or Z-drugs and subsequent dementia, even when exposures were cumulated or divided into long- and short-acting drugs. Some results were compatible with a protective effect.


Assuntos
Ansiolíticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Transtorno Bipolar/epidemiologia , Demência/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Estudos de Casos e Controles , Comorbidade , Dinamarca/epidemiologia , Transtorno Depressivo/epidemiologia , Transtorno Depressivo Maior/tratamento farmacológico , Diazepam/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipnóticos e Sedativos/uso terapêutico , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/epidemiologia , Razão de Chances , Oxazepam/uso terapêutico , Piperazinas/uso terapêutico , Modelos de Riscos Proporcionais , Fatores de Proteção , Fatores de Risco
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