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Purpose To study trends in incident use of benzodiazepines in France between 2006 and 2012. Methods A cross-sectional study repeated yearly was conducted using data from the French national healthcare insurance system. New benzodiazepine users were defined as users without any benzodiazepine dispensing in the year prior to the first dispensing of benzodiazepine in each year. Relative changes in incidence of use were calculated with the year 2006 as reference; confidence intervals for changes were estimated using the bootstrap method. Results Over the study period, the incident use of benzodiazepines decreased from 6.2% to 5.9%; this corresponded to a 5.1% decrease (95%CI: −6.8% to −4.2%) for 2012 compared to 2006. The decrease mainly concerned hypnotics (−15.5%; −21.2% to −15.3%) and appeared more pronounced in people aged 18–44 years. Incident use of anxiolytics remained stable overall during the period (4.0% of the population). Within anxiolytics, incident use of long half-life benzodiazepines (bromazepam, prazepam) decreased in favor of short half-life benzodiazepines (alprazolam, oxazepam). This change concerned patients aged 65–79 and patients aged 80 years and over. Nevertheless, in 2012, nearly one third of incident users aged 65 years and over started a treatment with a long half-life benzodiazepine, mostly bromazepam. Conclusions A limited decrease in incident benzodiazepine use was observed in France between 2006 and 2012 that concerned only hypnotics. Although congruent with recommendations, this improvement appears insufficient with regard to the level of exposure to these drugs in France. New actions especially targeting anxiolytic benzodiazepine use should be undertaken to consolidate these results. Copyright © 2016 John Wiley & Sons, Ltd.

The electrochemical behaviour of 1,4-benzodiazepines (bromazepam and alprazolam) was studied in Britton–Robinson (BR) buffer using cyclic voltammetry and differential pulse voltammetry on carbon paste electrode (CPE). Functional group of benzodiazepines is irreversibly reduced by the help of two electrons and two protons and the electrode process is controlled by adsorption (bromazepam), respectively, by diffusion (alprazolam) on CPE. The optimal conditions were found for their determination in the BR of pH 3 within concentration range from 8 × 10−7 to 1 × 10−4 mol dm−3. Limit of quantification 3.8 × 10−7 and 4.2 × 10−7 mol dm−3 was calculated for bromazepam and alprazolam, respectively. The proposed voltammetric method was applied to analysis of benzodiazepines (BDZs) in the pharmaceutical preparations Lexaurin® and Xanax® with recovery 94.9 % and relative standard deviation (RSD) 2.21 % for bromazepam and recovery 94.5 % with RSD 2.9 % for alprazolam.

Several model organisms have been employed to study the impacts of stress on biological systems. Different models of unpredictable chronic stress (UCS) have been established in rodents; however, these protocols are expensive, long-lasting, and require a large physical structure. Our group has recently reported an UCS protocol in zebrafish with several advantages compared to rodent models. We observed that UCS induced behavioral, biochemical, and molecular changes similar to those observed in depressed patients, supporting the translational relevance of the protocol. Considering that a pharmacological assessment is lacking in this zebrafish model, our aim was to evaluate the effects of anxiolytic (bromazepam) and antidepressant drugs (fluoxetine and nortriptyline) on behavioral (novel tank test), biochemical (whole-body cortisol), and molecular parameters (cox-2, tnf-α, il-6, and il-10 gene expression) in zebrafish subjected to UCS. We replicated previous data showing that UCS induces behavioral and neuroendocrine alterations in zebrafish, and we show for the first time that anxiolytic and antidepressant drugs are able to prevent such effects. Furthermore, we extended the molecular characterization of the model, revealing that UCS increases expression of the pro-inflammatory markers cox-2 and il-6, which was also prevented by the drugs tested. This study reinforces the use of zebrafish as a model organism to study the behavioral and physiological effects of stress. The UCS protocol may also serve as a screening tool for evaluating new drugs that can be used to treat psychiatric disorders with stress-related etiologies.

Background/Aim. Benzodiazepines are among the most frequently ingested drugs in self-poisonings. Elderly may be at greater risk compared with younger individuals due to impaired metabolism and increased sensitivity to benzodiazepines. The aim of this study was to assess toxicity of benzodiazepines in elderly attempted suicide. Methods. A retrospective study of consecutive presentations to hospital after self-poisoning with benzodiazepines was done. Collected data consisted of patient's characteristics (age, gender), benzodiazepine ingested with its blood concentrations at admission, clinical findings including vital signs and Glasgow coma score, routine blood chemistry, complications of poisoning, details of management, length of hospital stay and outcome. According the age, patients are classified as young (15-40-year old), middle aged (41-65-year old) and elderly (older than 65). Results. During a 2-year observational period 387 patients were admitted because of pure benzodiazepine poisoning. The most frequently ingested drug was bromazepam, the second was diazepam. The incidence of coma was significantly higher, and the length of hospital stay significantly longer in elderly. Respiratory failure and aspiration pneumonia occurred more frequently in old age. Also, flumazenil was more frequently required in the group of elderly patients. Conclusion. Massive benzodiazepines overdose in elderly may be associated with a significant morbidity, including deep coma with aspiration pneumonia, respiratory failure, and even death. Flumazenil is indicated more often to reduce CNS depression and prevent complications of prolonged unconsciousness, but supportive treatment and proper airway management of comatose patients is the mainstay of the treatment of acute benzodiazepine poisoning.

Introduction. Takayasu arteritis (TA) is a rare large vessel arteritis, affecting primarily aorta and its major branches. Its clinical manifestations can vary significantly - from asymptomatic to serious vascular events. Acute neurological complications are frequent at the onset of the disease and in relapses. Anxiety and depression are more frequent in TA patients than in general population as well as during relapses. Prevalence of transient ischemic attack or ischemic stroke in TA patients is approximately 10-20%. Case report. We presented a patient with TA that began with a depressive episode resulting in attempted suicide by bromazepame poisoning. This was subsequently followed by major ischemic stroke caused by thrombosis of the left middle cerebral artery (probably due to aortic arch embolism) successfully treated with intravenous thrombolysis. Conclusion. Intravenous thrombolysis appears to be safe and effective in patients with TA and stroke.

Four simple, sensitive and selective stability indicating spectrophotometric methods are presented for quantitative determination of the benzodiazepine drug; bromazepam (BMZ) and one of its reported potential impurities and degradation product; 2-(2-amino-5-bromobenzoyl) pyridine (ABP) in methanol. Method A, is isoabsorptive point coupled with D0 method, where good linearity was obtained by measuring the absorbance of BMZ at 264 nm (Aiso) in the concentration range of 2–25 μg mL−1, and the absorbance of ABP at its λmax 396 nm in concentration range of 0.5–24 μg mL−1. Method B, is ratio subtraction; the absorbance was measured at 233 nm for BMZ using 20 μg mL−1 of ABP, while ABP was determined directly at its λmax 396 nm using methanol as a solvent. Method C, was based on measuring the total peak amplitude of the first derivative of the ratio spectra (DD1) of BMZ from 301 to 326 nm using 10 μg mL−1 of ABP as a divisor and determination of ABP at peak amplitude of 293 nm using 5 μg mL−1 of BMZ as a divisor. In method D, ratio difference method, good linearity was achieved for determination of BMZ and ABP by measuring the differences between the amplitudes of ratio spectra at 312 nm and 274 nm and differences between the amplitudes of ratio spectra at 274 nm and 312 nm, respectively. The stability of BMZ was investigated under different ICH recommended forced degradation conditions. The suggested methods were then successfully applied for determination of BMZ in its pharmaceutical formulations.

Although information exists regarding the rate of benzodiazepines (BZDs) use in different countries, little information is available concerning the BZDs consumption in Morocco. To describe prescription rate in Morocco, a retrospective descriptive analysis of BZDs and their agonists use with the instituteIQIVIA database was performed during the period 2004-2017. The obtained data provide a dynamic approach to total BZDs consumption using an annual collection of sales data in Morocco and were expressed in terms of daily defined doses/ 1000 inhabitants / day. Data analysis showed that the major BZDs sold in Morocco were Alprazolam, Bromazepam, Nordazepam, Lorazepam, Parazepam, Diazepam and two benzodiazepine agonists, Zolpidem and Zopiclone. The Bromazepam was the molecule the most consumed during 2004-2016. In 2017, Alprazolam was the most consumed followed by Bromazepam, Nordazepam, Zolpidem, Lorazepam, Parazepam, Diazepam, Dipotassium clorazepate, Dipotassium Clorazypate and Zopiclone with 0.94, 0.91, 0.6, 0.55, 0.45, 0.32, 0.18, 0.18, 0.07 and 0.05 daily defined doses/ 1000 inhabitants / day respectively. The total amount consumed each year for all BZDs and their agonists in Morocco was 2.69, 2.77, 3, 3.17, 3.32, 3.54, 3.61, 3.81, 4.06, 4.30, 4.06, 3.94, 3.78 and 3.66 daily defined doses/ 1000 inhabitants / day, respectively during 2004-2017. To our knowledge, this is the first study that describes the consumption of BZDs and their agonists (Zolpidem, Zopiclone) in Morocco. This data may help the analytical toxicology laboratory and health organizations operating in the field of analytical biochemistry to develop specific BZDs quantification and detection methods needed for the Moroccan population.

The development of analytical methods capable of determining micropollutants is essential for quality control of drinking water. Benzodiazepines, a class of pharmaceuticals with anxiolytic properties, have received increasing attention as micropollutants. The purpose of this study was to develop an analytical method for determination of three benzodiazepine drugs (bromazepam, clonazepam and diazepam) in surface water. For the extraction of the matrix analytes, SPE cartridges (C18, 500 mg/3 mL) were used. The method was validated according to the quality criteria of the USEPA 8000D Validation Guide. The developed and validated method showed recovery values between 57 and 100%, RSD 0.9949. LD ranged between 2.70 and 5.00 ng L−1 for bromazepam and clonazepam respectively whereas LQ was 0.01 μg L−1 for all analytes. The matrix affected the signal intensity of clonazepam thus evidencing the matrix effect by analysis statistic (F test).

This study analysed the quality of information published on the internet regarding 4 benzodiazepines that are widely used in Brazil: alprazolam, bromazepam, clonazepam and diazepam. This choice is justified by the fact that these drugs are widely used and can generate chemical dependency, and the internet is an important source of information about them. We analysed 20 sites for each drug. More than half (56.3%) of the sites were classified as deficient or very deficient. The most frequent problems with the sites were the absence of a description of the person responsible for the site (60%), incomplete information (62.5%), the absence of a contact for additional information (45%) and the absence of the last date the site was updated (82%). These results reinforce concerns regarding the quality of the health information published on the internet, which has already been noted in the literature, and the need to adopt minimum quality criteria for this information.Este trabalho analisou a qualidade da informação veiculada na internet sobre 4 benzodiazepínicos amplamente utilizados no Brasil: alprazolam, bromazepam, clonazepam e diazepam. Essa escolha se justifica pelo fato desses medicamentos serem amplamente utilizados, poderem gerar dependência química e a internet ser importante fonte de informação sobre eles. Foram analisados 20 sites para cada medicamento. Mais da metade (56,3%) dos sites foram classificados como deficientes ou muito deficientes. Os problemas mais frequentes foram a ausência da descrição do responsável pelo sítio (60%), informação incompleta (62,5%), ausência de contato para informação adicional (45%) e da última data da atualização (82%). Os resultados reforçam a preocupação com a qualidade da informação em saúde veiculada na internet, já apontada pela literatura, e a necessidade de adoção de critérios mínimos de qualidade para esta informação.

Anxiety disorders (ADs) constitute one of the most common mental disorders and are characterized by anxiety, which is a fundamental psychological condition of life, pathological. TAs negatively affect the life of an individual and of the people with whom he lives, damaging the performance of everyday activities and social relationships. Even though there are some classes of anxiolytics in the clinic, many patients are relapsed or nonresponsive. In this scenario, the aim of this work was to synthesize, characterize and evaluate the anxiolytic properties of [{2- (7-Bromo-2-oxo-1,3-dihydro-2H-1,4-benzodiazepin-5-yl) 2-N, N-chloropalladium(II)], [(BMZ)PdCl2]. In this sense, the synthesis of the palladium (II) complex derived from bromazepam was performed with satisfactory yield, 75%. To understand the chemistry of the ligand as well as the complex obtained, two characterization techniques were used in which the ligand and the complex were subjected toNMR of 13C, 1H and HSQC analyzes. In addition, the complex was also characterized by the infrared (IR) technique and mass spectrometry coupled to gas chromatography (GC-MS). The results obtained from the NMR allowed to infer that the complex presented monomeric structure; the N4 and the pyridine N13 of the linker are the atoms that coordinate with the Pd(II). The IR allowed the detection of frequencies of stretches characteristic of the binder found also in the complex. The MS revealed the fragments of the complex. Regarding the anxiolytic activity, it was observed that the complex at the lowest dose (0.5 μg/kg) presented a significant reduction in the anxiety of the mice subjected to the plus maze test in relation to the control group (saline group), without causing alteration of the locomotor activity, and the analysis of the motor activity was also confirmed by the open field test. Likewise, it was possible to determine that the anxiolytic action of the complex occurs via GABAA receptor, since the animals that received pre-treatment with flumazenil and were treated with the complex did not present anxiolytic activity. Thus, the present study demonstrated that the [(BMZ)PdCl2] complex proved promising to the anxiolytic action, thus motivating those in the Catalysis and Chemical Reactivity Group (GCaR, Grupo de Catálise e Reatividade Química, em português) to seek a better understanding of this complex and probable analogs in the treatment of anxiety disorders. CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Os transtornos de ansiedade (TAs) configuram como um dos transtornos mentais mais comum, sendo caracterizados por uma ansiedade, que é uma condição psicológica fundamental a vida, patológica. Os TAs afetam negativamente a vida de um indivíduo e das pessoas com quem ele convive, trazendo prejuízos na execução das atividades do dia-a-dia e nos relacionamentos sociais. Mesmo existindo algumas classes de ansiolíticos na clínica, muito pacientes são recidivados ou não responsivos. Neste cenário suscitou o desenvolvimento deste trabalho que tem como objetivo sintetizar, caracterizar e avaliar as propriedades ansiolíticas do [{2-(7-Bromo-2-oxo-1,3-diidro-2H-1,4-benzodiazepin5-il)piridinil-κ2-N,N}cloropaládio(II)], [(BMZ)PdCl2]. Neste sentido, a síntese do complexo de paládio(II) derivado do bromazepam foi realizada com rendimento satisfatório, 75%. Para compreender a química do ligante, bem como do complexo obtido, foram utilizadas duas técnicas de caracterização, no qual o ligante e o complexo foram submetidos à análises por RMN de 13C, de 1H e HSQC. Além disso, o complexo também foi caracterizado pela técnica do infravermelho (IV) e por espectrometria de massas acoplada a cromatografia gasosa (CG-EM). Os resultados obtidos da RMN possibilitaram inferir que o complexo apresentou estrutura monomérica; o N4 e o N13 piridínico do ligante são os átomos que coordenam com o Pd(II). O IV possibilitou a detecção de frequências de estiramentos características do ligante encontradas também no complexo. Já a EM revelou os fragmentos referentes ao complexo. Em relação à atividade do tipo ansiolítica, foi observado que o complexo na menor dose (0,5 μg/kg) apresentou uma redução significativa na ansiedade dos camundongos sujeitos ao teste do labirinto em cruz elevado em relação ao grupo controle (grupo salina), sem causar alteração da atividade locomotora, sendo que a análise da atividade motora também foi confirmada pelo teste do campo aberto. Da mesma forma, foi possível determinar que a ação ansiolítica do complexo acontece via receptor GABAA, pois os animais que receberam pré-tratamento com flumazenil e foram tratados com o complexo não apresentaram atividade ansiolítica. Assim, o presente estudo demonstrou que o complexo [(BMZ)PdCl2] se mostrou promissor à ação ansiolítica, motivando assim aos que fazem parte do Grupo de Catálise e Reatividade Química (GCaR) a buscar o melhor entendimento deste complexo e de prováveis análogos no tratamento dos transtornos de ansiedade.

The consumption of psychoactive pharmaceuticals has increased worldwide, and wastewater treatment plants are not able to eliminate them from the effluent. An extensive review was carried out to assess the environmental risk (ERA model) based on secondary data about potential impacts on non-target organisms of seven psychoactive drugs consumed worldwide (alprazolam, bromazepam, citalopram, clonazepam, diazepam, lorazepam, and oxazepam). Risk quotients (RQs) were calculated according to the European Medicines Agency (EMA) on ERA of Medicinal Products For Human Use based on (i) the predicted and measured environmental concentrations (PEC and MEC, respectively) of the psychoactive drug in surface water, groundwater, and wastewater effluent and (ii) the predicted no-effect concentration (PNEC) derived from ecotoxicological assays or ECOSAR software. Furthermore, this study reviews and discusses non-standardized ecotoxicity assays, such as sublethal and behavioral effects on different organisms. In total, 903 MEC entries of psychoactive drugs and 162 data on ecotoxicological assays were gathered from the literature survey addressing behavioral effects (115), acute/chronic effects (35), and sublethal effects (12). Citalopram and diazepam were the only substances that are likely to pose an environmental risk (RQ > 1) to surface waters. Even though there is considerable amount of data on behavioral effects of psychoactive drugs to aquatic species, results are currently not integrated into the EMA risk assessment framework. The large amount of data on psychoactive drug concentrations and effects on non-target organisms collected, interpreted, and discussed in the present study should be used as a baseline for future improvement of ERA strategies.

Long-term treatment with benzodiazepines (BZD) should be avoided in dementia patients because of an increased risk of adverse events. We evaluated how continuously dementia patients were prescribed BZD over 12 months. For this observational study, we used claims data from a large German public sickness fund for 2014 and 2015, including patients with an incident diagnosis of dementia in 2014. The aim was to evaluate the continuity of treatment, the frequency of BZD prescriptions and defined daily doses were evaluated. In total, 1298 (5.6%) patients received 4.7±5.2 BZD prescriptions in 2015 on average. Thereof, lorazepam (47.5%), oxazepam (18.6%), diazepam (14.5%), and bromazepam (12.2%) were most often prescribed. 30.7% of the patients received at least one BZD prescription in each quarter of 2015. Although the total number of patients receiving BZD decreased in 2015, defined daily doses for single substances remained mainly unchanged. The incident diagnosis of dementia was not associated with modifications of prescription behavior. The treatment with BZD was not discontinued in a large proportion of dementia patients, increasing the risk of adverse events. Physicians' awareness of avoiding BZD should be improved and further evidence for the appropriate treatment of psychiatric symptoms in dementia (e.g. sleep disturbances, anxiety) is required.

The liquid chromatography-mass spectrometry (LC-MS) analysis of complex samples such as biological fluid extracts is widespread when searching for new biomarkers as in metabolomics. The success of this hyphenation resides in the orthogonality of both separation techniques. However, there are frequent cases where compounds are co-eluting and the resolving power of mass spectrometry (MS) is not sufficient (e.g., isobaric compounds and interfering isotopic clusters). Different strategies are discussed to solve these cases and a mixture of eight compounds (i.e., bromazepam, chlorprothixene, clonapzepam, fendiline, flusilazol, oxfendazole, oxycodone, and pamaquine) with identical nominal mass (i.e., m/z 316) is taken to illustrate them. Among the different approaches, high-resolution mass spectrometry or liquid chromatography (i.e., UHPLC) can easily separate these compounds. Another technique, mostly used with low resolving power MS analyzers, is differential ion mobility spectrometry (DMS), where analytes are gas-phase separated according to their size-to-charge ratio. Detailed investigations of the addition of different polar modifiers (i.e., methanol, ethanol, and isopropanol) into the transport gas (nitrogen) to enhance the peak capacity of the technique were carried out. Finally, a complex urine sample fortified with 36 compounds of various chemical properties was analyzed by real-time 2D separation LC×DMS-MS(/MS). The addition of this orthogonal gas-phase separation technique in the LC-MS(/MS) hyphenation greatly improved data quality by resolving composite MS/MS spectra, which is mandatory in metabolomics when performing database generation and search.

psychotropic medicines: bromazepam, nitrazepam, and triazolam. analysis using thin layer chromatography and high performance liquid chromatography methods aim: To optimize thin-layer chromatography and high-performance liquid chromatography methods for bromazepam, nitrazepam, triazolam and their mixture qualitative analysis. results: - This mobile phase is suitable for examined substances separation, the qualitative analysis in mixture and determination in pharmaceutical products. -HPLC methodic is suitable for examined substances separation, the qualitative analysis in mixture and determination in pharmaceutical products. methodics: - High performance liquid chromatography(HPLC) : HPLC method bromazepam, nitrazepam, triazolam and their mixture solutions of 0, 1 mg/ml in methanol were analyzed. Chromatograph with a photodiode array detector at wavelength 240 nm range and chromatographic column ACE C18 (5.0 cm x 2.1 mm) with sorbent particle size 5 μm were used for qualitative determination. The analysis was performed by using 0, 1 mol/L sulfuric acid-methanol – acetonitrile (7:8:9) mixture as eluent. Optimized methodic was applied in the analysis of pharmaceutical products “Bromazepam Lannacher” (G.L. Pharma GmbH), “Eunoctin” (Gedeon Richter Plc,), “Halcion” (Pfizer H.C.P) (authorized in LT medicines) test solutions in 0.1% sulphuric acid: ACN solvents. HPLC method was performed using ACE C18 (5.0 cm x 2.1 mm) chromatographic column. Gradient elution mode was used (a mixture of 0, 1% sulfuric acid buffer solvent and ACN solvent – as eluent). Flow rate 1 ml/min. Injection volume 10 μl. Photodiode array detector (200- 600 nm wavelength). Bromazepam, nitrazepam, triazolam absorption of UV light was similar as in scientific literature - Thin layer chromatography (TLC) : For optimization of TLC method bromazepam, nitrazepam, triazolam and their mixture solutions in methanol were analyzed. For mobile phase were used: cyclohexane, methanol, diethylamine, sulfuric acid, acetonitrile (solvents). For spots visualization was used: UV light lamp (254 nm; 365nm). Optimized methodic was applied for pharmaceutical products “Bromazepam Lannacher” (G.L. Pharma GmbH), “Eunoctin” (Gedeon Richter Plc,), “Halcion” (Pfizer H.C.P) (authorized in LT medicines) test solutions in cyclohexane-methanol-diethylamine (75:15:10) solvent system. The best mobile phases for bromazepam, nitrazepam and triazolam mixture qualitative analysis using TLC was: “Cyclohexane-methanol-diethylamine (75:15:10) solvents system with an appropriate ratio

Background: The introduction of monolithic rods and core-shell particles as new morphologies of packing materials different from the conventional totally porous particles resulted in a leap forward for performance in LC. Meanwhile, environmental safety has become increasingly important in many areas, especially in industry and research laboratories. Objective: This study compared the efficiencies of commercially available columns of different lengths and diameters when greener chromatographic conditions were utilized. The main purpose of this study is to help practitioners select the most appropriate stationary phase for faster and greener analysis. Methods: The three types of stationary phases were compared in terms of separation efficiency, number of theoretical plates, peak shape, selectivity, resolution, analysis time, mobile phase consideration, and permeability using six drug molecules. Results: Results indicated that core-shell and monolithic stationary phases had superiority over the conventional totally porous particles in terms of efficiency and speed of analysis. Monolithic rods had lower column backpressure and higher permeability, so they are more suitable for higher mobile phase flow rates and viscosities. However, core-shell particles provided enhanced peak shapes and number of theoretical plates. Conclusions: The choice will depend on the main purpose of analysis and the composition of the mobile phase. Compromise must be made to obtain the best trade-off between separation efficiency and analysis speed. Highlights: This study is the first to consider green chromatography concepts for the selection of the best stationary phase of new morphologies.

This study investigated the occurrence of four non-steroidal anti-inflammatory drugs (NSAIDs) and four benzodiazepines/anti-depressants (ADs) in municipal wastewater in Mardan city, Pakistan, and in River Kabul and River Indus receiving untreated sewage. Liquid chromatography with a triple quadrupole tandem mass spectrometry (LC-MS/MS) was used for the analysis of paracetamol, diclofenac, ibuprofen, and codeine (NSAIDs) and diazepam, bromazepam, lorazepam, and temazepam (ADs). Except codeine and lorazepam, all the target compounds were observed in sewage and surface water in various concentrations. In sewage, paracetamol was found at the higher end (32.4 μg/L) of the reported ranges in literature for other countries. Results of river samples showed that the target compounds were usually lower in concentration than the respective EC50 values for aquatic organisms. However, the levels for paracetamol and ibuprofen were critical depicting the consequence of untreated disposal. Environmental risk assessment by estimating the risk quotient (RQ) as the ratio of measured environmental concentration and predicted no-effect concentration showed medium to high (RQ > 1 and 0.1

Objectives Description of a fatal intoxication due to Kratom, including results of mitragynine quantitative analysis. Case history A 36-year-old man with a history of heroin, cocaine and drug (oxazepam and bromazepam) use was found dead in his bed. A plastic bag containing 50 g of an unidentified green powder was found near the corpse. The results of the autopsy revealed asphyxia with pulmonary edema, pancreatitis and petechial gastritis. Methods Toxicological screening was performed for ethanol, drugs and drugs of abuse by LC-MS/MS and GC-MS, in biological samples (peripheral blood, urine, gastric fluid, bile) and powder. Furthermore, compounds identified by screening were quantified in blood by LC-MS/MS. Results Mitragynine was identified in blood, urine and powder. A lethal concentration of mitragynine and oxazepam was found, associated with cocaine and central nervous system depressants (methadone, morphine, bromazepam). The postmortem peripheral blood concentrations are presented in Table 1 . Conclusion Kratom (Mitragyna speciosa), a plant traditionally used in Southeast Asia for its medicinal value in treating diarrhoea, fever or pain, is now popular in Western countries as a recreational drug or as a self-treatment for opioid dependence. Mitragynine, the main alkaloid found in Kratom, is an opiate mu receptor agonist and kappa receptor antagonist. It is described to produce stimulant effects at low doses, and sedative and/or euphoric effects at high doses. An increasing number of deaths is reported after Kratom use, especially in association with other central nervous system depressant drugs, with mitragynine concentrations ranging from 16 to 4800 ng/mL [1] . In this case, mitragynine and oxazepam were found in lethal concentration and were associated with other depressants of the central nervous system (methadone, morphine, bromazepam). Corroborated by the asphyxia syndrome observed at autopsy, all these data were in favor of the causal role of Kratom in the death.

A reversed-phase HPLC method was developed and validated for the determination of Bromazepam and its degradation products. The acidic hydrolysis of Bromazepam was carried out in 1N hydrochloric acid solution while the alkaline hydrolysis was carried out in 1N sodium hydroxide solution both at 95°C.Two degradation products were isolated and identi?ed by mass spectroscopy. Spectroscopic data indicated that (2-amino-5-bromophenyl)(pyridine-2-yl) methanone was the degradation product of this acid hydrolysis, whereas 4-bromobenzene- 1,2-diol was the degradation product of the alkaline hydrolysis. A mobile phase consisting Phosphate buffer pH 3.5 Acetonitrile (82:18 v/v) was used, and separation was done on a Zorbax Column C18 dimension 250x 4.6mm, particle size 5µ. Using A flow rate of 1 ml.min-1 while detection wavelength was 240.0nm.Retention times were 3.65, 2.60 and 1.85 for intact Bromazepam, acid and alkaline induced ion products respectively. The method showed good linearity in the concentration range of 20–100 µgmL−1. The intra- and interassay precision RSD% were 0.256 and 0.756 respectively .Statistical comparison between the results obtained for the analysis of Bromazepam in pure form and the reported HPLC method showed that values of the calculated t and F are less than the tabulated ones, which reveals that there is no significant difference between the compared methods with respect to accuracy and precision

Objective Our aim was to investigate and compare the neuromodulatory effects of bromazepam (6 mg) and modafinil (200 mg) during a sensorimotor task analyzing the changes produced in the absolute alpha power.Method The sample was composed of 15 healthy individuals exposed to three experimental conditions: placebo, modafinil and bromazepam. EEG data were recorded before, during and after the execution of the task. A three-way ANOVA was applied, in order to compare the absolute alpha power among the factors: Group (control, bromazepam and modafinil) Condition (Pre and Post-drug ingestion) and Moment (pre and post-stimulus).Results Interaction was found between the group and condition factors for Fp1, F4 and F3. We observed a main effect of moment and condition for the Fp2, F8 and Fz electrodes.Conclusion We concluded that drugs may interfere in sensorimotor processes, such as in the performance of tasks carried out in an unpredictable scenario.

Fabric phase sorptive extraction (FPSE), a recently introduced novel sample preparation technology, has been evaluated for the extraction of benzodiazepines from human blood serum. FPSE utilizes a flexible fabric surface as the substrate platform for creating sol-gel hybrid organic-inorganic sorbent coatings. FPSE media can be introduced directly into the sample containing the target analyte(s), requiring no need for prior sample pretreatment or clean-up. Benzodiazepines were selected as model analytes because they represent one of the most widely used therapeutic drugs in psychiatry and are also amongst the most frequently encountered drugs in forensic toxicology. The chromatographic separation of target analytes was performed on a LiChroCART-LiChrospher®100 RP-18e (5 µm, 250 × 4 mm) analytical column, operated at room temperature. Ternary gradient elution was applied with a mobile phase that consisted of acetonitrile, methanol and ammonium acetate (0.05 M), which was delivered at a flow rate of 1.0 mL/min. Diode array detection was performed with monitoring at 240 nm. FPSE was performed using cellulose fabric extraction media coated with sol-gel poly(ethylene glycol) (sol-gel PEG). Absolute recovery values in the equilibrium state for the examined benzodiazepines were found to be 27% for bromazepam, 63% for lorazepam, 42 % for diazepam and 39% for alprazolam. Copyright © 2015 John Wiley & Sons, Ltd.

Forensic toxicological drug analyses of human specimens are usually performed immediately after autopsy or on frozen preserved tissues. Occasionally, cases require analysis of drugs from tissues fixed in formalin solution. To improve the estimation of the level of drug in tissues following formalin fixation, we studied drug concentrations in human tissues, liver and kidney, that were collected from a drug-positive autopsy case. Parts of tissues were preserved in formalin solution for 1, 3, 6 and 13 months. Tissues obtained before and after preservation, along with tissue-exposed fixatives, were assayed using gas chromatography–mass spectrometry; all of the samples were assayed for the presence of drugs and changes in the drug concentrations both before and after preservation in formalin. Concentrations of assayed drugs decreased upon fixation in formalin; levels of these drugs did not necessarily show further decreases during subsequent storage in fixative, up to 13 months. Distinct trends in drug levels were found in liver and kidney. In liver, the levels of chlorpromazine, levomepromazine, and promethazine decreased to 23–39% at 1 month after preservation; all 3 of these drugs were detected at all tested time points of preservation. Bromazepam was not detected at 13 months after preservation. Milnacipran was the most unstable after preservation in formalin solution among all of the assayed drugs. In kidney, all assayed drugs exhibited reduced stability during preservation compared to levels in liver. Methamphetamine and methylenedioxymethamphetamine were not detected in any time points of tissues. The proportions of the drugs that remained within the tissues differed between liver and kidney. Also, S-oxide compounds of chlorpromazine and levomepromazine, which were not observed before preservation, were detected in fixed liver tissues and their fixatives at 3, 6 and 13 months of preservation. These results suggest that analyses in formalin-fixed tissues need to include analysis of various organ-tissues and their fixatives at multiple time points for the duration of preservation. These analyses should include detection of chemical degradation/denaturation products, such as S-oxides of chlorpromazine and levomepromazine.

The present study investigates the influence of bromazepam while executing a motor task. Specifically, we intend to analyze the changes in alpha absolute power under two experimental conditions, bromazepam and placebo. We also included analyses of theta and beta frequencies. We collected electroencephalographic data before, during, and after motor task execution. We used a Two Way ANOVA to investigate the condition (PL × Br6 mg) and moment (pre and post) variables for the following electrodes: Fp1, Fp2, F7, F3, Fz, F4, F8, C3, CZ and C4. We found a main effect for condition on the electrodes FP1, F7, F3, Fz, F4, C3 and CZ, for alpha and beta bands. For beta band we also found a main effect for condition on the electrodes Fp2, F8 and C4; for theta band we identified a main effect for condition on C3, Cz and C4 electrodes. This finding suggests that the motor task did not have any influence on the electrocortical activity in alpha, and that the existing modifications were a consequence due merely to the drug use. Despite its anxiolytic and sedative action, bromazepam did not show any significant changes when the individuals executed a finger extension motor task. O presente estudo investiga a influência do bromazepam durante a execução de uma tarefa motora. Especificamente, pretende-se analisar as mudanças na potência absoluta de alfa sob duas condições experimentais, bromazepam e placebo. Nós também incluímos as analises das frequências teta e beta. Foram coletados dados eletroencefalográficos antes, durante e depois da execução da tarefa motora. Usamos uma Anova de 2 fatores para investigar a condição (PL × Br6 mg) e variáveis no momento (pré e pós) para os seguintes eletrodos: Fp1, Fp2, F7, F3, Fz, F4, F8, C3, C4 e CZ. Encontramos um efeito principal para a condição e eletrodos FP1, F7, F3, Fz, F4, C3 e CZ para alfa e beta. Para beta também foi encontrado um efeito principal para condição nos eletrodos Fp2, F8 e C4; para theta nós identificamos um efeito principal para condition em C3, Cz e C4. Este achado sugere que a tarefa motora não tem qualquer influência sobre a atividade eletrocortical alfa e que as modificações existentes foram uma consequência devido o uso de drogas. Apesar de sua ação ansiolítica e sedativa, o bromazepam não apresentou mudança significativa quando os indivíduos executaram uma tarefa motora.

BACKGROUND: Tablet splitting is a well-established medical practice in clinical settings for multiple reasons, including cost savings and ease of swallowing. However, it does not necessarily result in weight-uniform half tablets. OBJECTIVES: To (a) investigate the effect of tablet characteristics on weight and content uniformity of half tablets, resulting from splitting 16 commonly used medications in the outpatient setting and (b) provide recommendations for safe tablet-splitting prescribing practices. METHODS: Ten random tablets from each of the selected medications were weighed and split by 5 volunteers (2 men and 3 women aged 25-44 years) using a knife. The selected medications were mirtazapine 30 mg, bromazepam 3 mg, oxcarbazepin 150 mg, sertraline 50 mg, carvedilol 25 mg, bisoprolol fumarate 10 mg, losartan 50 mg, digoxin 0.25 mg, amiodarone HCl 200 mg, metformin HCl 1,000 mg, glimepiride 4 mg, montelukast 10 mg, ibuprofen 600 mg, celecoxib 200 mg, meloxicam 15 mg, and sildenafil citrate 50 mg. The resulting half tablets were evaluated for weight and drug content uniformity in accordance with proxy United States Pharmacopeia (USP) specification (95%-105% for digoxin and 90%-110% for the other 15 drugs). Weight and drug content uniformity were assessed by comparing weight or drug content of the half tablets with one-half of the mean weight or drug content for all whole tablets in the sample. The percentages by which the weight and drug content of each whole tablet or half tablet differed from sample mean values were calculated. Other relevant physical characteristics of the 16 products were measured. RESULTS: A total of 52 of 320 half tablets (16.2%) and 48 of 320 half tablets (15.0%) fell outside of the proxy USP specification for weight and drug content, respectively. Bromazepam, carvedilol, bisoprolol, losartan, digoxin, and meloxicam half tablets failed the weight and content uniformity test; however, the half tablets for the rest of the medications passed the test. Mean percent weight loss after splitting was less than 1.5% for all drugs. Bromazepam, carvedilol, and digoxin showed the highest powdering loss during the tablet-splitting process. CONCLUSIONS: Tablet splitting could be safer and easier when drug- and patient-specific criteria have been met. Tablet size, shape, and hardness may also play a role in the decision to split a tablet or not. Tablets containing drugs with a wide therapeutic index and long half-life might be more suitable candidates for division. Dose variation exceeded a proxy USP specification for more than one-third of sampled half tablets of bromazepam, carvedilol, bisoprolol, and digoxin. Drug content variation in half tablets appeared to be attributed to weight variation due to fragment or powder loss during the splitting process.

Intoxication with calcium channel inhibitory drugs is rare but mortality rates reach 10 %. We report the case of a 5-year-old girl who had ingested five 240-mg tablets of extended-release verapamil (VLP) and a tablet of bromazepam. Thirty hours after the ingestion she had a vasoplegic shock, heart conduction disorders, and metabolic complications. She was treated in pediatric intensive care with continuous epinephrine and insulin and recovered completely 60h after the ingestion. This case underlines the danger of calcium channel blocker overdose, increased by the extended-release mechanism: the drug effect is to slow down gastric motility - which explains the latency of the symptoms - but this also increases the drug absorption, inducing a vicious circle. These mechanisms in calcium blocker intoxication need to be kept in mind in order to decrease the mortality of such accidents.

Diversion of prescription drugs is difficult to assess in quality and quantity. This study aimed to characterize diversion of prescription drugs in France through a comparative analysis of falsified prescriptions collected during three periods from 2001 to 2012. The data recorded in a national program which records all falsified prescriptions presented to community pharmacies were studied. Included data regarded: subjects, prescription forms, and drugs. Description of the dataset in three periods (2001-2004, 2005-2008, and 2009-2012) was completed with clustering analyses to characterize profiles of prescriptions and subjects associated with the most reported drugs. The 4469 falsified prescriptions concerned most often females (51.6%). Average age was 46.5 years. Zolpidem, bromazepam, and buprenorphine were the most frequent drugs. Alone, 13 drugs (1.7%, 13/772) represented more than 40% of the total reports (3055/7272). They were associated with three diversion profiles: (i) buprenorphine, flunitrazepam, and morphine were mentioned on overlapping secure prescription forms presented by young men; (ii) alprazolam, bromazepam, zolpidem, codeine/acetaminophen were mentioned on simple prescription forms presented by experienced women; and (iii) acetaminophen and lorazepam were mentioned on modified prescription forms presented by elderly subjects. Clonazepam, clorazepate, dextropropoxyphene, zopiclone moved between those profiles. The patterns of falsified prescriptions provided in this study contribute to enhance the scientific knowledge on the most diverted prescription drugs. The latter follow distinct trajectories across time depending on their pharmacology (including their abuse/addiction potential) and on their regulation's history. The close and continuous analysis of falsified prescriptions is an excellent way to monitor prescription drug diversion.

A novel methodology using liquid-liquid extraction with low temperature partitioning (LLE-LTP) and paper spray mass spectrometry (PS-MS) was developed to identify and quantify benzodiazepines in beverages. Four types of alcoholic beverages usually consumed in parties and bars were spiked with 5 distinct benzodiazepines (diazepam, alprazolam, bromazepam, clonazepam, and cloxazolam) simulating a drug-facilitated crime occurrence. The direct PS-MS analysis of the spiked beverages revealed a remarkable matrix effect with an unclear detection of protonated benzodiazepines. However, by the application of the LLE-LTP using liquid nitrogen, a prompt and doubtless detection of such compounds was achieved. The quantification potential of the LLE-LTP/PS-MS methodology was demonstrated by using beer as matrix, diazepam as target analyte and cloxazolam as an internal standard. Figures of merit (linearity, limit of detection, linear dynamic range, relative standard deviation, and recovery) were determined and adequate values were obtained. In conclusion, we demonstrated herein that the LLE-LTP/PS-MS methodology has potential to be applied directly at the crime scene through of a portable mass spectrometer and a thermal container for the transport of liquid nitrogen.

Aims Norway has introduced legal concentration limits in blood for 28 non-alcohol drugs in driving under the influence cases. As of 2016 this legislation also regulates the assessment of combined effects of multiple benzodiazepines and opioids. We herein describe the employed methodology for the equivalence tables for concentrations of benzodiazepines/z-hypnotics and opioids implemented in the Norwegian Road Traffic Act. Methods Legislative limits corresponding to impairment at blood alcohol concentrations (BAC) of 0.02%, 0.05% and 0.12% were established for 15 different benzodiazepines and opioids. This was based on a concept of a linear relationship between blood drug concentration and impairment in drug naive users. Concentration ratios between these drugs were used to establish conversion factors and calculate net impairment using diazepam and morphine equivalents. Results Conversion factors were established for 14 benzodiazepines/z-hypnotics (alprazolam, bromazepam, clobazam, clonazepam, etizolam, flunitrazepam, lorazepam, nitrazepam, nordiazepam, oxazepam, phenazepam, temazepam, zolpidem and zopiclone) and two opioids (methadone and oxycodone). Conclusions Conversion factors to calculate diazepam and morphine equivalents for benzodiazepines/z-hypnotics and selected opioids, respectively, have been operative in the Norwegian Road Traffic Act as of February 2016. Calculated equivalents can be applied by the courts to meter out sanctions.

Background The patterns of benzodiazepine prescriptions in older adults are of general and scientific interest as they are not yet well understood. The aim of this study was to compare the prescription patterns of benzodiazepines in elderly people in Germany to determine the share or proportion treated by general practitioners (GP) and neuropsychiatrists (NP). Methods This study included 31,268 and 6,603 patients between the ages of 65 and 100 with at least one benzodiazepine prescription in 2014 from GP and NP, respectively. Demographic data included age, gender, and type of health insurance coverage. The share of elderly people with benzodiazepine prescriptions was estimated in different age and disease groups for both GP and NP patients. The share of the six most commonly prescribed drugs was also calculated for each type of practice. Results The share of people taking benzodiazepines prescribed by GP increased from 3.2% in patients aged between 65 and 69 years to 8.6% in patients aged between 90 and 100 years, whereas this share increased from 5.4% to 7.1% in those seen by NP. Benzodiazepines were frequently used by patients suffering from sleep disorders (GP: 33.9%; NP: 5.5%), depression (GP: 17.9%; NP: 29.8%), and anxiety disorders (GP: 14.5%; NP: 22.8%). Lorazepam (30.3%), oxazepam (24.7%), and bromazepam (24.3%) were the three most commonly prescribed drugs for GP patients. In contrast, lorazepam (60.4%), diazepam (14.8%), and oxazepam (11.2%) were those more frequently prescribed to NP patients. Conclusion Prescription patterns of benzodiazepine in the elderly varied widely between GP and NP. .

Background Chronic treatment revisions optimise drug treatment and prevent potential drug related problems. Therefore, we started a new healthcare model based on multidisciplinary team work, integrated and focused on the patient. This programme is a tool to revise the benzodiazepine/Z-drug prescriptions, which are increasing in older patients, and may cause adverse effects. Purpose To evaluate the potentially inappropriate prescribing associated with benzodiazepines/Z-drugs in polymedicated patients and to determine the deprescription rate after multidisciplinary pharmacotherapy revision. Material and methods The primary care pharmacist checked chronic treatment through multidisciplinary pharmacotherapy revision with clinical, functional and psychosocial variables, and established recommendations. The physician agreed with the patient preferences, and revised the recommendations through weekly drug safety appointments. The multidisciplinary primary care team (pharmacist, physician, nurse and patient) decided on the deprescription modifications to make. Data collected: demographics, total number of drugs, number of drug related problems, and number and type of benzodiazepines/Z-drugs before and after the revision. Data are expressed as median (Q1–Q3). Results Patients revised: 125. Age 79.5 (75.8–84.0) years; women 30 (75%). Number of drugs 15 (13–17). Number of drug related problems/patient detected on revision 3 (2.0–3.25). Patients with a benzodiazepine/Z-drug prescribed >6 months 40 (32%) and out of these 9 (22.5%) taking 2 benzodiazepines/Z-drugs. Classification of benzodiazepines/Z-drugs: clonazepam 10 (20.4%); lorazepam 9 (18.4%); alprazolam, diazepam, lormetazepam 8 (16.3%) each; zolpidem 3 (6.1%), loprazolam 2 (4.1%) and 1 (2.0%) bromazepam. Total deprescription interventions: 49. In 4 (10%) patients the deprescription succeeded. Deprescribed drugs: 2 lorazepam, 1 loprazolam and 1 clonazepam. In 8 (20%) other patients benzodiazepine/Z-drug was switched to a better profile drug. Switched drugs: from alprazolam to lorazepam or zolpidem, from clonazepam to lorazepam, from diazepam to lorazepam or lormetazepam and from lormetazepam to zopiclona. Conclusion A third of our patients had a prescription of benzodiazepines/Z-drugs. Half of the benzodiazepines/Z-drugs prescribed had a long half-life. The benzodiazepine/Z-drug switching rate was higher than the deprescription rate. Multidisciplinary pharmacotherapy revision permitted detection of potentially inappropriate prescribing and identification of drug related problems to optimise chronic treatment. New strategies are being implemented to increase the benzodiazepine/Z-drug deprescription, such as consciousness raising in the patient and closer monitoring. References and/or acknowledgements PMID: 26141716. No conflict of interest

Background New technology can improve patient safety but also has the potential to introduce new errors and risks into healthcare delivery Purpose To evaluate the effect of an electronic medication administration record (eMAR) application on the rate of medication errors in medication administration recording (ME-MAR). Material and methods A before and after, quasi-experimental study was conducted in a university hospital that was implementing the eMAR application. eMAR application implementation took place in March 2014. Data collection was conducted in April 2012 (pre-) and June 2014 (post-) by two pharmacists. The ME-MAR found were clarified by the staff involved to discover the cause. A group of experts in patient safety was set up with the task of reviewing the ME-MAR to classify and determine their potential future risk. ME-MAR were classified according to the taxonomy defined by the Ruiz-Jarabo 2000 group. ME-MAR foermine the deprescription rate after multidisciplinary pharmacotherapy revision. Material and methods The primary care pharmacist checked chronic treatment through multidisciplinary pharmacotherapy revision with clinical, functional and psychosocial variables, and established recommendations. The physician agreed with the patient preferences, and revised the recommendations through weekly drug safety appointments. The multidisciplinary primary care team (pharmacist, physician, nurse and patient) decided on the deprescription modifications to make. Data collected: demographics, total number of drugs, number of drug related problems, and number and type of benzodiazepines/Z-drugs before and after the revision. Data are expressed as median (Q1–Q3). Results Patients revised: 125. Age 79.5 (75.8–84.0) years; women 30 (75%). Number of drugs 15 (13–17). Number of drug related problems/patient detected on revision 3 (2.0–3.25). Patients with a benzodiazepine/Z-drug prescribed >6 months 40 (32%) and out of these 9 (22.5%) taking 2 benzodiazepines/Z-drugs. Classification of benzodiazepines/Z-drugs: clonazepam 10 (20.4%); lorazepam 9 (18.4%); alprazolam, diazepam, lormetazepam 8 (16.3%) each; zolpidem 3 (6.1%), loprazolam 2 (4.1%) and 1 (2.0%) bromazepam. Total deprescription interventions: 49. In 4 (10%) patients the deprescription succeeded. Deprescribed drugs: 2 lorazepam, 1 loprazolam and 1 clonazepam. In 8 (20%) other patients benzodiazepine

Background: The association of mental disorder with cardiac disease is not a coincidence rather a strong relationship exists in between those two. Objective: We investigated the prescription pattern of psycholeptic drugs during the discharge of patients in a national cardiovascular hospital. Methods: Data was collected from the National Institute of Cardiovascular Diseases (NICVD) at Dhaka in Bangladesh. In total, 1076 prescriptions were collected randomly from July 2012 to June 2013. Data were analyzed by using the software Statistical Package for Social Science (SPSS, version 22). Results: Benzodiazepine was the highest (99.3%) prescribed psycholeptic class while Bromazepam (87.49%) the highest advised molecule. Psycholeptics were advised for 15 (38.77%), 10 (19.91%), 30 (15.72%) and 7 (13.39%) days. The patient group without psycholeptic medication (M=6.64 day) spent significantly (p < 0.05) a longer duration in the hospital compared to the psycholeptic medication (Mean=5.06 day) group. Age is significantly (p < 0.05) associated with the duration of staying in hospital and polymorbidity. Also, polymorbidity (p < 0.05) is significantly associated with the polypharmacy. No significant (p < 0.05) correlation has been found between age and polypharmacy. Duration of psycholeptics intake was not significantly (p < 0.05) related to either age, or polymorbidity,or length hospital stay. Conclusion: This study revealed that bromazepam is the utmost prescribed drug of choice at NICVD, Bangladesh. Frequent prescription of bromazepam indicates that this kind of patients' needs enough sleep to reduce their mental stress.

Pharmaceuticals as environmental contaminants have received a lot of interest over the past decade but, for several pharmaceuticals, relatively little is known about their occurrence in European surface waters. Benzodiazepines, a class of pharmaceuticals with anxiolytic properties, have received interest due to their behavioral modifying effect on exposed biota. In this study, our results show the presence of one or more benzodiazepine(s) in 86% of the analyzed surface water samples (n = 138) from 30 rivers, representing seven larger European catchments. Of the 13 benzodiazepines included in the study, we detected 9, which together showed median and mean concentrations (of the results above limit of quantification) of 5.4 and 9.6 ng L−1, respectively. Four benzodiazepines (oxazepam, temazepam, clobazam, and bromazepam) were the most commonly detected. In particular, oxazepam had the highest frequency of detection (85%) and a maximum concentration of 61 ng L−1. Temazepam and clobazam were found in 26% (maximum concentration of 39 ng L−1) and 14% (maximum concentration of 11 ng L−1) of the samples analyzed, respectively. Finally, bromazepam was found only in Germany and in 16 out of total 138 samples (12%), with a maximum concentration of 320 ng L−1. This study clearly shows that benzodiazepines are common micro-contaminants of the largest European river systems at ng L−1 levels. Although these concentrations are more than a magnitude lower than those reported to have effective effects on exposed biota, environmental effects cannot be excluded considering the possibility of additive and sub-lethal effects.

Objective. To describe dental prescriptions for anxiolytics, sedatives, and hypnotics for Brazilian outpatients in 2010. Methods. A cross-sectional study was conducted using data on the use of anxiolytics, sedatives, and hypnotics from the Brazilian Health Surveillance Agency, Brazil, 2010. For each prescription, prescribed drugs and the prescribed amount were identified. Prescribed medications were classified according to Anatomical Therapeutic Chemical code. We calculated the number of Defined Daily Doses (DDD) for anxiolytics, sedatives, and hypnotics by code, their mean DDD, and DDD per inhabitant per year. Results. There were 16,436 prescriptions dispensed, including anxiolytics, sedatives, and hypnotics. These prescriptions corresponded to 3,555,780.50 mg, distributed as 2,286,200.50 mg (64.30%) of anxiolytics and 1,269,580.00 mg (35.70%) of sedatives and hypnotics. This amount allowed treating approximately 474,106 individuals (number of DDD). The anxiolytics most frequently dispensed were bromazepam (25.30%), alprazolam (19.19%), and diazepam (15.60%). Sedatives and hypnotics mostly prescribed were zolpidem (9.55%), midazolam (6.99%), and flunitrazepam (2.14%). The per capita rates (100,000 inhabitants) of anxiolytics and sedatives/hypnotics were 6.83 and 1.78, respectively. Conclusions. Benzodiazepines and derivatives were the most frequently prescribed drugs. There was a low rate of dental prescriptions for anxiolytics, sedatives, and hypnotics, although excessive doses were concentrated in the same prescription.

The boron-doped diamond electrodes (BDDEs) with different dopant levels were applied as advanced, mercury-free and modification-free electroanalytical platforms for simple and reliable quantification of benzodiazepines, bromazepam (BZ) and alprazolam (ALZ). Cyclic voltammetric measurements revealed that the electrode reactions of both analytes were manifested by one irreversible and diffusion-controlled reduction peak at -1.10V in Britton-Robinson buffer of pH 11 for BZ using lab-made BDDE with 1000 ppm B/C ratio and -0.84V in BR buffer of pH 5 for ALZ using commercial BDDE with 1000 ppm B/C ratio. Differential pulse voltammetry was used for construction of calibration curves for BZ and ALZ, respectively, with the analytical parameters as follows: the linear dynamic ranges of 1 x 10(-6)-1 x 10(-4) and 8 x 10(-7)-1 x 10(-4) mol/L, the detection limit of 3.1 x 10(-7) and 6.4 x 10(-7) mol/L and the excellent repeatability with the relative standard deviation below 3% for both drugs. The developed methods were applied to analysis of the pharmaceutical tablets with the recoveries from 97.33 to 100.85% for BZ and from 94.14 to 101.32% for ALZ. The usage of BDDEs as advanced electrochemical sensors in drug analysis represents a facile and effective analytical approach which may replace mercury-based sensors and chemically modified electrodes in previous benzodiazepines sensing. This is the peer-reviewed version of the following article: Samiec, P.; Švorc, Ľ.; Stanković, D. M.; Vojs, M.; Marton, M.; Navrátilová, Z. Mercury-Free and Modification-Free Electroanalytical Approach towards Bromazepam and Alprazolam Sensing: A Facile and Efficient Assay for Their Quantification in Pharmaceuticals Using Boron-Doped Diamond Electrodes. Sensors and Actuators, B: Chemical 2017, 245, 963–971. [https://doi.org/10.1016/j.snb.2017.02.023] Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3081]

Ultrasound-assisted dispersive liquid–liquid microextraction (UA-DLLME) combined with ultra-performance liquid chromatography (UPLC) was developed for the determination of seven benzodiazepines (alprazolam, bromazepam, clonazepam, diazepam, lorazepam, lormetazepam and tetrazepam) in urine samples and hospital wastewater. Several parameters affecting UA-DLLME efficiency such as type and dispersive solvent volume and ionic strength were investigated. The effects of pH, ultrasonic time and extraction solvent volume on the extraction efficiency were studied simultaneously using a Doehlert design and desirability functions. The optimal conditions were: 0.5 mL of sample; 1.6 mL acetone, as a dispersive solvent; 160 μL of chloroform, as an extraction solvent; pH 9; 4.5 min of ultrasound application; 0.2 g of NaCl and 8 min of centrifugation at 3500 rpm. The chromatographic separation of benzodiazepines was carried out by a UPLC system using a binary mobile phase composed of aqueous phosphate buffer (0.001 M, pH 6) and acetonitrile, ACN in gradient elution mode (4 min total analysis). Under the optimized conditions, the calibration curves showed good linearity in the studied ranges with determination coefficients higher than 0.994. The limits of quantification (LOQs) ranged from 1.8 to 7.4 ng mL−1 and 0.05 to 0.42 ng mL−1 in urine and wastewater, respectively. Intra- and inter-day precision ranged from 3.1 to 14.1% and the recoveries ranged from 81 to 124%. The application of the proposed analytical procedure in human urine samples and wastewater from a hospital and municipal treatment plants revealed the presence of benzodiazepines.

Vibratory angioedema is a rare form of physical urticaria, hereditary or acquired, which occurs at body sites exposed to vibrations. Pathogenic mechanisms of disease are not completely clear and, consequently, current pharmacological treatment is sometimes unsatisfactory. We report the case of a horn player affected by acquired vibratory angioedema, relapsing after prolonged use of the instrument and resistant to systemic antihistamines and corticosteroids, which successfully responded to therapy with low doses of amitriptyline and bromazepam. A neuroinflammatory mechanism can be likely implicated in the pathogenesis of vibratory angioedema, in line with many different cutaneous/mucosal diseases involving a complex interplay of homeostatic/allostatic systems. Furthermore, in mucosal diseases, such as vibratory angioedema, physical/psychological stressors have a relevant role. In such cases, because of the complex interplay between nervous and immune system, the pharmacological activity of benzodiazepines and typical antidepressants may downregulate neuroinflammation.

A systematic observational study is performed in general population of age group 18 - 60 years to collect enough data on the irrational dispensing pattern and self medication of benzodiazepines. There were two separate specially designed Performa’s , one for the OPD pharmacy or dispensary in different communities of Karachi and one for the general population of variable demographic status duly filled by 190 out of 200 OPD pharmacies app roached, (n = 190 with response rate 95 %) and 478 out of 508 people approached (n = 478 with response rate 94 .09 %) In this study 478 individual participated. Mean age of population was 43.62 ± 17 years. 44.6 % were male (n = 213 ) and 55.4 % were female (n = 265 ) the common Benzodiazepines reported to be used by study population are Alprazolam 54 %, Bromazepam 40 %, Clorazepate, Lorazepam and Azolam 2 % each. The three primary reasons reported lead to the use of benzodiazepines by general population are depression 64 %, sleep disturbance 19 % and pain 17 %. There were 68 people (29 %) confessed that they are usi ng it without any prescription from GP. By the Performa filled by OPD community pharmacies findings are benzodiazepines are the 6 th largest selling drug class. Alprazolam and Bromezepam both are the top most selling benzodiazepines members 88.52 % followed by Lorazepam 6.39 %, Clorazepate 0.09 % and others 5.0 %. Among 190 pharmacies visited, around 79 pharmacies (41.57 %) reported to dispense benzodiazepines without prescription. Significant variable with respect to rate of use of b enzodiazepines in the co mmunity were educational status, socio - economical background, occupation, marital status etc with p < 0.000 when Pearson chi - square test were applied.

Herein, we report a case of an assisted suicide committed by application of 34 matrix-based fentanyl-containing transdermal therapeutic systems (TTS) with different release rates. The TTS were supplied by the husband but administered by the deceased herself. Besides routine systematic toxicological analysis (STA), the concentrations of fentanyl and norfentanyl were determined in the blood (femoral and heart), urine, stomach content, brain, lung tissue, musculus iliopsoas, liver, kidney, bile and in some of the used TTS by LC-MS/MS. Blood levels of fentanyl were 60.6 μg/L in femoral blood and 94.1 μg/L in heart blood. These concentrations are in good concordance with levels described in cases with accidental or lethal suicidal fentanyl patch application. The organ distribution indicates an influence of post-mortem redistribution. The levels of residual fentanyl in the TTS were also determined. STA furthermore revealed supratherapeutic levels of bromazepam. Thus, the cause of death was a combination of fentanyl and bromazepam intoxication. However, considering the determined levels of fentanyl and norfentanyl in the entire set of specimens and the high toxicity in comparison to bromazepam, fentanyl was the leading toxic noxa.