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.

• Klíčová slova
• Anxiolytics, Bromazepam, Clobazam, Oxazepam, Temazepam,
• MeSH
• benzodiazepiny analýza   MeSH
• chemické látky znečišťující vodu analýza   MeSH
• klobazam MeSH
• monitorování životního prostředí metody   MeSH
• oxazepam analýza   MeSH
• řeky chemie   MeSH
• temazepam analýza   MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• benzodiazepiny MeSH
• chemické látky znečišťující vodu MeSH
• klobazam MeSH
• oxazepam MeSH
• temazepam MeSH

We present an autopsy case involving benzodiazepines and diphenidine. Quantitative toxicological analysis showed concentrations of 7-aminoflunitrazepam (a flunitrazepam metabolite), 7-aminonimetazepam (a nimetazepam metabolite), chlorpheniramine and diphenidine in femoral blood of 0.086 µg/ml, 0.027 µg/ml, 0.066 µg/ml, and 0.073 µg/ml, respectively. Death was attributed to combined toxicity due to the influence of multiple drug interactions.

• Klíčová slova
• multiple drug interaction - benzodiazepine - diphenidine.,
• MeSH
• benzodiazepiny * otrava   MeSH
• lékové interakce MeSH
• lidé MeSH
• piperidiny otrava   MeSH
• pitva MeSH
• příčina smrti MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzodiazepiny * MeSH
• diphenidine MeSH Prohlížeč
• piperidiny MeSH

BACKGROUND AND PURPOSE: Opioids and benzodiazepines are frequently combined in medical as well as in non-medical contexts. At high doses, such combinations often result in serious health complications attributed to pharmacodynamics interactions. Here, we investigate the contribution of the metabolic interactions between oxycodone, diazepam and diclazepam (a designer benzodiazepine) in abuse/overdose conditions through ex vivo, in vivo and in silico approaches. EXPERIMENTAL APPROACH: A preparation of pooled human liver microsomes was used to study oxycodone metabolism in the presence or absence of diazepam or diclazepam. In mice, diazepam or diclazepam was concomitantly administered with oxycodone to mimic acute intoxication. Diclazepam was introduced on Day 10 in mice continuously infused with oxycodone for 15 days to mimic chronic intoxication. In silico modelling was used to study the molecular interactions of the three drugs with CYP3A4 and 2D6. KEY RESULTS: In mice, in acute conditions, both diazepam and diclazepam inhibited the metabolism of oxycodone. In chronic conditions and at pharmacologically equivalent doses, diclazepam drastically enhanced the production of oxymorphone. In silico, the affinity of benzodiazepines was higher than oxycodone for CYP3A4, inhibiting oxycodone metabolism through CYP3A4. Oxycodone metabolism is likely to be diverted towards CYP2D6. CONCLUSION AND IMPLICATIONS: Acute doses of diazepam or diclazepam result in the accumulation of oxycodone, whereas chronic administration induces the accumulation of oxymorphone, the toxic metabolite. This suggests that overdoses of opioids in the presence of benzodiazepines are partly due to metabolic interactions, which in turn explain the patterns of toxicity dependent on usage. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

• Klíčová slova
• benzodiazepines, designer benzodiazepines, diazepam, diclazepam, metabolic interactions, opioids, oxycodone,
• MeSH
• benzodiazepiny toxicita   MeSH
• cytochrom P-450 CYP3A MeSH
• diazepam farmakologie   MeSH
• lidé MeSH
• modely u zvířat MeSH
• myši MeSH
• opioidní analgetika toxicita   MeSH
• oxykodon * MeSH
• oxymorfon MeSH
• předávkování léky * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzodiazepiny MeSH
• cytochrom P-450 CYP3A MeSH
• diazepam MeSH
• opioidní analgetika MeSH
• oxykodon * MeSH
• oxymorfon MeSH

We studied the adverse effects of four benzodiazepines frequently measured in European surface waters. We evaluated bioaccumulation potential of oxazepam, bromazepam, temazepam, and clobazam in freshwater fish species - perch (Perca fluviatilis) and we conducted a series of behavioral trials to assess their potential to alter boldness, activity, and social behavior. All selected endpoints were studied individually for each target benzodiazepine and as a mixture of all tested compounds to assess possible combinatory effects. We used a three-dimensional automated tracking system to quantify the fish behavior. The four compounds bioconcentrated differently in fish muscle (temazepam > clobazam > oxazepam > bromazepam) at high exposure (9.1, 6.9, 5.7, 8.1 µg L-1, respectively) and low exposure (0.5, 0.5, 0.3, 0.4 µg L-1, respectively) concentrations. A significant amount of oxazepam was also measured in fish exposed to temazepam, most likely because of the metabolic transformation of temazepam within the fish. Bromazepam, temazepam, and clobazam significantly affected fish behavior at high concentration, while no statistically significant changes were registered for oxazepam. The studied benzodiazepines affected behavior in combination, because the mixture treatment significantly changed several important behavioral traits even at low concentration, while no single compound exposure had such an effect at that dose. Based on our results, we conclude that effects of pharmaceuticals on aquatic environments could be underestimated if risk assessments only rely on the evaluation of single compounds. More studies focused on the combinatory effects of environmentally relevant mixtures of pharmaceuticals are necessary to fill the gaps in this knowledge.

• MeSH
• benzodiazepiny metabolismus   toxicita   MeSH
• chemické látky znečišťující vodu metabolismus   toxicita   MeSH
• chování zvířat účinky léků   MeSH
• oxazepam metabolismus   toxicita   MeSH
• ryby metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzodiazepiny MeSH
• chemické látky znečišťující vodu MeSH
• oxazepam MeSH

Benzodiazepines (BZDs) and Z-drugs are strongly addictive substances, acting on identical GABA receptors. Detoxification should be long-term and gradual, usually by tapering a long-acting BZD (diazepam) but no suitable commercial pharmaceutic product exists with the necessary low drug content. This review describes the specific pharmacological aspects and comparisons of individual BZDs in relation to their effects and addictiveness. The success of the treatment relates to the patients comfort during this process. Patients are typically afraid of switching to a more suitable long-acting BZD (diazepam), and become stressed during the tapering and anxious from withdrawal symptoms. These obstacles could be overcome through individualized detoxification according to already published withdrawal schedules based on the administration of very precise diazepam doses in a long-term gradual tapering with possible addition of adjuvant drugs. Dose reduction does not change external appearance of the dosage form, and the patient could be treated until the placebo phase. Individually prepared pharmaceutics with different and precise diazepam contents can be used for comfortable detoxification and also may eliminate psychogenic stress during switching, tapering, and the withdrawal period.

• Klíčová slova
• Z-drugs, addiction, benzodiazepines, detoxification, tapering, withdrawal,
• MeSH
• abstinenční syndrom prevence a kontrola   MeSH
• benzodiazepiny aplikace a dávkování   škodlivé účinky   MeSH
• diazepam terapeutické užití   MeSH
• lidé MeSH
• metabolická inaktivace MeSH
• poruchy spojené s užíváním psychoaktivních látek farmakoterapie   MeSH
• rozvrh dávkování léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• benzodiazepiny MeSH
• diazepam MeSH

The present study explored whether the profiles of action of benzodiazepines on intraspecies conflict behavior in mice are different. The occurrence of seven behavioral elements was observed in aggressive and timid singly-housed male mice treated with drugs in paired interactions with untreated non-aggressive males. At low doses, some benzodiazepines (alprazolam, oxazepam and diazepam) inhibited defenses, escapes, or attacks, but did not reduce other activities (social sniffing, walking, rearing), and actually increased most of them. At comparable doses, other benzodiazepines (flunitrazepam, nitrazepam, clonazepam and chlordiazepoxide) stimulated only social sniffing, but reduced rearing or walking. Further benzodiazepines (triazolam and lorazepam) reduced defenses, escapes and attacks only at doses that suppressed most of the remaining activities as well. Thus, the nine benzodiazepines tested exhibited different profiles of action in the present study. Alprazolam, oxazepam and diazepam appeared least sedative, while triazolam and lorazepam were most sedative.

• MeSH
• agrese účinky léků   MeSH
• anxiolytika farmakologie   MeSH
• benzodiazepiny MeSH
• chování zvířat účinky léků   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• sociální chování MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anxiolytika MeSH
• benzodiazepiny MeSH

A new ultra high performance liquid chromatography with electrospray ionization time of flight mass spectrometry method for the selective and sensitive separation, identification, and determination of selected designer benzodiazepines (namely, pyrazolam, phenazepam, etizolam, flubromazepam, diclazepam, deschloroetizolam, bentazepam, nimetazepam, and flubromazolam) in human serum was developed. The separation of the studied designer benzodiazepines was achieved on C18 chromatographic column using gradient elution within 6 min without any significant matrix interferences. Liquid-liquid extraction with butyl acetate was applied for serum samples cleanup and preconcentration of studied designer benzodiazepines. The method was validated in terms of linearity, limit of detection, limit of quantification, matrix effects, specificity, precision, accuracy, recovery, and sample stability. The limit of detection values were 0.10-0.15 ng/mL. The method was applied to a spiked serum sample to demonstrate its applicability for systematic toxicology analysis. Furthermore, a capillary chromatographic method with micellar electrokinetic chromatography was used for the estimation of partition coefficients of studied designer benzodiazepines as important parameters to evaluate their pharmacological and toxicological properties.

• Klíčová slova
• benzodiazepines, liquid chromatography, mass spectrometry, micellar electrokinetic chromatography, partition coefficients,
• MeSH
• benzodiazepiny krev   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací * MeSH
• lidé MeSH
• limita detekce MeSH
• micely MeSH
• reprodukovatelnost výsledků MeSH
• vysokoúčinná kapalinová chromatografie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzodiazepiny MeSH
• micely MeSH

While outpatients or other users of therapeutic drugs have to be informed about the risk of impaired functioning during driving or work, the prescribing physician needs to be familiar with the side effects of alternative drugs in order to select the most suitable treatment. With this aim, several types of benzodiazepine anxiolytics in low anxiolytic doses (diazepam 5 mg or 10 mg, nitrazepam 5 mg, oxazepam 10 mg, medazepam 10 mg, and alprazolam 0.2 or 0.5 mg-per 2m2 body surface) were tested under laboratory conditions for their effects on vigilance performance. In a double-blind design, 145 healthy volunteers performed a 60 min vigilance test (composed of discriminatory reactions to acoustic stimuli and a secondary visual tracking task) and four short psychomotor tests (lasting 1-7 min each) before and after a single dose of drug or placebo. Subjects described their perception of the drug effect with the help of a mood check list, and fatigue, sleepiness, and effort scales. Only diazepam 5 mg and 10 mg, alprazolam 0.5 mg, and nitrazepam 5 mg caused significant deterioration in vigilance performance along with perceived sleepiness and the need for a greater effort to overcome it. The onset of diazepam effect was quicker, whereas alprazolam effect lasted longer. No effect was noted in the short psychomotor tests except for the Bourdon Cancellation Test, where the first phase of diazepam effect was registered.

• MeSH
• akustická stimulace MeSH
• alprazolam farmakologie   MeSH
• arousal účinky léků   MeSH
• benzodiazepiny farmakologie   MeSH
• časové faktory MeSH
• diazepam farmakologie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• lidé MeSH
• nitrazepam farmakologie   MeSH
• psychiatrické posuzovací škály MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky kontrolované MeSH
• klinické zkoušky MeSH
• Názvy látek
• alprazolam MeSH
• benzodiazepiny MeSH
• diazepam MeSH
• nitrazepam MeSH

A simple, rapid and fully automated flow injection method with fluorimetric detection after hydrolysis with H2SO4 in ethanolic or methanolic medium at room temperature has been developed for the determination of 1,4-benzodiazepines (oxazepam, diazepam and nitrazepam) in pharmaceutical formulations. The calibration curves are linear in the ranges (mg ml(-1)) of oxazepam (0.025-0.150), diazepam (0.010-0.125) and nitrazepam (0.010-0.150), with detection limits of 0.01, 0.005 and 0.005 mg ml(-1), respectively, and RSD (1% (n = 10). The measurement throughput is 60 h(-1) using a 200-microl sample volume obtained by the direct dissolution of formulations in alcohol.

• MeSH
• anxiolytika analýza   MeSH
• autoanalýza MeSH
• benzodiazepiny analýza   MeSH
• diazepam analýza   MeSH
• fluorescenční spektrometrie MeSH
• hydrolýza MeSH
• indikátory a reagencie MeSH
• kalibrace MeSH
• koncentrace vodíkových iontů MeSH
• nitrazepam analýza   MeSH
• oxazepam analýza   MeSH
• průtoková injekční analýza MeSH
• regresní analýza MeSH
• spektrofotometrie ultrafialová MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anxiolytika MeSH
• benzodiazepiny MeSH
• diazepam MeSH
• indikátory a reagencie MeSH
• nitrazepam MeSH
• oxazepam MeSH

INTRODUCTION: Previous research has raised concerns about high prevalence of drug-related problems, polypharmacy and inappropriate benzodiazepine prescribing in nursing homes (NHs) and confirmed lack of studies from Central and South-Eastern Europe. The aim of our study was to determine the prevalence and characteristics of polypharmacy, hyperpolypharmacy and inappropriate benzodiazepine prescribing in NH residents in Croatia. METHODS: Data from 226 older NH residents from five Croatian NHs were collected using the InterRAI Long-Term Care Facilities assessment form. The prevalence and determinants of polypharmacy/hyperpolypharmacy and patterns of inappropriate benzodiazepine prescribing were documented. RESULTS: The prevalence of polypharmacy (49.6%) and hyperpolypharmacy (25.7%) among NH residents was high. In our study, 72.1% of NH residents were prescribed at least one psychotropic agent, 36.7% used 2-3 psychotropics and 6.6% used 4+ psychotropics. Among benzodiazepine users (55.8%), 28% of residents were prescribed benzodiazepines in higher than recommended geriatric doses, 75% used them for the long term and 48% were prescribed concomitant interacting medications. The odds of being prescribed polypharmacy/hyperpolypharmacy were significantly higher for older patients with polymorbidity (6+ disorders, proportional odds ratio (POR) = 19.8), type II diabetes (POR = 5.2), ischemic heart disease (POR = 4.6), higher frailty (Clinical Frailty Scale (CFS ≥5); POR = 4.3) and gastrointestinal problems (POR = 4.8). CONCLUSIONS: Our research underscores the persistent challenge of inappropriate medication use and drug-related harms among older NH residents, despite existing evidence and professional campaigns. Effective regulatory and policy interventions, including the implementation of geriatrician and clinical pharmacy services, are essential to address this critical issue and ensure optimal medication management for vulnerable NH populations.

• Klíčová slova
• Nursing home residents, geriatric deprescribing, inappropriate benzodiazepine prescribing, polypharmacy/hyperpolypharmacy, psychiatric polypharmacy/hyperpolypharmacy,
• MeSH
• benzodiazepiny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• domovy pro seniory statistika a číselné údaje   MeSH
• lékařská praxe - způsoby provádění statistika a číselné údaje   normy   MeSH
• lidé MeSH
• nevhodné předepisování * statistika a číselné údaje   MeSH
• pečovatelské domovy * statistika a číselné údaje   MeSH
• polypharmacy * MeSH
• prevalence MeSH
• psychotropní léky terapeutické užití   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Chorvatsko epidemiologie   MeSH
• Názvy látek
• benzodiazepiny * MeSH
• psychotropní léky MeSH