BACKGROUND: Opioid maintenance treatment (OMT) has the potential to reduce mortality rates substantially. We aimed to compare all-cause and overdose mortality among OMT patients while in or out of OMT in two different countries with different approaches to OMT. METHODS: Two nation-wide, registry-based cohorts were linked by using similar analytical strategies. These included 3,637 male and 1,580 female patients enrolled in OMT in Czechia (years 2000-2019), and 6,387 male and 2,078 female patients enrolled in OMT in Denmark (years 2007-2018). The direct standardization method using the European (EU-27 plus EFTA 2011-2030) Standard was employed to calculate age-standardized rate to weight for age. All-cause and overdose crude mortality rates (CMR) as number of deaths per 1,000 person years (PY) in and out of OMT were calculated for all patients. CMRs were stratified by sex and OMT medication modality (methadone, buprenorphine, and buprenorphine with naloxone). RESULTS: Age-standardized rate for OMT patients in Czechia and Denmark was 9.7/1,000 PY and 29.8/1,000 PY, respectively. In Czechia, the all-cause CMR was 4.3/1,000 PY in treatment and 10.8/1,000 PY out of treatment. The overdose CMR was 0.5/1,000 PY in treatment and 1.2/1,000 PY out of treatment. In Denmark, the all-cause CMR was 26.6/1,000 PY in treatment and 28.2/1,000 PY out of treatment and the overdose CMR was 7.3/1,000 PY in treatment and 7.0/1,000 PY out of treatment. CONCLUSION: Country-specific differences in mortality while in and out of OMT in Czechia and Denmark may be partly explained by different patient characteristics and treatment systems in the two countries. The findings contribute to the public health debate about OMT management and may be of interest to practitioners, policy and decision makers when balancing the safety and accessibility of OMT.

• Klíčová slova
• buprenorphine, buprenorphine with naloxone, methadone, mortality, opioid agonist treatment, opioid maintenance treatment, registry-based study, treatment outcomes,
• MeSH
• buprenorfin * terapeutické užití   MeSH
• lidé MeSH
• methadon škodlivé účinky   MeSH
• opiátová substituční terapie škodlivé účinky   metody   MeSH
• poruchy spojené s užíváním opiátů * farmakoterapie   MeSH
• předávkování léky * epidemiologie   farmakoterapie   etiologie   MeSH
• registrace MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• buprenorfin * MeSH
• methadon MeSH

INTRODUCTION: Among people receiving current or previous opioid maintenance treatment (OMT), the leading cause of premature death is an opioid overdose. However, other causes of mortality remain high in this group. An understanding of causes of deaths across multiple settings can be useful in informing more comprehensive prevention responses. The aim of this study was to describe all non-overdose causes of death in three national cohorts (Czechia, Denmark, and Norway) among OMT patients and to explore associations of non-overdose mortality with age and gender. METHODS: This prospective comparative cohort study used national mortality registry databases for OMT patients from Czechia (2000-2019), Denmark (2000-2018), and Norway (2010-2019). Crude mortality rates and age-standardized mortality rates (ASMRs) were calculated as deaths per 1,000 person years for cause-specific mortality. RESULTS: In total, 29,486 patients were included, with 5,322 deaths recorded (18%). We found variations in causes of death among the cohorts and within gender and age groups. The leading non-overdose causes of death were accidents in Czechia and Denmark, and neoplasms in Norway. Cardiovascular deaths were highest in Czechia, particularly for women in OMT (ASMR 3.59 vs. 1.24 in Norway and 1.87 in Denmark). CONCLUSION: This study found high rates of preventable death among both genders and all age groups. Different demographic structures, variations in risk exposure, as well as variations in coding practices can explain the differences. The findings support increased efforts towards screening and preventative health initiatives among OMT patients specific to the demographic characteristics in different settings.

• Klíčová slova
• Mortality, Opioid maintenance treatment, Overdose, Registry, Substance abuse,
• MeSH
• dokonaná sebevražda statistika a číselné údaje   MeSH
• dospělí MeSH
• kardiovaskulární nemoci * mortalita   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory * mortalita   MeSH
• opiátová substituční terapie MeSH
• poruchy spojené s užíváním opiátů * mortalita   terapie   MeSH
• předávkování léky mortalita   MeSH
• příčina smrti * MeSH
• prospektivní studie MeSH
• registrace MeSH
• sexuální faktory MeSH
• úrazy a nehody * mortalita   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Dánsko epidemiologie   MeSH
• Norsko epidemiologie   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

INTRODUCTION: Drug-related mortality is a key epidemiological indicator that is collected nationally and internationally. Significant efforts were made in 2006-2007 to improve the quality of data concerning drug-related mortality in the Czech Republic. The aim of this article is to identify the effect of a quality improvement project on the drug-induced mortality data reported in the General Mortality Registry (GMR), and to demonstrate how to identify, quantify and interpret changes in drug-induced mortality based on the example of the Czech Republic. METHODS: We extracted data on illicit drug-induced deaths from the Czech Republic GMR and Special Mortality registry (SMR) for the years between 2004 and 2012, and aggregated monthly and quarterly time series. We applied a new procedure to identify structural breakpoints in time series based on dating structural changes in standard linear regression models. RESULTS: In the GMR, breakpoints were identified in three time series: (i) opioid-related deaths; (ii) other stimulant-related deaths; and (iii) total drug-induced deaths. In the SMR, the structural breaks were identified for opioids, volatile substances and selection D time series. In each of these time series, the analysis identified a decrease in the intercepts in the different segments. DISCUSSION AND CONCLUSIONS: The structural breaks identified and quantified in the GMR time series were plausibly caused by the quality improvement efforts that started in 2006. These results demonstrate that it is critical for the analysis and use of drug mortality data collected in the registries to identify practice changes in the relevant registries, to quantify their influence and to adjust mortality estimates accordingly.

• Klíčová slova
• drug-induced deaths, drug-related mortality, overdose, structural change, time series,
• MeSH
• artefakty MeSH
• časové faktory MeSH
• lidé MeSH
• opioidní analgetika MeSH
• předávkování léky * MeSH
• stimulanty centrálního nervového systému * MeSH
• zakázané drogy * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• opioidní analgetika MeSH
• stimulanty centrálního nervového systému * MeSH
• zakázané drogy * MeSH

BACKGROUND: The aim of this study was to assess the epidemiological profile of unintentional opioid overdoses, the prevalence and number of psychotropic substances involved in opioid overdoses. METHODS: This was a descriptive study, in which 180 participants were enrolled, and covered a nine-years-period. For collecting data was used the National patient electronic system "My term". The variables as gender, age, duration of opioid dependence, number of overdoses, type of substance, number of antidote ampoules, duration of hospitalization were analyzed. Severity of poisoning was made by using the Poison severity score. RESULTS: Opioid overdose cases were significantly higher among males than females. Mean age with standard deviation (SD) was 32.23 ± 6.71 years. Mean years (±SD) of duration of opioid use disorder was 11.60 ± 5.89 years. The most commonly used primary substance was methadone in 68.89% and heroin in 31.11% cases. Twenty patients were treated with mechanical ventilation because of the severe respiratory depression. Poison severity score was moderate in 51.11%, severe in 45.56% and fatal in 3.33% of the cases. CONCLUSION: Most of the cases, predominantly males used one or two substances. The combination of methadone and benzodiazepine was most frequently used and the most common way was by injecting the abused substances. In most of the subjects PSS score was moderate and severe with no differences between genders.

• Klíčová slova
• Flumazenil, Naloxone, opioids, overdose, poison severity score,
• MeSH
• dospělí MeSH
• lidé MeSH
• předávkování opiáty epidemiologie   terapie   MeSH
• prevalence MeSH
• sexuální faktory MeSH
• univerzity * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Republika Severní Makedonie epidemiologie   MeSH

The second part of the review deals in detail with the diagnostics and treatment of toxic alcohols poisoning and management and indication of extracorporeal removal techniques in intoxication with other drugs, theophylline, valproic acid, metformin and metformin associated lactic acidosis, respectively. The extracorporeal treatment enhances the clearance of the toxin and corrects patients metabolic disturbances as well. It is necessary to use this treatment in severe intoxications. Indication of this invasive procedure falls within clinicians and nephrologists competence being advised by a toxicologist. This review could help make fast decisions.

• Klíčová slova
• extracorporeal treatment, hemodialysis, intoxication, overdose, poisoning,
• MeSH
• acidóza laktátová * MeSH
• dialýza ledvin MeSH
• hypoglykemika * farmakokinetika   MeSH
• lidé MeSH
• metformin * farmakokinetika   MeSH
• předávkování léky * terapie   MeSH
• theofylin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• hypoglykemika * MeSH
• metformin * MeSH
• theofylin MeSH

Supporting clearance of a toxic substance by an extracorporeal removal technique is one of the advanced treatment methods applied in poisoned patient management. General indications stem from toxicokinetics of the poison while individual indications are determined by poisoning severity. The first part of this review deals in detail with particular options of extracorporeal treatment in toxicology and also with its specific application when treating lithium and salicylates poisoning or dabigatran overdose. The aim of this review is to facilitate the clinicians and nephrologists decision making whether to indicate this invasive procedure, to communicate and summarize the existing recommendations and to highlight the most important ways of how to treat poisoning by specific toxic substances.

• Klíčová slova
• extracorporeal treatment, hemodialysis, intoxication, overdose, poisoning,
• MeSH
• antitrombiny otrava   MeSH
• dabigatran otrava   MeSH
• dialýza ledvin * MeSH
• kinetika MeSH
• lidé MeSH
• předávkování léky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitrombiny MeSH
• dabigatran MeSH

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are currently the most effective lipid-lowering drugs, effectively reducing the plasma total cholesterol and low-density lipoprotein, while also decreasing three triacylglycerols and increasing plasma high-density lipoprotein to a certain extent. However, the excessive or long-term use of statins can cause in vitro cytotoxicity, in vivo liver injury, liver necrosis, kidney damage, and myopathy in both human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with statins, and various antioxidants have been evaluated to investigate their protective roles against statin-induced liver, kidney, and muscle toxicities. Widespread attention has been given to statin-induced oxidative stress, with and without the use of other drugs. Much of the information about the mechanism for this reduction comes from cell culture and in experimental animal studies. The primary focus of this article is to summarize the research progress associated with oxidative stress as a plausible mechanism for statin-induced toxicity, as well as its metabolic interactions. This review summarizes the research conducted over the past five years into the production of reactive oxygen species, oxidative stress as a result of statin treatments, and their correlation with statin-induced toxicity and metabolism. Statin-induced metabolism involves various CYP450 enzymes, which provide potential sites for statin-induced oxidative stress, and these metabolic factors are also reviewed. The therapeutics of a variety of compounds against statin-induced organ damage based on their anti-oxidative effects is also discussed to further understand the role of oxidative stress in statin-induced toxicity. This review sheds new light on the critical roles of oxidative stress in statin-induced toxicity and prevention of this oxidative damage, as well as on the contradictions and unknowns that still exist regarding statin toxicity and the cellular effects in terms of organ injury and cell signaling pathways.

• Klíčová slova
• Metabolic interaction, Oxidative stress, Statins, Toxicology,
• MeSH
• lékové interakce MeSH
• lidé MeSH
• oxidační stres účinky léků   MeSH
• předávkování léky MeSH
• statiny škodlivé účinky   farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• statiny MeSH

Recreational use of the potent synthetic opioid 3,4- dichloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide (U-47700) is rising, accompanied by increasingly frequent cases of serious intoxication. This article reports a case of near-fatal U-47700 intoxication. A man was found unconscious (with drug powder residues). After 40 h in hospital (including 12 h of supported ventilation), he recovered and was discharged. Liquid chromatography/high-resolution mass spectrometry (LC/HRMS) or gas chromatography/mass spectrometry (GC/MS) were used to detect and quantify substances in powders, serum and urine. Powders contained U-47700 and two synthetic cannabinoids. Serum and urine were positive for U-47700 (351.0 ng/mL), citalopram (

• Klíčová slova
• 3,4- dichloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide, U47700, clonazolam, forensic science, forensic toxicology, novel benzodiazepine, novel psychoactive substance, synthetic opioid,
• MeSH
• benzamidy škodlivé účinky   analýza   MeSH
• benzodiazepiny analýza   MeSH
• chromatografie kapalinová MeSH
• citalopram analýza   MeSH
• dospělí MeSH
• hmotnostní spektrometrie MeSH
• lidé MeSH
• midazolam analýza   MeSH
• odhalování abúzu drog MeSH
• plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
• předávkování léky * MeSH
• soudní toxikologie MeSH
• zakázané drogy škodlivé účinky   analýza   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• benzamidy MeSH
• benzodiazepiny MeSH
• citalopram MeSH
• midazolam MeSH
• U-47700 MeSH Prohlížeč
• zakázané drogy MeSH

Lithium is widely used in psychiatry to treat bipolar affective disorders since 1970 but little is known about the incidence, clinical course and associated factors of acute lithium intoxication. Moderate and severe cases of lithium intoxication are rare. This case reports a patient with acute lithium intoxication (serum level of 3.7 mmol/L) with neurological symptoms imitating stroke, which affects the differential diagnosis in the pre-hospital and hospital care. Patient was treated with forced diuresis and dismissed 21 days after admission.

• MeSH
• antimanika škodlivé účinky   terapeutické užití   MeSH
• bipolární porucha farmakoterapie   MeSH
• cévní mozková příhoda diagnóza   MeSH
• diferenciální diagnóza MeSH
• lidé MeSH
• lithium krev   MeSH
• lithiumkarbonát škodlivé účinky   terapeutické užití   MeSH
• předávkování léky krev   diagnóza   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• antimanika MeSH
• lithium MeSH
• lithiumkarbonát MeSH