Non-fentanyl new synthetic opioids - An update.

BACKGROUND: New synthetic opioids (NSO) constitute one of the fastest-growing group of New Psychoactive Substances, which emerged on the illicit drug marker in the second half of 2000's. The most popular and the largest NSO subgroup are high potency fentanyl and its analogs. Subsequent to core-structure scheduling of fentanyl-related substances many opioids with different chemical structures are now emerging on the illicit drug market, rendering the landscape highly complex and dynamic. METHODS: PubMed, Scopus and Google Scholar were searched for appropriate articles up to December 2022. Moreover, a search for reports was conducted on Institutional websites to identify documentation published by World Health Organization, United Nations Office on Drugs and Crime, United States Drug Enforcement Administration, and European Monitoring Centre for Drugs and Drug Addiction. Only articles or reports written in English were selected. RESULTS: Non-fentanyl derived synthetic opioids, i.e., 2-benzylbenzimidazoles (nitazenes), brorphine, U-compounds, AH-7921, MT-45 and related compounds are characterized, describing them in terms of available forms, pharmacology, metabolism as well as their toxic effects. Sample procedures and analytical techniques available for detection and quantification of these compounds in biological matrices are also presented. Finally, as overdoses involving highly potent NSO may be difficult to reverse, the effectiveness of naloxone as a rescue agent in NSO overdose is discussed. CONCLUSIONS: Current review presents key information on non-fentanyl derived NSO. Access to upto-date data on substances of abuse is of great importance for clinicians, public health authorities and professionals performing analyses of biological samples.

Psychiatric and neurological complications of long COVID.

COVID-19 was primarily considered a pulmonary disease with extrapulmonary manifestations. As the pandemic spread, there has been growing evidence that the disease affects various organs/systems, including the central and peripheral nervous systems. Accumulation of clinical data demonstrates that in a large population of survivors impairments in the function of one or more organs may persist for a long time, a phenomenon commonly known as post COVID or long COVID. Fatigue and cognitive dysfunction, such as concentration problems, short-term memory deficits, general memory loss, a specific decline in attention, language and praxis abilities, encoding and verbal fluency, impairment of executive functions, and psychomotor coordination, are amongst the most common and debilitating features of neuropsychatric symptoms of post COVID syndrome. Several patients also suffer from compromised sleep, depression, anxiety and post-traumatic stress disorder. Patients with long COVID may demonstrate brain hypometabolism, hypoperfusion of the cerebral cortex and changes in the brain structure and functional connectivity. Children and adolescents represent a minority of COVID-19 cases, so not surprisingly data on the long-term sequelae after SARS-CoV-2 infections in these age groups are scarce. Although the pathogenesis, clinical characteristics, epidemiology, and risk factors of the acute phase of COVID-19 have been largely explained, these areas are yet to be explored in long COVID. This review aims to provide an update on what is currently known about long COVID effects on mental health.

Use of fentanyl, butyrfentanyl and furanylfentanyl as discussed on Polish online forums devoted to 'designer drugs'. / Uzywanie fentanylu, butyrylofentanylu i furanylofentanylu w opinii uzytkowników polskich forów internetowych poswieconych "dopalaczom".

OBJECTIVES: The study was aimed to analyze information posted by users of synthetic opioids on Polish online drug discussion forums. Special emphasis was given to sources of drugs and their availability, routes of administration, dosages, expected and toxic effects. METHODS: 6,143 reports related to synthetic opioids, posted between 2005 and mid 2019 on three widely available popular Polish online forums devoted to psychoactive substances, i.e., hyperreal.info/talk, dopek.info and forum.dopalamy, were collected and analyzed. The article presents data on three most popular opioids, i.e., fentanyl, butyrfentanyl and furanylfentanyl. RESULTS: Fentanyl was the most widely used and relatively easily accessible synthetic opioid in Poland. Butyrfentanyl and furanylfentanyl were far less popular. The main source of fentanyl was diversion of medicines, notably transdermal patches. Fentanyl, butyrfentanyl and furanylfentanyl are administered orally, buccally, sublingually, intranasally, by inhalation and intravenously. Concomitant use of fentanyl and its derivatives with other psychoactive compounds increases the risk of severe adverse effects. CONCLUSIONS: Our study contributed to amore comprehensive understanding of problems related to abuse of fentanyl, butyrfentanyl and furanylfentanyl in Poland. In the light of the relatively high popularity of pharmaceutical fentanyl used for non-medical purposes, there is an urgent need for more strict control over illegal sales of fentanyl transdermal preparations via the Internet, as well as disposal of used patches. Furthermore, patients using fentanyl should be warned that giving it to another person is against the law, and may lead to development of addiction and other serious health consequences. It is important to educate the society in order to increase awareness of the problem of opioid use, especially by young people, and to pay attention to signals which may indicate addiction among family members.

Role of Chemokines in the Development and Progression of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurogenerative disorder manifested by gradual memory loss and cognitive decline due to profound damage of cholinergic neurons. The neuropathological hallmarks of AD are intracellular deposits of neurofibrillary tangles (NFTs) and extracellular aggregates of amyloid ß (Aß). Mounting evidence indicates that intensified neuroinflammatory processes play a pivotal role in the pathogenesis of AD. Chemokines serve as signaling molecules in immune cells but also in nerve cells. Under normal conditions, neuroinflammation plays a neuroprotective role against various harmful factors. However, overexpression of chemokines initiates disruption of the integrity of the blood-brain barrier, facilitating immune cells infiltration into the brain. Then activated adjacent glial cells-astrocytes and microglia, release massive amounts of chemokines. Prolonged inflammation loses its protective role and drives an increase in Aß production and aggregation, impairment of its clearance, or enhancement of tau hyperphosphorylation, contributing to neuronal loss and exacerbation of AD. Moreover, chemokines can be further released in response to growing deposits of toxic forms of Aß. On the other hand, chemokines seem to exert multidimensional effects on brain functioning, including regulation of neurogenesis and synaptic plasticity in regions responsible for memory and cognitive abilities. Therefore, underexpression or complete genetic ablation of some chemokines can worsen the course of AD. This review covers the current state of knowledge on the role of particular chemokines and their receptors in the development and progression of AD. Special emphasis is given to their impact on forming Aß and NFTs in humans and in transgenic murine models of AD.

Carfentanil - from an animal anesthetic to a deadly illicit drug.

The use of novel synthetic opioids as recreational drugs has become a public health concern as they are implicated in numerous fatal intoxications across the world. Synthetic opioids have played a major role in the United States opioid crisis and may contribute to a similar opioid epidemic in Europe. The most prominent group of designer opioids consists of fentanyl and its analogues. At present, carfentanil is the most dangerous fentanyl derivative. It was recently detected as an adulterant to other illicit drugs and counterfeit pharmaceuticals, contributing to life-threatening hospital admissions and fatalities. Toxic exposure to carfentanil typically occurs through injection, insufflation or inhalation. Carfentanil produces similar pharmacotoxicological effects to other opioids. However, due to its extraordinary potency, reversing carfentanil-induced severe and recurring respiratory depression requires administration of multiple or higher than standard doses of naloxone. Toxicological reports indicate that carfentanil use is strongly connected to polydrug use. Detection of carfentanil requires specific and sensitive analytical methods that are not commonly available in hospitals. Since abuse of carfentanil is an emerging problem, particularly in the United States, there is an urgent need to develop new techniques for rapid determination of intoxication evoked by this drug as well as new treatment regimens for effective overdose maintenance. This review presents current knowledge on pharmacological activity of carfentanil, prevalence and patterns of use, and analytical methods of its detection. Special emphasis is given to carfentanil-related non-fatal and lethal overdose cases.

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment.

Synthetic cathinones appeared on the market in the 2000s as new psychoactive substances and gained significant prevalence among drug abusers. Cathinones produce psychostimulant and empathogenic effects by enhancing dopaminergic, noradrenergic, and serotoninergic neurotransmission in the brain, and those which potently and selectively enhance dopaminergic transmission are considered to have higher abuse potential. The present study examines the behavioral effects related to psychostimulant properties, abuse potential, and addiction in DBA/2J mice of two cathinones with different profile of action on monoamine system, 4-chloromethcathinone (4-CMC), and 4-methoxy-pyrrolidinopentiophenone (4-MeO-PVP). 4-CMC and 4-MeO-PVP increase spontaneous locomotor activity after acute treatment and produce behavioral sensitization after 7-day intermittent treatment, which is a common feature of drugs of abuse. 4-MeO-PVP, but not 4-CMC, produces conditioned place preference after 4 days, indicating its rewarding properties. Finally, the ability of 4-CMC and 4-MeO-PVP to induce withdrawal symptoms after discontinuation from 14-day treatment was assessed using a battery of tests for behavioral markers of depression in mice: a tail suspension test, a forced swim test, measuring despair, and a sucrose preference test, measuring anhedonia. None of the three tests revealed increased depressive symptoms. Moreover, neither spontaneous locomotor activity nor motor performance on a rotarod was impaired after 14-day treatment with the tested compounds. These results indicate that 14-day treatment of mice with 4-CMC or 4-MeO-PVP does not induce significant withdrawal symptoms after cessation, nor significant impairment of dopaminergic circuitry resulting in motor impairment. The current study shows that 4-CMC and 4-MeO-PVP produce abuse-related behavioral changes in mice, which are more pronounced after more dopamine-selective 4-MeO-PVP.

Four Synthetic Cathinones: 3-Chloromethcathinone, 4-Chloromethcathinone, 4-Fluoro-α-Pyrrolidinopentiophenone, and 4-Methoxy-α-Pyrrolidinopentiophenone Produce Changes in the Spontaneous Locomotor Activity and Motor Performance in Mice with Varied Profiles.

Two chloromethcathinones, 3-chloromethcathinone (3-CMC) and 4-chloromethcathinone (4-CMC), and two para-substituted α-pyrrolidinophenones, 4-methoxy-α-pyrrolidinopentiophenone (4-MeO-PVP) and 4-fluoro-α-pyrrolidinopentiophenone (4-F-PVP), represent synthetic cathinones, the second most frequently abused group of new psychoactive substances (NPSs), which has aroused a worldwide health concern in the last decade. Synthetic cathinones act as psychostimulants by elevating extracellular levels of monoaminergic neurotransmitters. This study investigates effects of 3-CMC, 4-CMC, 4-MeO-PVP, and 4-F-PVP on the spontaneous locomotor activity and motor performance of mice. Additionally, neurotoxicity of substituted methcathinones against SH-SY5Y neuroblastoma cells was evaluated. All test cathinones stimulate in a dose-dependent manner horizontal locomotor activity of mice. Consistently to our prior findings, pyrrovalerones, but not methcathinone derivatives, produce dose-dependent elevation of vertical locomotor activity (rearing behavior). None of the tested compounds decreases the time spent on the accelerating rotarod, pointing to the lack of considerable motor disability in mice after acute exposition. Only 4-MeO-PVP at the high tested dose (20 mg/kg) increases motor performance of mice. Considering that α-pyrrolidinophenones are highly potent and selective DA uptake inhibitors, while chloromethcathinones enhance non-selective DA/5-HT release, we suggest that the increase of vertical locomotor activity and performance on rotarod in mice may serve as a behavioral indicator of the monoaminergic profile of synthetic cathinones. Finally, this study gives first insights into cytotoxicity of both 3-CMC and 4-CMC displayed against SH-SY5Y cells, which emerges and intensifies after prolonged incubation, suggesting the indirect mechanism of action, unrelated to interactions with monoamine transporters.

NBOMes-Highly Potent and Toxic Alternatives of LSD.

Recently, a new class of psychedelic compounds named NBOMe (or 25X-NBOMe) has appeared on the illegal drug market. NBOMes are analogs of the 2C family of phenethylamine drugs, originally synthesized by Alexander Shulgin, that contain a N-(2-methoxy)benzyl substituent. The most frequently reported drugs from this group are 25I-NBOMe, 25B-NBOMe, and 25C-NBOMe. NBOMe compounds are ultrapotent and highly efficacious agonists of serotonin 5-HT2A and 5-HT2C receptors (Ki values in low nanomolar range) with more than 1000-fold selectivity for 5-HT2A compared with 5-HT1A. They display higher affinity for 5-HT2A receptors than their 2C counterparts and have markedly lower affinity, potency, and efficacy at the 5-HT2B receptor compared to 5-HT2A or 5-HT2C. The drugs are sold as blotter papers, or in powder, liquid, or tablet form, and they are administered sublingually/buccally, intravenously, via nasal insufflations, or by smoking. Since their introduction in the early 2010s, numerous reports have been published on clinical intoxications and fatalities resulting from the consumption of NBOMe compounds. Commonly observed adverse effects include visual and auditory hallucinations, confusion, anxiety, panic and fear, agitation, uncontrollable violent behavior, seizures, excited delirium, and sympathomimetic signs such mydriasis, tachycardia, hypertension, hyperthermia, and diaphoresis. Rhabdomyolysis, disseminated intravascular coagulation, hypoglycemia, metabolic acidosis, and multiorgan failure were also reported. This survey provides an updated overview of the pharmacological properties, pattern of use, metabolism, and desired effects associated with NBOMe use. Special emphasis is given to cases of non-fatal and lethal intoxication involving these compounds. As the analysis of NBOMes in biological materials can be challenging even for laboratories applying modern sensitive techniques, this paper also presents the analytical methods most commonly used for detection and identification of NBOMes and their metabolites.

Induction of immediate early genes expression in the mouse striatum following acute administration of synthetic cathinones.

BACKGROUND: Synthetic cathinones (SCs) form one of the most prominent group of the New Psychoactive Substances. SCs enhance central dopaminergic and noradrenergic neurotransmission, and are used as substitutes for illicit psychostimulants, namely cocaine, amphetamine, and methamphetamine. Changes in the expression of immediate early genes (IEGs) in the striatum underlie the addictive potential of drugs of abuse belonging to distinct pharmacologic groups. This work was aimed to assess the impact of acute administration of the prominent SCs on the mRNA levels of IEGs in the mouse striatum. METHODS: Effects of 3,4-MDPV, 2,3-MDPV, α-PVP, PV8, PV9, methcathinone (MC) and 3-fluoromethcathinone (3-FMC) on the mRNA levels of ten IEGs, one and two hours after exposure, were measured in the mouse striatum using the quantitative RT-PCR technique. RESULTS: All SCs used in the study produced increased mRNA levels of the following IEGs: Areg, c-fos, Csrnp1, Dusp1, Dusp14, Egr2, Egr4 and FosB. Additionally, the majority of SCs increased the expression of Homer1 and c-jun. The magnitude of observed changes varied by the drug, analyzed gene and, in many cases, by time after administration. CONCLUSIONS: This study demonstrates that SCs increase the expression of IEGs in the mouse striatum, which may lead to a plethora of effects, as proteins encoded by the analyzed genes are involved in diverse actions, including an acute response to the drug and the neuroplasticity underlying the development of addiction.

An expanding world of new psychoactive substances-designer benzodiazepines.

The abuse of new psychoactive substances (NPS) has been increasing dramatically since the late 2000s worldwide. Between 2009 and 2017, a total of 803 individual NPS were reported to the United Nations Office of Drugs and Crime by 111 countries and territories. Although the most popular compounds are synthetic cannabinomimetics and psychostimulatory derivatives of cathinone (so-called ß-keto-amphetamines), novel benzodiazepines have recently emerged on the recreational drug market. The misuse/abuse of "designer benzodiazepines" (DBZD), a common name for the benzodiazepine class NPS, has become an increasing problem in many countries. The DBZD group includes pharmaceutical drug candidates that have never been approved for medical use, compounds that were synthesized by a simple structural modification of a registered drug, and some active metabolites of registered benzodiazepines. This survey presents members of the DBZD group, describes the epidemiological trends and clinical effects associated with DBZD use, and discusses available data on their metabolism. Special emphasis is given to cases of intoxications involving these compounds.

Methcathinone and 3-Fluoromethcathinone Stimulate Spontaneous Horizontal Locomotor Activity in Mice and Elevate Extracellular Dopamine and Serotonin Levels in the Mouse Striatum.

Methcathinone (MC) and 3-fluoromethcathinone (3-FMC) are well-known members of the synthetic cathinone derivatives, the second most abused group of novel psychoactive substances (NPS). They are considered as methamphetamine-like cathinones, as they elicit their psychostimulatory effects via inhibition of monoamine uptake and enhanced release. The present study examines the effects of MC and 3-FMC on the spontaneous locomotor activity of mice and extracellular levels of dopamine and serotonin in the mouse striatum. Both MC and 3-FMC produced a dose-dependent increase of horizontal locomotor activity, but no significant changes in rearing behavior were observed. The locomotor stimulation induced by MC and 3-FMC is mediated by activation of dopaminergic neurotransmission, as selective D1-dopamine receptor antagonist, SCH 23390, abolished the effects of both drugs. In line with pharmacological data obtained by previous in vitro studies, MC and 3-FMC produced potent increases of extracellular dopamine and serotonin levels in the mouse striatum. Taken together, results presented within this study confirm previous findings and expand our knowledge on the pharmacology of MC and 3-FMC along with their behavioral effects.

Effects of the new generation α-pyrrolidinophenones on spontaneous locomotor activities in mice, and on extracellular dopamine and serotonin levels in the mouse striatum.

PURPOSE: Pyrovalerone derivatives (α-pyrrolidinophenones) form a distinct branch of synthetic cathinones, a popular group of novel psychoactive substances, and exert strong psychostimulatory effects resulting from their high potency to inhibit dopamine (DA) and norepinephrine transporters, with negligible activity at the serotonin (5-HT) transporter. In contrast to the old generation α-pyrrolidinophenones, 3,4-MDPV and α-PVP, there is limited data on the pharmacology and toxicology of the novel analogs. Therefore, the present study assesses the in vivo effects of two new pyrovalerones, PV8 and PV9, along with those of α-PVP, on spontaneous locomotor activities of mice and extracellular DA and 5-HT levels in the mouse striatum. METHODS: Spontaneous locomotor activity was measured using Opto-Varimex Auto-Track. Effects of tested compounds on extracellular levels of DA and 5-HT in the striatum were studied by an in vivo microdialysis technique; their concentrations in dialysate fractions were analyzed by high-performance liquid chromatography with electrochemical detection. RESULTS: α-PVP, PV8 and PV9 stimulated mice locomotor activity (an effect being blocked by D1-dopamine receptor antagonist, SCH 23390), and increased extracellular levels of DA and 5-HT in the striatum. Observed effects depend on dose, time and compound under investigation, with α-PVP being more potent than PV8 and PV9. When used at the same dose, the pyrovalerones produced effects significantly weaker than a model, old generation psychostimulant, methamphetamine. CONCLUSIONS: Enhancement of dopaminergic neurotransmission plays a dominant role in the psychomotor stimulation caused by α-PVP, PV8 and PV9. Extending an aliphatic side chain beyond a certain point leads to the decrease in their potency in vivo.

Abuse of fentanyl: An emerging problem to face.

Fentanyl is a potent synthetic opioid used as a narcotic analgesic supplement in general and regional anesthesia as well as in management of persistent, severe chronic pain. Alarming epidemiological and forensic medicine reports, accumulated mainly during the last two decades, point to a growing increase in illicit use of fentanyl, mainly in North America and Europe. Toxicological data indicates that fentanyl use is inextricably linked with polydrug use. There are two main sources of fentanyl on the "recreational" drug market. First, the most common, combines illicitly manufactured fentanyl from clandestine sources. The drug is often mixed up with heroin ("fake heroin") to increase its potency at a little cost, or included in cocaine products. It can also be mixed into and sold as oxycodone-, hydrocodone- or alprazolam-containing tablets. The other way to gain fentanyl is through the diversion of fentanyl-containing medicines, especially transdermal patches (FTPs). Fentanyl extracted from FTP can be administered intravenously, insufflated or inhaled after volatilization. The drug can also be delivered by oral or transmucosal application of the whole patch, or by rectal insertion. The most common overdose symptoms are coma, lethargy, respiratory depression and arrest. Although naloxone, an opioid receptor antagonist, is the standard drug for fentanyl overdose rescue, attempts to revive patients with naloxone could be unsuccessful, due to the rapid onset of fentanyl's action. As the fentanyl problem is constantly growing, there is an urgent need for new, effective harm-reduction strategies and technologies, as well as overdose maintenance.

Cytotoxicity of α-Pyrrolidinophenones: an Impact of α-Aliphatic Side-chain Length and Changes in the Plasma Membrane Fluidity.

Pyrovalerone derivatives (α-pyrrolidinophenones) form a branch of synthetic cathinones, a second most prominent group of novel psychoactive substances. Although the toxicity of 3,4-MDPV, a progenitor of the α-pyrrolidinophenones, is well described, little is known of the potential cytotoxicity of the new members of this group entering the recreational drug market each year. The present study assesses the cytotoxicity of members of the α-pyrrolidinophenone group, i.e., α-PVP, its longer side-chain derivatives PV8 and PV9, and their 4-fluoro- and 4-methoxy-analogs, against model cell lines for the nervous system (SH-SY5Y), liver (Hep G2) and upper airway epithelium (RPMI 2650), and cardiomyocytes (H9C2(2-1)). Additionally, an impact of pyrovalerones on the fluidity of the plasma membrane, as the potential mechanism of their cytotoxicity, was examined. The longer side-chain α-pyrrolidinophenones and their fluoro- and methoxy-analogs produce more pronounced maximal cytotoxicity, with regard to mitochondrial activity and cell membrane integrity, than the five-carbon α-PVP and its substituted derivatives. The report demonstrates, for the first time, that changes of fluidity of the interior part of plasma membrane contribute to the cytotoxicity of pyrovalerone derivatives, in addition to the previously reported mechanisms. Taking into consideration our previous findings that PV8 and PV9 produce weaker psychostimulatory effects than α-PVP, the higher cytotoxicity of the new generation of pyrovalerones can pose a serious threat to abusers, as it is possible that longer-chain compounds may be taken in higher doses to obtain similar levels of stimulation.

An Expanding World of Novel Psychoactive Substances: Opioids.

The abuse of novel psychoactive substances (NPS) has been increasing dramatically worldwide since late 2000s. By the end of 2015, more than 560 NPS had been reported to the European Monitoring Centre for Drugs and Drug Addiction. Although the most popular compounds are synthetic cannabinoids and psychostimulatory derivatives of cathinone (so-called ß-keto-amphetamines), novel synthetic opioids have recently emerged on the recreational drug market. They include fentanyl (a potent narcotic analgesic) and its analogs (e.g., acetylfentanyl, acryloylfentanyl, carfentanil, α-methylfentanyl, 3-methylfentanyl, furanylfentanyl, 4-fluorobutyrylfentanyl, 4-methoxybutyrylfentanyl, 4-chloroisobutyrylfentanyl, 4-fluoroisobutyrylfentanyl, tetrahydrofuranylfentanyl, cyclopentylfentanyl, and ocfentanil) and compounds with different chemical structures, such as AH-7921, MT-45, and U-47700. This survey provides an overview of the pharmacological properties, pattern of use, and desired and unwanted effects of the above-listed novel opioids. Special emphasis is given to cases of non-fatal and lethal intoxication involving these compounds.

Treatment guidelines for Circadian Rhythm Sleep-Wake Disorders of the Polish Sleep Research Society and the Section of Biological Psychiatry of the Polish Psychiatric Association. Part I. Physiology, assessment and therapeutic methods. / Standardy leczenia zaburzen rytmu okolodobowego snu i czuwania opracowane przez Polskie Towarzystwo Badan nad Snem i Sekcje Psychiatrii Biologicznej Polskiego Towarzystwa Psychiatrycznego. Czesc I. Fizjologia, metody oceny i oddzialywania terapeutyczne.

Majority of the physiological processes in the human organism are rhythmic. The most common are the diurnal changes that repeat roughly every 24 hours, called circadian rhythms. Circadian rhythms disorders have negative influence on human functioning. The aim of this article is to present the current understanding of the circadian rhythms physiological role, with particular emphasis on the circadian rhythm sleep-wake disorders (CRSWD), principles of their diagnosis and chronobiological therapy. The guidelines are based on the review of recommendations from the scientific societies involved in sleep medicine and the clinical experiences of the authors. Researchers participating in the preparation of guidelines were invited by the Polish Sleep Research Society and the Section of Biological Psychiatry of the Polish Psychiatric Association, based on their significant contributions in circadian rhythm research and/or clinical experience in the treatment of such disorders. Finally, the guidelines were adjusted to the questions and comments given by the members of both Societies. CRSWD have a significant negative impact on human health and functioning. Standard methods used to assess CRSWD are sleep diaries and sleep logs, while the actigraphy, when available, should be also used. The most effective methods of CRSWD treatment are melatonin administration and light therapy. Behavioral interventions are also recommended. Afourteen-day period of sleep-wake rhythm assessment in CRSWD enables accurate diagnosis, adequate selection of chronobiological interventions, and planning adequate diurnal timing of their application. This type of assessment is quite easy, low-cost, and provides valuable indications how to adjust the therapeutic approach to the circadian phase of the particular patient.

Treatment guidelines for Circadian Rhythm Sleep - Wake Disorders of the Polish Sleep Research Society and the Section of Biological Psychiatry of the Polish Psychiatric Association. Part II. Diagnosis and treatment. / Standardy leczenia zaburzen rytmu okolodobowego snu i czuwania Polskiego Towarzystwa Badan nad Snem i Sekcji Psychiatrii Biologicznej Polskiego Towarzystwa Psychiatrycznego. Czesc II. Diagnoza i leczenie.

AIM: Circadian rhythm sleep-wake disorders (CRSWD) are a group of disorders, in which the timing of sleep and wakefulness significantly differs from a patient's expectations or socially acceptable times. The aimof the article is to present the current principles for the diagnosis and treatment of CRSWD in adults and children. METHOD: Guidelines proposed as CRSWD treatment standard are based on the recommendations from the scientific societies involved in the sleep research and medicine. Researchers participating in the guidelines preparation were invited by the Polish Sleep Research Society and the Section of Biological Psychiatry of the Polish Psychiatric Association based on their significant contribution to the circadian rhythm research and/or clinical experience in the treatment of these disorders. Finally, the guidelines were adjusted to the questions and comments given by the members of both Societies. RESULTS: Patients with endogenous CRSWD are often misdiagnosed and treated for insomnia or hypersomnia. Therefore, each patient reporting sleep-wake disorders should be interviewed about the quality of sleep and its timing during free days (e.g. weekends, holidays). Avalid CRSWD diagnosis can be also established by using sleep diaries/logs and actigraphy. The treatment of choice for CRSWD is chronotherapy, which involves melatonin application, light therapy, and behavioral interventions. Sleep disorders associated with shift work and time zone changes are a growing health problem. Interventions for these disorders should primarily focus on prevention. CONCLUSIONS: The main problem in the treatment of CRSWD is an invalid diagnosis. Hypnotics and/or psychostimulants are often used instead of chronotherapeutic interventions, what can alleviate symptoms but is not an effective treatment.

The effects of topiramate on lipopolysaccharide (LPS)-induced proinflammatory cytokine release from primary rat microglial cell cultures.

A growing body of evidence suggests that inflammatory processes and activation of glial cells could contribute to seizures and epileptogenesis. In various animal studies on epilepsy, proinflammatory cytokines have been demonstrated to exert a proconvulsive activity. On the other hand, it is suggested that antiepileptic drugs could modulate immune system activity. The aim of the present study was to investigate whether topiramate, a new generation antiepileptic drug with a complex mechanism of action, could affect the lipopolysaccharide (LPS)-induced release of TNF-α, IL-1ß and IL-6 from primary rat microglial cell cultures. Proinflammatory cytokines were measured in supernatants of primary rat microglial cell culture with enzyme-linked immunosorbent assay kits. Additionally, the effect of the drug on LPS-evoked changes in mitochondrial metabolic activity was evaluated with the aid of the MTT test. Topiramate (1, 10, 100µg/ml; 24h incubation) produced a statistically significant decrease in LPS-stimulated IL-1ß and IL-6 levels from primary rat microglial cells in a concentration-dependent manner. The drug used at a concentration of 100µg/ml also significantly suppressed TNF-α release. Incubation of microglial cells with topiramate for 24h prevented the LPS-induced increase in their mitochondrial activity. It is suggested that the anti-cytokine action of topiramate could provide an additional mechanism in its antiepileptic activity.

Cytotoxic Activity of Pyrovalerone Derivatives, an Emerging Group of Psychostimulant Designer Cathinones.

The growing popularity of novel psychoactive substances (NPS) has aroused the concerns of public health specialists. The pyrovalerone derivatives are a branch of synthetic cathinones, a very popular group of psychostimulant NPS. Despite numerous case reports of fatal intoxications, little is known about the cytotoxicity of these substances. Therefore, this study was aimed to evaluate the toxic properties of pyrovalerone, its highly prevalent derivative 3,4-methylenedioxypyrovalerone (3,4-MDPV) with its two major metabolites (catechol-MDPV and methylcatechol-MDPV) and the structural isomer 2,3-MDPV, together with newer members of the group, i.e., α-pyrrolidinovalerothiophenone (α-PVT) and α-pyrrolidinooctanophenone (PV9), using model human cell lines for neurons (SH-SY5Y), hepatocytes (Hep G2), and upper airway epithelium (RPMI 2650). We found that the first generation pyrovalerones (pyrovalerone, 3,4-MDPV, and 2,3-MDPV) produced a modest decrease of mitochondrial activity in the three examined cell lines, but were active in lower concentrations than methamphetamine used as a reference psychostimulant compound. Since catechol-MDPV displayed greater toxic potential than the parent compound, we suggest that the toxicity of 3,4-MDPV could be attributed to activity of this metabolite. Strikingly, the two new generation pyrovalerones, α-PVT and PV9, seem to be the most potent cytotoxic compounds: both induced highly pronounced mitochondrial dysfunction; the latter also demonstrated significant damage to cell membranes. The reported in vitro toxic activity of pyrovalerone cathinones against different cell types reinforces existing concerns regarding the health risks associated with the intake of these drugs.

JWH-133, a Selective Cannabinoid CB2 Receptor Agonist, Exerts Toxic Effects on Neuroblastoma SH-SY5Y Cells.

Endocannabinoid system plays an important role in the regulation of diverse physiological functions. Although cannabinoid type 2 receptors (CB2) are involved in the modulation of immune system in peripheral tissues, recent findings demonstrated that they are also expressed in the central nervous system and could constitute a new target for the treatment of neurodegenerative disorders. At present, very little is known about the potential effects of CB2-mimetic drugs on neuronal cells. This study aimed to examine whether JWH-133, a selective CB2 receptor agonist, affects the survival of SH-SY5Y neuroblastoma cell line, a widely used experimental in vitro model to study mechanisms of toxicity and protection in nigral dopaminergic neurons. Cell viability was assessed using two complementary methods: MTT test measuring mitochondrial activity and LDHe test indicating disruption of cell membrane integrity. In addition, cell proliferation was measured using BrdU incorporation assay. JWH-133 (10-40 µM) induced a concentration-dependent decrease of SH-SY5Y cell viability and proliferation rate. Using AM-630, a reverse agonist of CB2 receptors, as well as Z-VAD-FMK, a pan-caspase inhibitor, we demonstrated that the cytotoxic effect of JWH-133 presumably was not mediated by activation of CB2 receptors or by caspase pathway. Results of this work suggest that agonists of CB2 receptors when administered in multiple/high doses may induce neuronal damage.