Relative abuse liability of gamma-hydroxybutyric acid, flunitrazepam, and ethanol in club drug users

OBJECTIVES: Despite the increasing concern about gamma-hydroxybutyric acid (GHB) toxicity, there are few studies examining the clinical pharmacology of GHB and its abuse potential. To evaluate GHB-induced subjective and physiological effects, its relative abuse liability and its impact on psychomotor performance in club drug users. MATERIALS AND METHODS: Twelve healthy male recreational users of GHB participated in 5 experimental sessions in the framework of a clinical trial. The study was randomized, double-blind, double-dummy, and crossover. Drug conditions were a single oral dose of GHB (40 or 60 mg/kg), ethanol (0.7 g/kg), flunitrazepam (1.25 mg), and placebo. Study variables included vital signs (blood pressure, heart rate, oral temperature, pupil diameter), psychomotor performance (digit symbol substitution test, balance, Maddox-Wing), subjective effects (a set of 13 visual analogue scales, Addiction Research Center Inventory-49 items, and Evaluation of the Subjective Effects of Substances with Potential of Abuse questionnaires), and pharmacokinetics. RESULTS: All active conditions induced positive effects related to their abuse potential. The administration of GHB produced euphoria and pleasurable effects with slightly higher ratings than those observed for flunitrazepam and ethanol. Gamma-hydroxybutyric acid induced a biphasic time profile with an initial stimulant-like effect related to the simultaneous rise of plasma concentrations and a latter sedative effect not related to GHB kinetics. Gamma-hydroxybutyric acid increased blood pressure and pupil diameter. Ethanol induced its prototypical effects, and flunitrazepam produced marked sedation. Gamma-hydroxybutyric acid and flunitrazepam impaired psychomotor performance, digit symbol substitution test, and balance task, whereas ethanol, at the dose tested, induced only mild effects exclusively affecting the balance task. CONCLUSIONS: Our results suggest a high abuse liability of GHB and flunitrazepam in club drug users.     

From Death to Death Certificate: What do the Dead say?

This is an overview of medicolegal death investigation and death certification. Postmortem toxicological analysis, particularly for ethanol and drugs of abuse, plays a large role in the forensic investigation of natural and unnatural deaths. Postmortem drug concentrations must be interpreted in light of the autopsy findings and circumstances. Interpretations of drug and ethanol concentrations are important for death certification, but they also may be important for other stakeholders such as police, attorneys, public health practitioners, and the next-of-kin.     

组蛋白修饰在酒精成瘾中的作用及机制

酒精是全世界最常用且已被公认的成瘾物质,随着我国经济的快速发展,与饮酒相关的健康问题和社会问题亦急剧增加。酒精成瘾是一种精神疾病,会对人体带来多方面的影响。本文从表观遗传学的角度介绍酒精成瘾对组蛋白修饰的作用及其机制,有助于读者了解酒精成瘾的发生机制以及与之相关的长期神经适应。     

Current clinical aspects of drug-facilitated sexual assaults in sexually abused victims examined in a forensic emergency unit

Sexual assault is defined as any undesired physical contact of a sexual nature perpetrated against another person and is a prevalent problem presenting at emergency departments, emergency forensic medicine units, and rape crisis centres worldwide. Drug-facilitated sexual assault (DFSA) is a complex problem that is encountered with increasing frequency. But this problem is often underrepresented because most DFSAs are not reported by the frightened victims or are diagnosed as an acute drug or alcohol intoxication, thereby bypassing sexual abuse diagnosis and appropriate care. Proper care must be taken to ensure the chain of custody. Emergency physicians need to be aware of the phenomenon and work together with reference emergency forensic medicine units and rape crisis centres, which are capable of taking care of the male and female victims of sexual abuse. If no attention is given to the risk of DFSA, then toxicological samples (urine, blood, hair) and other biologic evidence may remain unidentified and semen, vaginal secretions, and vaginal epithelial cells cannot be genetically typed by a crime laboratory. This article reports the main clinical aspects of DFSA encountered in emergency departments at the beginning of the 21st century and the experience of an emergency forensic medicine unit based at a hospital (Compiègne, France). Guidelines are proposed for clinical examination of DFSA victims, clinical forensic medical examination, and accurate samplings for further toxicological and biological evidence.     

Latest advances in studies of phosphodiesterases(PDEs):Implication in CNS disorders

Phosphodiseterases(PDEs),a superfamily of 11 enzymes(PDE1-11) that hydrolyze cyclic nucleotides(cAMP and cGMP),mediate a variety of peripheral and central functions.PDE inhibitors can be used for treatment of various diseases,including peripheral diseases such as chronic obstructive pulmonary disease(COPD),sexual dysfunction,and heart failures,and CNS disorders such as Alzheimer′s disease,depression,schizophrenia,anxiety,alcoholism,Parkinson′s disease,Huntington’s disease,and stroke.While to date there have been no PDE inhibitors approved for clinic utility for CNS disorders,significant progresses have been made in preclinical and clinical studies in this area.More specifically,we have found that inhibition of PDE4,which specifically catalyzes the hydrolysis of cAMP,reversed memory deficits produced by hippocampal infusions of β amyloid peptide 1-42(Aβ1-42).Consistent with this,the PDE4 inhibitor rolipram also attenuated Aβ42-induced inflammatory responses,apoptosis,and deficit in cAMP/CREB signaling in the hippocampus.In addition,using mice deficient in a specific PDE4 subtype(PDE4A,4B,or 4D),we identified that PDE4A and PDE4D may be the major subtypes in these processes.We also demonstrated that PDE4 might be a novel target for treatment of alcoholism.Rolipram selectively reduced ethanol preference in mice and rats,which drink excessive ethanol.This appears to be contributed by PDE4B,which is enriched in the striatum and nucleus accumbens,the brain regions mediating alcohol dependence and abuse,although the role of PDE4A cannot be excluded.PDE10 may also be involved in ethanol drinking behavior.Finally,studies to date have demonstrated that disruption of PDE1 or PDE10 could be beneficial for cognitive dysfunction in schizophrenia.Taken together,increasing demonstrations suggest that PDEs,in particular PDE1,PDE4,and PDE10,are important targets for treatment of CNS disorders,including Alzheimer′s disease,depression,schizophrenia,and alcoholism.     

Hair as a biological indicator of drug use, drug abuse or chronic exposure to environmental toxicants

In recent years hair has become a fundamental biological specimen, alternative to the usual samples blood and urine, for drug testing in the fields of forensic toxicology, clinical toxicology and clinical chemistry. Moreover, hair-testing is now extensively used in workplace testing, as well as, on legal cases, historical research etc. This article reviews methodological and practical issues related to the application of hair as a biological indicator of drug use/abuse or of chronic exposure to environmental toxicants. Hair structure and the mechanisms of drug incorporation into it are commented. The usual preparation and extraction methods as well as the analytical techniques of hair samples are presented and commented on. The outcomes of hair analysis have been reviewed for the following categories: drugs of abuse (opiates, cocaine and related, amphetamines, cannabinoids), benzodiazepines, prescribed drugs, pesticides and organic pollutants, doping agents and other drugs or substances. Finally, the specific purpose of the hair testing is discussed along with the interpretation of hair analysis results regarding the limitations of the applied procedures.     

Methamphetamine-induced neurotoxicity: the road to Parkinson’s disease

Studies have implicated methamphetamine exposure as a contributor to the development of Parkinson’s disease. There is a significant degree of striatal dopamine depletion produced by methamphetamine, which makes the toxin useful in the creation of an animal model of Parkinson’s disease. Parkinson’s disease is a progressive neurodegenerative disorder associated with selective degeneration of nigrostriatal dopaminergic neurons. The immediate need is to understand the substances that increase the risk for this debilitating disorder as well as these substances’ neurodegenerative mechanisms. Currently, various approaches are being taken to develop a novel and cost-effective anti-Parkinson’s drug with minimal adverse effects and the added benefit of a neuroprotective effect to facilitate and improve the care of patients with Parkinson’s disease. A methamphetamine-treated animal model for Parkinson’s disease can help to further the understanding of the neurodegenerative processes that target the nigrostriatal system. Studies on widely used drugs of abuse, which are also dopaminergic toxicants, may aid in understanding the etiology, pathophysiology and progression of the disease process and increase awareness of the risks involved in such drug abuse. In addition, this review evaluates the possible neuroprotective mechanisms of certain drugs against methamphetamine-induced toxicity.     

Analytical techniques in androgen anabolic steroids (AASs) analysis for antidoping and forensic purposes

A survey on the main analytical challenges related to the analysis of Androgen Anabolic Steroids (AASs) is reported. AASs analysis is an issue regarding antidoping analyses as well as forensic toxicology applications. This paper reports an overview of the more recent literature regarding various aspects of sample preparation, analytical techniques and interpretation of results for AASs identification in biological samples. New analytical approaches, mainly for their application to the antidoping field, are reported. The application of AASs analysis in forensic cases is also described, taking into consideration mainly the different biological samples that can be analysed for forensic purposes. Particular attention was played on the application of hair analysis as alternative biological specimen for the determination of AASs abuse.     

Methods for treating neurological conditions (WO2011159945)

This patent application claims that inhibition of p21-activated kinases (PAK) reverses, partially reverses or delays clinical signs in neurological conditions (main claim for Huntington's disease (HD), substance abuse and addiction, Parkinson's disease, depression, bipolar disorder, anxiety disorder, posttraumatic stress disorder and neurofibromatosis). Several compounds with a pyrido-[2,3-d]pyrimidine-7(8H)-one core and high affinity to the catalytic domain of PAK1-4 are described in the patent. These PAK inhibitors are hypothesized to exert beneficial effects on clinical symptoms via modulation of dendritic spine morphology and/or synaptic function. Preliminary preclinical data suggest that PAK inhibition may be an interesting approach for the treatment of HD, neurofibromatosis and fragile X syndrome, while data for other neurological conditions are missing. Current limitations call for a comprehensive characterization of the role of PAK dysfunction in neurological disorders before further testing the effect of PAK inhibitors in relevant preclinical models. If ever, it will probably take many years before the most promising compounds will head to the clinic for further assessment in patients with neurological disorders.     

Forensic child abuse evaluation: a review

This review discusses the forensic medical and psychological assessments of children and adolescents suspected of being victims of sexual or physical abuse/neglect. Evaluation of the whole child and the need to minimize trauma during the investigative and assessment processes are stressed. The forensic medical examination is reviewed, including the specifics of the pediatric anogenital examination. The key components of the forensic medical examination in sexual assault cases are also reviewed, with particular attention to maintaining the integrity of the process. Special emphasis is placed on the forensic interview in child sexual abuse cases, the best evidence available and areas in need of further research.     

Training community‐based clinicians in screening and brief intervention for substance abuse problems: Translating evidence into practice

Screening and brief intervention in general health care settings are efficacious but have not been widely adopted. Our objective was to assess the effect of an educational intervention on clinicians’ substance abuse‐related clinical practices. The study was a telephone survey of practicing physicians, nurses, psychologists, physician's assistants, and social workers who attended a half‐day continuing education course on one of four occasions. The course covered the stages of behavioral change and motivational counseling, using primarily role play with standardized patients. Of 87 course attendees, 70 (80%) completed the interview. Months to years after the course, most (91%) reported that the course made an impact on their practice. Most (78%) of respondents reported that they frequently or always asked new patients who drank alcohol a formal screening questionnaire such as the CAGE, and 94% frequently or always assessed their substance abusing patients’ readiness to change. Most respondents reported that since taking the course they were more likely (1) to screen patients for alcohol or drug related problems (86%) and (2) to ask patients about their substance abuse on a follow‐up visit (96%). After exposure to an active‐learning half‐day continuing education course, clinicians reported improvement with and high rates of desirable substance abuse‐related clinical practices up to 5 years later. Continuing education efforts that incorporate active learning directed toward practicing clinicians show promise for improving rates of brief intervention for alcohol and other drug abuse.     

Parental substance abuse and risks to children’s safety,health and psychological development

Abstract

Aims: This study looks at the connection between parents’ substance abuse and their 0–6 years old children’s somatic and psychological health. Methods: A retrospective population-based cohort study based on Finnish health care and social welfare registers. The participants were all children born in Finland in 1997 (N?=?58,667) and 2002 (N?=?55,146) and their biological parents. Children were followed up for hospitalisations because of injuries, somatic illness and psychiatric disorders. The association between hospitalisations and parents’ substance abuse as well as living with the abusing parent were estimated using logistic regression. Findings: Children’s hospitalisations for all reasons were more prevalent if the mother or the father had a substance abuse problem. Mother’s substance abuse increased the children’s risk of hospitalisations for somatic illness (OR?=?1.34) and psychiatric disorders (OR?=?1.33, father’s substance abuse increased the risk of hospitalisation because of psychiatric disorders (OR?=?1.18). The risks were even higher if both parents were substance abusers. Conclusions: Parents’ substance abuse can cause a variety of harms to children, which may be related to unsafe environment, long-standing stress, and non-adequate responding to the child’s needs. Multi-professional work with substance abusing parents and their children is crucial in order to reduce children’s risks for poor health.     

Madelung's Syndrome: multiple symmetrical lipomatosis, alcoholism, pseudoliposarcoma and progressive neuropathy

Three cases of multiple symmetrical lipomatosis (Madelung's disease) are described occurring in three male alcoholics presenting to a Gastroenterology Unit. The patients all had the characteristic development and distribution of multiple lipomata and the later occurrence of a severe progressive peripheral neuropathy. Two patients had alcohol related liver disease.     

Parkinson’s disease: the most common diagnostic mistakes in Lithuania

Parkinson’s disease (PD) belongs to group of neurodegenerative diseases. PD diagnosis is clinical, based on these signs: tremor, rigidity, bradykinesia, akinesia or hypokinesia. The aim of the work was to determine the frequency of separate clinical forms of Parkinson’s disease and difficulties at this disease diagnosis. After examining 267 patients, foreseen clinical criterion of Parkinson’s disease correspond 202 (44.0% persons) ? 115 women and 87 men and for 65 patients diagnosis of PD was not confirmed, because they did not correspond with accepted criteria of Parkinson’s disease. While analyzing clinical peculiarities of disease we ascertained that rigidity-tremor form of disease prevailed for 152 (75.2%, 86 women and 66 men) patients. The rigidity form was more rare ? 28 (13.9%, 13 women and 15 men). Not very frequent was a tremor form of disease -? 22 (10.9%, 16 women and 6 men) patients. According to data of our research, for almost one fourth of patients (65, 24.3%) the diagnosis of Parkinson’s disease was not confirmed after clinical examination. These patients did not correspond with clinical criteria of PD. The data of our research maintain that for almost one fourth (one fourth of what?) (24.3%) the diagnosis was incorrect. Although these patients did not correspond with accepted criteria of PD, they had been treated with antiparkinsonic medications. The PD diagnosis for them was determined only according to separate symptoms: tremor, gait alterations or memory deterioration and behaviour alternations. It must be noted, that symptoms of Wilson’s disease, MSA or brain infarction were estimated as PD. Examining patients at home, we ascertained that not all patients use prescribed L-dopa preparations. A part of patients or their relatives stopped using of this drug independently. We also made note of the fact that urinary incontinence manifested using dopamine agonist ropinirole. This side effect became significant problem for patient himself and for his relatives.     

Anomie, alcohol abuse and alcohol consumption: a prospective-analysis

Cross-sectional and 36-month prospective analyses of the relationships among anomie and both alcohol abuse and alcohol consumption patterns provided little support that anomie was directly associated with ethanol ingestion patterns in a sample of 302 male air traffic controllers. This lack of association was observed for self-reported alcohol consumption, interview-established alcohol abuse and biochemical markers of alcohol intake. In addition, anomie was not predictive of change in alcohol use/abuse over 36 months, controlling for baseline levels of alcohol use and abuse and for relevant demographic factors. Measurement of anomie and alcohol use/abuse, the relative importance of anomie in various socioeconomic groups and issues related to prospective research on this topic are discussed.     

Is There a Common Biological Basis for Reinforcement from Alcohol and Other Drugs?

Vulnerability to substance abuse is an important emerging issue. A critical aspect of this phenomenon is the degree to which individuals who abuse on substance are likely to abuse other substances, alone or in combination with each other. The extent to which several distinct drugs will come to serve as positive reinforcers within genetically defined subjects defines their commonality. Questions in this area are directed at determining whether reinforcement from and abuse of alcohol and other drugs define variations within a single behavioral phenomenon, or whether reinforcement and abuse must be individually defined for each substance involved. Findings related to this commonality issue are now emerging from the areas of pharmacogenetics and operant drug self-administration. Previous studies have shown that ethanol can be readily established as a positive reinforcer in LEWIS rats, as well as C57BL/6J mice. In low ethanol preferring F344 rats, ethanol maintains significant but low levels of responding. Ethanol does not maintain lever pressing behavior in BALB/cJ mice, and is avoided in DBA/2J mice. Initial findings reported in this paper show that these genotypic patterns of reinforcement from ethanol appear to correlate highly with patterns of reinforcement from cocaine and opiates. From these findings it is concluded that (1) there exist important genetic determinants of drug reinforced behavior; and (2) drug seeking behaviors maintained by ethanol, cocaine and opiates may have at least some common biological determinants.     

Use of total reflection X-ray fluorescence (TXRF) for the evaluation of heavy metal poisoning due to the improper use of a traditional ayurvedic drug

An Indian patient referred to Clinica del Lavoro ‘L.Devoto’ of Milano showed clinical signs of heavy metal poisoning, possibly related to a sustained 6-month use of approx. 3 g/day of a traditional preparation (a whitish powder with a ‘mineral’ appearance) to treat urological problems. To confirm the causal relationship between the disease and the use of such product, metal testing was performed on the patient's hair and the ayurvedic remedy samples by total reflection X-ray fluorescence (TXRF). For TXRF analysis 1-cm cut of the patient's hair was directly deposited onto the quartz glass sample carrier, then 10 μl of nitric acid 65% were added and dried in air. TXRF showed high versatility, rapid and simultaneous element detection, and short analysis time, thus supporting a wider use in emergency medicine and in forensic analyses.     

The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP): pharmacokinetic and pharmacodynamic clinical and forensic aspects

New psychoactive substances (NPS), often referred as ‘legal highs’ or ‘designer drugs’, are derivatives and analogs of existing psychoactive drugs that are introduced in the recreational market to circumvent existing legislation on drugs of abuse. This work aims to review the state-of-the-art regarding chemical, molecular pharmacology, and in vitro and in vivo data on toxicokinetics of the potent synthetic cathinone α-pyrrolidinovalerophenone (α-PVP or flakka or zombie drug). Chemical, pharmacological, toxicological, and clinical effects of α-PVP were searched in PubMed (U.S. National Library of Medicine) and governmental websites without limitation of the period. α-PVP is a wide spread and easy to get special type of synthetic cathinone with seemingly powerful cocaine-like stimulant effects, high brain penetration, high liability for abuse and with increased risk of adverse effects such as tachycardia, agitation, hypertension, hallucinations, delirium, mydriasis, self-injury, aggressive behavior, and suicidal ideations. α-PVP undergoes extensive metabolism via different pathways and the α-PVP itself or its metabolites β-hydroxy-α-PVP and α-PVP lactam represent the main targets for toxicological analysis in urine. There is a limited knowledge regarding the short- and long-term effects of α-PVP and metabolites, and pharmacogenetic influence, hence further clinical and forensic toxicological studies are required. Moreover, since α-PVP cannot be detected with classic routine analysis procedures, statements on the frequency of their consumption cannot be made.     

Is there a common biological basis for reinforcement from alcohol and other drugs?

Vulnerability to substance abuse is an important emerging issue. A critical aspect of this phenomenon is the degree to which individuals who abuse one substance are likely to abuse other substances, alone or in combination with each other. The extent to which several distinct drugs will come to serve as positive reinforcers within genetically defined subjects defines their commonality. Questions in this area are directed at determining whether reinforcement from and abuse of alcohol and other drugs define variations within a single behavioral phenomenon, or whether reinforcement and abuse must be individually defined for each substance involved. Findings related to this commonality issue are now emerging from the areas of pharmacogenetics and operant drug self-administration. Previous studies have shown that ethanol can be readily established as a positive reinforcer in LEWIS rats, as well as C57BL/6J mice. In low ethanol preferring F344 rats, ethanol maintains significant but low levels of responding. Ethanol does not maintain lever pressing behavior in BALB/cJ mice, and is avoided in DBA/2J mice. Initial findings reported in this paper show that these genotypic patterns of reinforcement from ethanol appear to correlate highly with patterns of reinforcement from cocaine and opiates. From these findings it is concluded that (1) there exist important genetic determinants of drug reinforced behavior; and (2) drug seeking behaviors maintained by ethanol, cocaine and opiates may have at least some common biological determinants.     

Sigma-1 receptors: potential targets for the treatment of substance abuse

Drug abuse is currently a large economic and societal burden in countries around the globe. Many drugs of abuse currently lack adequate therapies aimed at treating both the addiction and negative complications often associated with their use. Sigma-1 receptors were discovered over 30 years ago and have recently become targets for the development of pharmacotherapies aimed at treating substance abuse and addiction. In vivo preclinical studies have revealed that sigma receptor ligands are able to ameliorate select behavioral effects of many drugs of abuse including cocaine, methamphetamine, ethanol and nicotine. In addition, recent studies have begun to elucidate the mechanisms by which sigma-1 receptors modulate the effects of these drugs on neurotransmission, gene regulation and neuroplasticity. Overall, these recent findings suggest that compounds targeting sigma-1 receptors may represent a potential new class of therapeutics aimed at treating drug abuse. Future studies involving clinical populations will be critical for validating the therapeutic potential of sigma-1 receptor ligands for the treatment of substance abuse.