The interactive effects of alcohol and temazepam on P300 and reaction time

The present research investigated the separate and interactive effects of the minor tranquilliser, temazepam, and a low dose of alcohol on the amplitude and latency of P300 and on reaction time. Twenty-four participants completed four drug treatments in a repeated measures design. The four drug treatments, organised as a fully repeated 2 x 2 design, included a placebo condition, an alcohol only condition, a temazepam only condition, and an alcohol and temazepam combined condition. Event-related potentials were recorded from midline sites Fz, Cz, and Pz within an oddball paradigm. The results indicated that temazepam, with or without the presence of alcohol, reduced P300 amplitude. Alcohol, on the other hand, with or without the presence of temazepam, affected processing speed and stimulus evaluation as indexed by reaction time and P300 latency. At the low dose levels used in this experiment alcohol and temazepam appear not to interact, which suggests that they affect different aspects of processing in the central nervous system. (C) 2003 Elsevier Inc. All rights reserved.

Drug use patterns and mental health of regular amphetamine users during a reported 'heroin drought'

Aims The present study extends the findings of a pilot study conducted among regular amphetamine users in Newcastle, NSW, in 1998. It compares key features between current participants in a state capital city (Brisbane) and a regional city (Newcastle) and between the 1998 and current Newcastle sample. Design Cross-sectional survey. Setting Brisbane and Newcastle, Australia. Participants The survey was conducted among 214 regular amphetamine users within the context of a randomized controlled trial of brief interventions for amphetamine use. Measurements Demographic characteristics, past and present alcohol and other drug use and mental health, treatment, amphetamine-related harms and severity of dependence. Findings The main findings were as follows: (i) the rate of mental health problems was high among regular amphetamine users and these problems commonly emerged after commencement of regular amphetamine use; (ii) there were regional differences in drug use with greater accessibility to a wider range of drugs in a state capital city and greater levels of injecting risk-taking behaviour outside the capital city environment; and (iii) there was a significant increase in level of amphetamine use and percentage of alcohol users, a trend for a higher level of amphetamine dependence and a significant reduction in the percentage of people using heroin and benzodiazepines among the 2002 Newcastle cohort compared to the 1998 cohort. Conclusions Further longitudinal research is needed to elucidate transitions from one drug type to another and from recreational to injecting and regular use and the relationship between drug use and mental health in prospective studies among users. Implications Intervention research should evaluate the effectiveness of interventions aimed at: preventing transition to injecting and regular use of amphetamines; toward reducing levels of depression among amphetamine users and interventions among people with severe psychopathology and personality disorders; and toward reducing the prevalence of tobacco dependence among amphetamine users.

The effect of a reduction in heroin supply on fatal and non-fatal drug overdoses in New South Wales, Australia

Objective: To examine the impact of a sudden and dramatic decrease in heroin availability, concomitant with increases in price and decreases in purity, on fatal and non-fatal drug overdoses in New South Wales, Australia. Design and setting: Time-series analysis was conducted where possible on data on overdoses collected from NSW hospital emergency departments, the NSW Ambulance Service, and all suspected drug-related deaths referred to the NSW Coroner's court. Main outcome measures: The number of suspected drug-related deaths where heroin and other drugs were mentioned; ambulance calls to suspected opioid overdoses; and emergency department admissions for overdoses on heroin and other drugs. Results: Both fatal and non-fatal heroin overdoses decreased significantly after heroin supply reduced; the reductions were greater among younger age groups than older age groups. There were no clear increases in non-fatal overdoses with cocaine, methamphetamines or benzodiazepines recorded at hospital emergency departments after the reduction in heroin supply. Data on drug-related deaths suggested that heroin use was the predominant driver of drug-related deaths in NSW, and that when heroin supply was reduced overdose deaths were more likely to involve a wider combination of drugs. Conclusion: A reduction in heroin supply reduced heroin-related deaths, and did not result in a concomitant increase, to the same degree, in deaths relating to other drugs. Younger people were more affected by the reduction in supply.

Topological side-chain classification of beta-turns: Ideal motifs for peptidomimetic development

beta-turns are important topological motifs for biological recognition of proteins and peptides. Organic molecules that sample the side chain positions of beta-turns have shown broad binding capacity to multiple different receptors, for example benzodiazepines. beta-turns have traditionally been classified into various types based on the backbone dihedral angles (phi 2, psi 2, phi 3 and psi 3). Indeed, 57-68% of beta-turns are currently classified into 8 different backbone families (Type I, Type II, Type I', Type II', Type VIII, Type VIa1, Type VIa2 and Type VIb and Type IV which represents unclassified beta-turns). Although this classification of beta-turns has been useful, the resulting beta-turn types are not ideal for the design of beta-turn mimetics as they do not reflect topological features of the recognition elements, the side chains. To overcome this, we have extracted beta-turns from a data set of non-homologous and high-resolution protein crystal structures. The side chain positions, as defined by C-alpha-C-beta vectors, of these turns have been clustered using the kth nearest neighbor clustering and filtered nearest centroid sorting algorithms. Nine clusters were obtained that cluster 90% of the data, and the average intra-cluster RMSD of the four C-alpha-C-beta vectors is 0.36. The nine clusters therefore represent the topology of the side chain scaffold architecture of the vast majority of beta-turns. The mean structures of the nine clusters are useful for the development of beta-turn mimetics and as biological descriptors for focusing combinatorial chemistry towards biologically relevant topological space.

Synthesis and evaluation of N1-substituted-3-propyl-1,4-benzodiazepine-2-ones as cholecystokinin (CCK2) receptor ligands

A novel synthetic approach towards N1-alkylated 3-propyl-1,4-benzodiazepines was developed in five synthetic steps from 2-amino-4-chlorobenzophenone, in which the N-oxide 4 served as a key intermediate. The structure-activity relationship optimization of this 3-prophyl-1,4-benzodiazepine template was carried out on the N1-position by selective alkylation reactions and resulted in a ligand with an improved affinity on the cholecystokinin (CCK2) receptor. The N-allyl-3-propyl-benzodiazepine 6d displayed an affinity towards the CCK2 (CCK-B) receptor of 170 nM in a radiolabelled receptor-binding assay. The anxiolytic activity of this allyl-3-propyl-1,4-benzodiazepine 6d was subsequently determined in in-vivo psychotropic assays. This novel ligand had ED50 values of 4.7 and 5.2 mg kg-1 in the black and white box test and the x-maze, respectively, and no significant sedation/muscle relaxation was observed.

The synthesis and evaluation of small organic molecules as cholecystokinin antagonists

Cholecystokinin (CCK) is a peptide hormone, present in the alimentary and the CNS. It is the most abundant peptide in the brain. CCK has been implicated in a number of disorders. The link between CCK and anxiety was the basis for this research. A comprehensive discussion on the many types of CCK receptor antagonists is included. For the drug discovery process, a number of synthetic approaches have been investigated and alternative chemical approaches developed. 1,4-Benzodiazepine analogues were prepared, with substitutents In the 1,2 & 3- position of the benzodiazepine scaffold varied, and substituted 3-anilino benzodiazepines exhibited the greatest in vitro activity towards the CCKA receptor subtype. Through extensive screening, pyrazolinone-ureido derivatives were identified, optimised, SAR studied and re-screened. A comprehensive in vivo study on the most active analogue is included, which has a number of common structural features with L-36S, 260 including activity. Pyrazolinone-amide derivatives, bearing the tryptophan moiety were equally active. A number of existing and novel furan- 2(SH)-one building blocks were prepared, from which a selected mini-library of 4- amino-substituted furan-2(SH)-ones were prepared and evaluated. All synthesised compounds were evaluated in a CCK radiolabelled binding assay (CCKA & CCKB), with compounds demonstrating receptor selectivity and lead structures being discovered. The work in this thesis has identified a number of highly active prime structures, from which further investigations are essential in providing more in vitro & in vivo data and the need to prepare more analogues.

Unused medicines with potential for misuse or abuse in primary care

To assess the quantity and nature of prescribed medicines with potential for misuse returned to community pharmacies and general practice surgeries. Setting Community pharmacies (n = 51, 85% total) and general practice surgeries (n = 42, 69%) within the boundaries of Eastern Birmingham Primary Care Trust, UK. Method Medicines returned spontaneously by patients to participating sites were collected over eight weeks in May and June 2003. Data were recorded for each medicinal item including: patient sex, recommended International Non-proprietary Name (rINN), strength, form, legal classification, quantity and number of doses per day. Medicines were categorised into BWF therapeutic groups. A 'medicinal item' was defined as the total number of dose units of a medicine of the same form, strength and date of issue, returned for a given patient. Key findings Medicines were returned from 910 patients comprising 3765 medicinal items (2782 (73.9%) prescription-only medicines and 356 (9.5%) controlled drugs). Substantial amounts of unused, prescribed medicines with potential to cause harm or for misuse were returned, with analgesics, psychoactive and antiepileptic agents comprising 19.4% of returned medicinal items. Medicines of note that were returned included paracetamol-containing medicines (16 630 tablets), morphine (56 g), diamorphine (4.3 g), tramadol (2840 tablets and capsules), benzodiazepines (677 tablets) and tricyclic antidepressants (2831 tablets). Conclusions Substantial quantities of prescribed medicines with potential to cause harm or be misused are routinely present in the community. The management of these unused medicines, and in particular controlled drugs, Is currently inadequate and further work is required to identify the legislative and patient-centred processes required to minimise the potential for these medicines to be misused or cause harm. © 2007 The Authors.

Synthesis of substituted 3-anilino-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ones and their evaluation as cholecystokinin-ligands

3-Amino-1,4-benzodiazepines as well as chemically related diverse amines were prepared from oxazepam and subsequently screened on the cholecystokinin receptor in a radiolabel binding assay. Oxazepam 2 was activated via its 3-chloro-1,4-benzodiazepine intermediate 3 and was reacted with a large series of aliphatic and aromatic amines. The substituted 3-anilino-1,4-benzodiazepine structure was identified as lead structure in a diverse series of 3-amino-1,4-benzodiazepines 4-38 and the full SAR (structure-activity relationship) optimisation provided 3-anilinobenzodiazepines 16-38 with CCK 1 receptor selectivity to CCK 2. The compounds 18, 24, 28 and 33 have shown affinities at the CCK 1 receptor of 11, 10, 11 and 9 nM, respectively. These equipotent CCK 1 ligands were fully evaluated in behaviour pharmacological essays. An antidepressant effect was identified in the tail suspension- and the Porsolt swimming-test. The ED 50 values for 24 and 28 were determined in these assays as 0.46 and 0.49 mg/kg. The mixed antagonist 37 showed in addition to the antidepressant effects anxiolytic properties. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

Antidepressant/anxiolytic and anti-nociceptive effects of novel 2-substituted 1,4-benzodiazepine-2-ones

Oxazepam (4a) has been used as overall starting material in the synthesis of novel 2-substituted 1,4-benzodiazepines. By reacting Oxazepam 4a with commercially available hydrazines, hydrazides, semicarbazide, aminoguanidine and N,N-dimethylamino aniline in ethanol under acetic conditions, a series of diazenyl-1,4-benzodiazepines 5a-5i and 2-amino- 1,4-benzodiazepine 5k were obtained in good yields. These novel compounds served as new chemical entities (NCE) for testing in mice. The diazo-benzodiazepine 5d has shown a promising antidepressant effect in initial experiments in vivo at a dose of 5 mg/kg. The highly coloured 2-aminobenzodiazepine derivative 5k showed over a dose range from 5-50 mg/kg an analgesic effect in mice. © Singh et al.

Consumo privado de ansiolíticos benzodiazepínicos e sua correlação com indicadores sociodemográficos nas capitais brasileiras

This work aims to analyze the distribution of anxiolytics and their frequency of consumption in the period of 2010 to 2012, on the Federal District and at other Brazilian cities, as well as evaluating the correlation between such consumption and its demographic, epidemiological, economic and social characteristics for each region of this study. Into the analysis, it was observed that social, economic and cultural factors seem to influence the over-consumption of these drugs in many countries. Based on this, the benzodiazepines (BDZs) have achieved great popularity among members of the medical community and among the general population, mainly because of its safety and effectiveness in controlling symptoms of anxiety, insomnia and convulsions. Concerning the methodology of this work, an ecological study was performed having as sampling Brazilian capitals and as data source the 2010 Population Census, as well as information from IBGE, DATASUS and ANVISA. Still in the case of the methodological procedure, a multiple linear regression was used. Through descriptive analysis, it was demonstrated that the Northern region has the lowest average on consumption of these drugs (being 0.24 DHD in Manaus); meanwhile in the capitals of the Southeast, higher means were identified (reaching 7.29 DHD in Belo Horizonte), with a national average of 3.04 DHD. Among the drugs analyzed, it was found that Alprazolam is the most dispensed by pharmacies and private drugstores, averaging 2.00 DHD for Brazilian capitals. A análise de regressão linear múltipla mostrou que 76% da variação no consumo foi explicada pela variação da densidade populacional (β = 0,310 p = 0,045) e pela percentagem de médicos (β = 0,507 p = 0,016). Therefore, it was concluded that the consumption of anxiolytics of short half-life has been increasing over the years, mainly in the cities of greater population density and with the highest concentration of doctors

The changing epidemiology of Ebstein's anomaly and its relationship with maternal mental health conditions: a European registry-based study

OBJECTIVES: The aim of this study was to describe the epidemiology of Ebstein's anomaly in Europe and its association with maternal health and medication exposure during pregnancy.

DESIGN: We carried out a descriptive epidemiological analysis of population-based data.

SETTING: We included data from 15 European Surveillance of Congenital Anomalies Congenital Anomaly Registries in 12 European countries, with a population of 5.6 million births during 1982-2011. Participants Cases included live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly. Main outcome measures We estimated total prevalence per 10,000 births. Odds ratios for exposure to maternal illnesses/medications in the first trimester of pregnancy were calculated by comparing Ebstein's anomaly cases with cardiac and non-cardiac malformed controls, excluding cases with genetic syndromes and adjusting for time period and country.

RESULTS: In total, 264 Ebstein's anomaly cases were recorded; 81% were live births, 2% of which were diagnosed after the 1st year of life; 54% of cases with Ebstein's anomaly or a co-existing congenital anomaly were prenatally diagnosed. Total prevalence rose over time from 0.29 (95% confidence interval (CI) 0.20-0.41) to 0.48 (95% CI 0.40-0.57) (p<0.01). In all, nine cases were exposed to maternal mental health conditions/medications (adjusted odds ratio (adjOR) 2.64, 95% CI 1.33-5.21) compared with cardiac controls. Cases were more likely to be exposed to maternal β-thalassemia (adjOR 10.5, 95% CI 3.13-35.3, n=3) and haemorrhage in early pregnancy (adjOR 1.77, 95% CI 0.93-3.38, n=11) compared with cardiac controls.

CONCLUSIONS: The increasing prevalence of Ebstein's anomaly may be related to better and earlier diagnosis. Our data suggest that Ebstein's anomaly is associated with maternal mental health problems generally rather than lithium or benzodiazepines specifically; therefore, changing or stopping medications may not be preventative. We found new associations requiring confirmation.

Global slowing of network oscillations in mouse neocortex by diazepam

SCHEFFZUK, C. , KUKUSHKA, V. , VYSSOTSKI, A. L. , DRAGUHN, A. , TORT, A. B. L. , BRANKACK, J. . Global slowing of network oscillations in mouse neocortex by diazepam. Neuropharmacology , v. 65, p. 123-133, 2013.

Sedação consciente em Odontopediatria

O medo e a ansiedade estão estreitamente relacionados com o tratamento dentário e, infelizmente, na população infantil este facto assume uma magnitude aumentada traduzindo-se muitas vezes de forma negativa no comportamento da criança comprometendo ou mesmo inviabilizando a execução do mesmo. O tratamento dentário de pacientes pediátricos com problemas comportamentais pode ser um verdadeiro desafio para o médico dentista e as tradicionais técnicas de controlo comportamental não farmacológicas nem sempre são suficientes para conseguir a cooperação da criança pelo que, em muitos casos, é necessária a associação dos mesmos a técnicas farmacológicas. A sedação consciente é utilizada em odontopediatria como uma técnica de controlo comportamental farmacológica, que visa induzir na criança, um estado mínimo de depressão da consciência, tornando-a passível de cooperar e viabilizando que os tratamentos necessários sejam efectuados com segurança. Existem inúmeros fármacos, técnicas e associações das mesmas que podem ser utilizadas para o efeito sendo que actualmente, em odontopediatria, predomina a prática da sedação consciente inalatória com protóxido de azoto e a utilização de benzodiazepinas como o midazolam. Apesar das muitas técnicas descritas, nenhuma delas é passível de ser administrada a todos os pacientes, pelo para cada caso, tendo em conta todas as particularidades, haverá uma técnica mais adequada. Apesar prática da sedação consciente ser uma mais-valia em odontopediatria, não é isenta de riscos e o médico dentista deve ter formação adequada para a providenciar de forma segura. Diferentes entidades publicaram guidelines que visam orientar a prática segura da sedação e minimizar o risco de incidentes.