Search

Background: Australian and international guidelines recommend benzodiazepines and related drugs (hereafter "benzodiazepines") as second-line, short-term medications only. Most benzodiazepines are prescribed by general practitioners (GPs; family physicians). Australian GP registrars ("trainees" or "residents" participating in a post-hospital training, apprenticeship-like, practice-based vocational training program), like senior GPs, prescribe benzodiazepines at high rates. Education within a training program, and experience in general practice, would be expected to reduce benzodiazepine prescribing.Objective: To establish if registrars' prescribing of benzodiazepines decreases with time within a GP training program DESIGN: Longitudinal analysis from the Registrar Clinical Encounters in Training multi-site cohort study PARTICIPANTS: Registrars of five of Australia's 17 Regional Training Providers. Analyses were restricted to patients ≥ 16 years.Main Measures: The main outcome factor was prescription of a benzodiazepine. Conditional logistic regression was used, with registrar included as a fixed effect, to assess within-registrar changes in benzodiazepine-prescribing rates. The "time" predictor variable was "training term" (6-month duration Terms 1-4). To contextualize these "within-registrar" changes, a mixed effects logistic regression model was used, including a random effect for registrar, to assess within-program changes in benzodiazepine-prescribing rates over time. The "time" predictor variable was "year" (2010-2015).Key Results: Over 12 terms of data collection, 2010-2015, 1161 registrars (response rate 96%) provided data on 136,809 face-to-face office-based consultations. Two thousand six hundred thirty-two benzodiazepines were prescribed (for 1.2% of all problems managed). In the multivariable model, there was a significant reduction in within-program benzodiazepine prescribing over time (year) (p = < 0.001, OR = 0.94, CI = 0.90, 0.97). However, there was no significant change in 'within-registrar' prescribing over time (registrar Term) (p = 0.92, OR = 1.00 [95% CI = 0.94-1.06]).Conclusions: Despite a welcome temporal trend for reductions in overall benzodiazepine prescribing from 2010 to 2015, there is still room for improvement and our findings suggest a lack of effect of specific GP vocational training program education and, thus, an opportunity for targeted education. [ABSTRACT FROM AUTHOR]

Rationale: Clozapine is the gold-standard medicine for treating refractory schizophrenia but there are some notable serious adverse events (AE). We aimed to analyse reported rates of clozapine cardiac and haematological AEs in Australia.Methods: Using data from the Therapeutic Goods Administration, we examined all reported clozapine AEs (1993-2014) with a specific focus on neutropenia, myocarditis and cardiomyopathy. We related AEs to clozapine-dispensing data in Queensland, scaled up to Australia.Results: There were 8561 AEs reported: neutropenia (13.7%), myocarditis (9.3%) and cardiomyopathy (3.8%). Reported rates of myocarditis and cardiomyopathy increased after 1999 following a myocarditis case series from Sydney. Cardiomyopathy AE rates have remained stable since then but myocarditis AEs have increased steadily. Neutropenia was more common in women, while cardiomyopathy and myocarditis were more common in men. There were five reported deaths from neutropenia and cardiomyopathy.Conclusions: The rates of serious AEs (including deaths) are low and likely an underestimate of true rates and need to be considered by clinicians in balancing the risks and benefits. Continued education on the monitoring and treatment of these AEs for consumers, carers and health professionals is essential and reporting these to the relevant national reporting agency is crucial. [ABSTRACT FROM AUTHOR]

(5 S,8 S,10a R)- tert-butyl 5-( tert-butoxycarbonylamino)-2,6-dioxooctahydro-1 H-pyrrolo[2,1-d][1,5]oxazocine-8-carboxylate 5, containing an original proline-like moiety, was prepared through Yamaguchi lactonization. However, it was observed that this 8 + 5 bicyclic lactone was spontaneously rearranged to the corresponding 7 + 5 bicyclic lactam under acid conditions, used to remove the Boc/ tBu protecting groups. Both core structures were confirmed by one-dimensional and two-dimensional NMR, as well as HRMS. The new proline-like moieties are unknown up to now, and the 7 + 5 bicyclic lactam, much more stable than its precursor, may represent a valuable template to develop constrained non-peptide mimetics. [ABSTRACT FROM AUTHOR]

Rationale: Antipsychotic dosage is generally adjusted by physicians depending on the stability of the patient and the response to that particular drug. Our hypothesis is that patients with previous suicide attempt are prescribed higher doses of antipsychotics. Objective: We examined the dosage and patterns of antipsychotic use in regard to past suicidal behaviour. Methods: For this study, 304 subjects with schizophrenia spectrum disorders between the ages of 18 and 75 were recruited. A cross-sectional assessment was used for this study, in which data were collected from each patient through an interview and self-report questionnaires. The percentages of the Compendium of Pharmaceuticals and Specialties (CPS) maximum recommended daily dose were applied to standardize antipsychotic dosages across different treatments. We compared the standardized dosage of antipsychotics in schizophrenics with previous suicide attempts and those who have never attempted suicide. Results: Applying the ANCOVA, our preliminary results show no significant difference ( P = 0.467) in antipsychotic dosage in the attempters and non-attempters. The prescribed clozapine dosage fails to show a significant relationship with suicidal history ( P >0.05). Conclusions: In summary, our analysis does not show antipsychotic dosage adjustment based on past suicide attempt, after controlling for the current suicidal ideation and hopelessness. [ABSTRACT FROM AUTHOR]

The efficiency of benzodiazepines on mouse model of anticholinesterase poisoning was shown. The protective effects of clonazepam and midazolam were observed at high (1 TD, incoordination) and medium (0.3 TD) doses and the effects of phenazepam and diazepam were found only at high doses. Midazolam produced the most pronounced protective effect: administration of this drug significantly increased the protective index of atropine+HI-6 combination during poisoning. [ABSTRACT FROM AUTHOR]

The biological underpinnings of schizophrenic polydipsia are poorly understood. This study is aimed at fulfilling the requisites of an experimental model of this syndrome through the quinpirole (QNP) induction of non-regulatory drinking in rats. In a first experiment, clozapine (10 and 40 mg/kg p.o.) was substituted for haloperidol during the last 5 days of 10 days QNP (0.5 mg/kg i.p.) administration and water intake measured at 5 h. In a second experiment, animals treated with QNP alone or in combination with clozapine were assessed for water intake and prepulse inhibition (PPI). Expression of genes coding for the dopaminergic D2 receptor, as well as for the early genes BDNF (brain-derived neurotrophic factor) and c-Fos in prefrontal cortex, hippocampus, and striatum was also evaluated. Clozapine prevented QNP-induced drinking at 10 and 40 mg/kg, but only at 40 mg/kg when it was substituted for haloperidol. In the second experiment, QNP-treated rats showed both non-regulatory drinking and PPI disruption. Both these effects were prevented by clozapine 40 mg/kg. QNP-reduced BDNF expression in the hippocampus and increased c-Fos in the prefrontal cortex. This effect was prevented by clozapine. Given by itself, clozapine reduced the expression of both D2 receptors and BDNF in the prefrontal cortex and striatum. The present study lends further support to the hypothesis that non-regulatory drinking induced by QNP in rats is a robust and reliable pharmacological effect that might model psychotic polydipsia also in its sensitivity to clozapine. [ABSTRACT FROM AUTHOR]

Schizophrenia is characterized by disturbances in attention and information processing that can be measured by latent inhibition (LI). Research has implicated significant aberrations in dopaminergic (DA) neurotransmission in this disorder. The objectives of this study were as follows: to probe whether bupropion disrupts LI; to compare its efficacy to the effects of GBR12783 (specific DA uptake inhibitor) and to amphetamine (DA releaser); to test if antipsychotics would reverse LI deficits induced by bupropion, GBR12783, and amphetamine; and to probe if rolipram (phosphodiesterase-4 inhibitor), which increases cyclic AMP (cAMP) similarly to antipsychotics, effectively corrects drug-induced LI deficits. Based on its efficacy in drug addiction, we also asked if bupropion could block the effect of amphetamine. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in C57BL/6J mice. Mice previously received 0 (nonpreexposed) or 40 noise exposures (preexposed) followed by two or four noise-foot shock pairings. Bupropion abolished LI in mice, which was corrected by rolipram, but not by haloperidol and clozapine. GBR12783 and amphetamine, but not antidepressants, also disrupted LI, and this was reversed by antipsychotics and rolipram. Both bupropion and amphetamine disrupted LI via conditioning session. Paradoxically, bupropion and GBR12783 also blocked the amphetamine-induced LI deficit. Efficacy of rolipram but not antipsychotics to reverse the effects of bupropion suggests novel cAMP-dependent and D2 receptor-independent mechanisms of the bupropion-induced LI deficit. Further detailed biochemical analysis of bupropion-induced LI deficit might be a fruitful approach in developing new antipsychotics. [ABSTRACT FROM AUTHOR]

Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABAA (γ-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on α1-containing GABAA receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell-type-specific expression of α1-containing GABAA receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing α1 may be devoid of addiction liability. [ABSTRACT FROM AUTHOR]

Historically, schizophrenia has been associated with early-onset, persistent symptoms, and progressive decline accompanied by poor functional recovery. The advent of effective drugs in the 1950s improved symptom control, at least from the standpoint of positive features (e.g. hallucinations, delusions). However, even here the response was limited and efficacy in other symptom domains (cognitive, deficit/negative) was minimal. With clozapine as the prototype, the second-generation antipsychotics arrived in the 1990s with claims of improved tolerability, as well as greater and broader clinical efficacy, all of which was to translate to gains in functional outcome and quality of life. The capacity of these drugs to effect such changes has since been tempered, but it remains that the research and hope generated served as an impetus to redefine outcomes. A medical-based model, centred on pharmacotherapy and symptom resolution, has given way to a re-conceptualization of schizophrenia and treatment goals. There is a clearer distinction between clinical and functional outcomes, and, with this, greater attention has been given to these other symptom domains that curtail improvement in the latter. At the same time, a concerted shift to shared decision making has underscored quality-of-life issues that benefit from, but cannot be guaranteed by, either clinical or functional improvement. To this end, the field has now embraced a recovery model that is seen as a process, multidimensional and individualized, rather than dichotomous and symptom driven. [ABSTRACT FROM AUTHOR]

A series of S-substituted and 1,2-annelated derivatives of 2,3-benzodiazepine has been obtained on the basis of 2,3-benzodiazepine-1-thione. [ABSTRACT FROM AUTHOR]

Background: The use of antidepressants and benzodiazepines is increasing in Australia and worldwide, and it is thought that some of the prescribing of these classes of drugs may be inappropriate. However, the demographic characteristics of the subgroups of the population responsible for this increase remain unexplored. Objective: The aim of this study was to examine changes in the utilization of antidepressants and benzodiazepines between different age groups within Australia from 2003 to 2006. Methods: The Australian Pharmaceutical Benefits Scheme administrative database was used to obtain dispensing data for all antidepressants and publicly subsidized benzodiazepines. Changes in utilization {amounts and patterns of use of different compounds) were compared between different age groups from 2003 to 2006. The WHO Anatomic Therapeutic Chemical/Defined Daily Dose system was used. Results: Use of antidepressants increased from 2003 to 2006. and in each year increased with age. with those ⩾65 years having the greatest use. Differences were seen in the antidepressant most utilized, with the elderly using more tricyclic antidepressants than those who are younger. The utilization of benzodiazepines decreased from 2003 to 2006 in elderly individuals and those receiving social welfare benefits. Individuals aged ⩾85 years had the highest use of benzodiazepines and used more long-acting benzodiazepines compared with those aged 35-44 years. Couclusion: The elderly still account for most use per capita of benzodiazepines. Some of this use may be inappropriate (e.g. use of long-acting benzodiazepines) and. hence, may represent a useful target for future educational intervention. The elderly also still account for the largest per capita use of antidepressants. [ABSTRACT FROM AUTHOR]

The development and validation of animal models of the cognitive impairments of schizophrenia have remained challenging subjects. We review evidence from a series of experiments concerning an animal model that dissociates between the disruption of attentional capacities during acute illness periods and the cognitive load-dependent impairments that characterize periods of remission. The model focuses on the long-term attentional consequences of an escalating-dosing pretreatment regimen with amphetamine (AMPH). Acute illness periods are modeled by the administration of AMPH challenges. Such challenges result in extensive impairments in attentional performance and the “freezing” of performance-associated cortical acetylcholine (ACh) release at pretask levels. During periods of remission (in the absence of AMPH challenges), AMPH-pretreated animals’ attentional performance is associated with abnormally high levels of performance-associated cortical ACh release, indicative of the elevated attentional effort required to maintain performance. Furthermore, and corresponding with clinical evidence, attentional performance during remission periods is exquisitely vulnerable to distractors, reflecting impaired top-down control and abnormalities in fronto–mesolimbic–basal forebrain circuitry. Finally, this animal model detects the moderately beneficial cognitive effects of low-dose treatment with haloperidol and clozapine that were observed in clinical studies. The usefulness and limitations of this model for research on the neuronal mechanisms underlying the cognitive impairments in schizophrenia and for drug-finding efforts are discussed. [ABSTRACT FROM AUTHOR]

We report on two cases of drug-drug interactions between ciprofloxacin and clozapine. The first case was a 46-year-old male patient receiving a daily dose of clozapine 900 mg. He was admitted to hospital with urosepsis and was treated with a 5-day course of ciprofloxacin and amoxicillin. Two days after completion of antibacterial therapy, the patient developed symptoms of rhabdomyolysis. Clozapine therapy was discontinued and measurement of the patient's clozapine plasma concentration 1 day after cessation of clozapine therapy and 3 days after cessation of ciprofloxacin treatment showed that it was in excess of recommended therapeutic levels. The second patient was a 58-year-old male patient treated with a daily dose of clozapine 300 mg. He was admitted to hospital because of delirium and suspected urinary tract infection or pneumonia. Treatment with ciprofloxacin was initiated. Measurement of clozapine plasma concentrations prior to and 3 days after commencement of ciprofloxacin showed that clozapine concentrations doubled over that time period. We suggest that inhibition of cytochrome P450 (CYP) enzymes 1A2 and 3A4 by ciprofloxacin resulted in delayed clozapine metabolism and elevated clozapine plasma concentrations. This might cause severe adverse effects. We advise using another antibacterial agent or reducing the clozapine dose and monitoring clozapine levels when this antipsychotic agent is used in combination with ciprofloxacin. [ABSTRACT FROM AUTHOR]

Clozapine and quetiapine have a low incidence of extrapyramidal side effects at clinically effective doses, which appears to be related to their significantly lower occupancy of striatal dopamine D2 receptors (DA D2r) compared to typical antipsychotic drugs (APDs). Animal studies have indicated that clozapine and quetiapine produce selective effects on cortical and limbic regions of the brain and in particular on dopaminergic neurotransmission in these regions. Previous PET and SPECT studies have reported conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D2r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D2r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D2r using PET with [18F]fallypride in six schizophrenic subjects receiving clozapine monotherapy and in seven schizophrenic subjects receiving quetiapine monotherapy. Doses were chosen clinically to minimize psychopathology at tolerable levels of side effects such as drowsiness. All had minimal positive symptoms at the time of the study. Regional receptor occupancies were estimated using mean regional DA D2r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D2r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D2r, 59.8% (p=0.05, corrected for multiple comparisons), and significantly lower levels of occupancy in the substantia nigra, 18.4% (p=0.0015, corrected for multiple comparisons). Quetiapine also produced preferential occupancy of temporal cortical DA D2r, 46.9% (p=0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D2r. The therapeutic effects of clozapine and quetiapine appear to be achieved at less than the 65% threshold for occupancy seen with typical APDs, consistent with the involvement of non-DA D2r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D2r, sparing occupancy of substantia nigra receptors, and non-DA D2r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.Neuropsychopharmacology (2006) 31, 1991–2001. doi:10.1038/sj.npp.1301108; published online 31 May 2006 [ABSTRACT FROM AUTHOR]

A convenient method is proposed for the synthesis of the previously unknown 4-aryl-1,3-diphenyl-1,4,5,10-tetrahydropyrazolo[3,4-b][1,5]benzodiazepines by cyclocondensation of 5-(2-aminoanilino)-1,3-diphenylpyrazole with aromatic aldehydes. The reaction only takes place very selectively with aldehydes which contain electron acceptor substituents in the aryl fragment. [ABSTRACT FROM AUTHOR]

Rationale: Clozapine inhibits sympathetic outflow to the cutaneous vascular bed. Clozapine reverses hyperthermia and cutaneous vasoconstriction induced by 3,4- methylenedioxymethamphetamine (MDMA, Ecstasy) or by lipopolysaccharide (LPS). Clozapine also reverses cutaneous vasoconstriction elicited by exposure to cold. These actions distinguish clozapine from haloperidol. Clozapine could also inhibit sympathetic cutaneous vasomotor alerting responses (SCVARs), vasoconstrictor episodes that reflect emotional/psychological function, and this property might also distinguish clozapine from haloperidol. Objectives: Experiments in rats determined whether clozapine and haloperidol inhibit SCVARs, and whether SR46349B (a 5HT2A receptor antagonist), 8-OH-DPAT (a 5-HT1A agonist), L741,626 (a dopamine D2 antagonist) or SCH23390 (a dopamine D1 antagonist) have clozapinelike effects on SCVARs. Methods: Mean level and pulse amplitude of the tail artery Doppler flow signal were recorded in conscious freely moving rats before and after alerting stimuli (e.g. tapping the cage), and expressed as a SCVAR index (fall to zero flow implies SCVAR index of 100%, no fall implies 0%). Results: Clozapine (0.0625- 1.0 mg/kg, s.c.) dose-dependently increased resting tail blood flow. After 1 mg/kg, the SCVAR index was 18±1%, compared with 83±2% after vehicle. SR46349B (0.01- 1.0 mg/kg) and 8-OH-DPAT (0.25 mg/kg) had similar but less potent effects on cutaneous blood flow and o SCVARs. Haloperidol (0.005-0.5 mg/kg) and L741,626 (1 mg/kg) had no or little effect on these variables. SCH23390 mildly inhibited SCVARs. Conclusions: Clozapine, but not haloperidol, increases resting cutaneous blood flow and decreases SCVARs. Antagonism at 5-HT2A receptors and agonism at 5-HT1A receptors could contribute to these actions. [ABSTRACT FROM AUTHOR]

Rationale: Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on the efficacy of reinforcers. A mathematical model (Killeen PR (1994) Mathematical principles of reinforcement. Behav Brain Sci 17:105-172) affords a basis for quantifying the effects of drugs on progressive ratio schedule performance. The model postulates a bitonic function relating response rate and ratio size. One parameter of the function, a, expresses the motivational effect of the reinforcer, whereas another parameter, δ, expresses the minimum time needed to execute a response, and is regarded as an index of 'motor capacity'. Previously we found that the atypical antipsychotic clozapine increased a, indicating an increase in reinforcer efficacy; a similar effect was observed with the 5-hydroxytryptamine (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). It has been suggested that some of clozapine's behavioural effects are mediated by agonistic action at 5-HT1A receptors. Objective: This study was conducted to compare the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance. Methods: Rats were trained under a time-constrained progressive ratio schedule (50-min sessions). In experiment 1, they received acute doses of clozapine (4 mg kg-1) and 8-OH-DPAT (100 µg kg-1), alone and in combination with the 5-HT1A receptor antagonist N-[2-(4- [2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-yridinylcyclohexanecarboxamide (WAY-100635; 30 µg kg-1). In experiment 2, the effects of clozapine (2, 4 and 8 mg kg-1) and 8-OH-DPAT (25, 50 and 100 µg kg-1) were compared between intact rats and rats whose 5-HTergic pathways had been ablated by 5,7-dihydroxytryptamine (5,7-DHT). Results: In both experiments, clozapine and 8-OH-DPAT increased a and δ. In experiment 1, WAY-100635 abolished the effect of 8-OH-DPAT on a and δ, but did not alter clozapine's effects on these parameters. In experiment 2, the effects of clozapine and 8-OH-DPAT did not differ between sham-lesioned and 5,7-DHT-lesioned rats. Conclusions: The results confirm previous findings on the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance. 8-OH-DPAT's effects are probably mediated by post-synaptic 5-HT1A receptors; clozapine's effects are mediated by a different mechanism, which does not appear to involve 5-HT1A upon an intact 5-HTergic pathway. [ABSTRACT FROM AUTHOR]

Background: Benzodiazepines comprise a class of drugs that when used as monotherapy are generally acknowledged to pose a risk for injury by increasing the likelihood of falls, fall-related injuries, adverse drug events and car accidents. Benzodiazepines may also be used concomitantly with other high risk medications that may further exacerbate the risk of injury. The aim of this study is to examine the occurrence of the concomitant use of benzodiazepines and other drugs and then quantify the indirect effect of these drug combinations on the likelihood of an injury-related health care episode.Methods: A multivariate model was specified that included outpatient prescription data and inpatient/outpatient medical utilisation records for 13,745 patients at a Veterans Administration hospital system over a 3-year period (1999-2001). We analysed 1,33,872 outpatient benzodiazepine prescriptions and >1.5 million non-benzodiazepine prescriptions for the study population. Micromedex software was used to identify combinations of benzodiazepines and other drugs that are likely to result in 'major' interactions. We then further restricted our focus to the use of these drug combinations within a 30-day period prior to an injury-related medical event. The adjusted odds ratio on a variable characterising concomitant use of a benzodiazepine and another drug within this period was used to quantify the relative risk of injury. The principal outcome was the estimated risk of an injury-related health care episode within a 30-day period when taking both a benzodiazepine and another drug with a 'major' severity rating as defined by Micromedex. The risk of injury was adjusted for comorbidities, hospital discharges, marital status, age, mean arterial pressure and body mass index, as well as the dose of benzodiazepine (converted to diazepam equivalents) and duration of benzodiazepine treatment.Results: Of the 1,110 unique individuals who experienced an injury, 790 (71.2%) patients had used a benzodiazepine in combination with another drug. Furthermore, only 4.3% (320/7522) of the patients taking benzodiazepines who did not have concomitant drug use experienced an injury. The occurrence of this concomitant use increased the odds of an injury >2-fold in the model. Dose and duration of benzodiazepine use, as well as certain comorbidities, were also associated with an increased risk for injury, whereas being married reduced the risk.Conclusions: This is the first large-scale study to quantify the impact of concomitant use of benzodiazepines and other drugs on the risk of injury in a population of Veterans Administration patients. It demonstrates the utility of expanding the focus of inappropriate medication usage to include analyses that link potentially inappropriate drug use with health care utilisation for injuries. [ABSTRACT FROM AUTHOR]

Background: Inappropriate (long-term) use of benzodiazepines (BZDs) is a reason for concern. Several studies have suggested that hospitalisation may be a determinant for initiation of BZD use as well as for long-term use. However, the available evidence is conflicting. Objective: To determine whether hospitalisation induces initiation of BZD use and subsequent long-term use. Methods: A retrospective follow-up study was conducted. Randomly, 10,000 patients who had been hospitalised were selected (index date). Non-hospitalised patients, matched on age and gender, were sampled from the same living region and assigned the same index date as the corresponding hospitalised patient. Patients were included if adequate medication data were available from 18 months before to 18 months after the index date. Initiation of BZD use was defined as a prescription for a BZD or BZD-related hypnotic without a prescription for any of these drugs during the prior 6 months. Long-term use was defined as a period of consecutive use for at least 6 months following initiation. Results: In this study, 8,681 hospitalised patients and an equal number of non-hospitalised patients were finally included. Overall, the relative risk for initiation of BZD use was almost twice as high [IDR 1.97 (95%CI 1.84-2.10)] among hospitalised patients as in non-hospitalised patients. This relative risk was most clearly elevated during the time window from 3 months before to 3 months after hospitalisation [IDR 4.81 (95%CI 4.08-5.67)]. The relative risk for long-term use during the entire 36-month observation period was not higher [IDR 1.04 (95%CI 0.95-1.13)] among hospitalised patients than among non-hospitalised patients. Within the time window of 3 months before and after hospitalisation, the relative risk for long-term use was significantly lower for the hospitalised group [RR 0.82 (CI 0.69-0.98)]. Conclusion: Our results confirm that hospitalisation is associated with an increased risk for initiation of BZD use; the risk is highest during the 3 months just before and after hospitalisation. However, hospitalisation appeared not to be a determinant for long-term use of BZDs. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs are effective in the treatment of cannabis-induced psychosis, but only clozapine appears effective in the treatment of comorbid schizophrenia and cannabis use. The unique effects of clozapine on cannabis use could, therefore, be due to an as yet unidentified interaction between clozapine and the endogenous cannabinoid system. To address this hypothesis, we used in situ radioligand binding and quantitative autoradiography with the selective cannabinoid CB1 receptor agonist, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (side chain-2,3,4(N)-3H) ([3H]CP 55940) to measure the density of the CB1 receptor in frontal cortex, hippocampus, nucleus accumbens and striatum from rats treated with a variety of antipsychotic drugs. Clozapine significantly decreased [3H]CP 55940 binding in the nucleus accumbens compared with vehicle after 1 (35.0±14.0 vs. 71.2±8.5 fmol/mg estimated tissue equivalent (ete); P=0.03) and 3 months (42.3±4.0 vs. 71.1±16.3 fmol/mg ete; P<0.04) of treatment, an effect not observed with haloperidol, chlorpromazine or olanzapine. In rats treated with clozapine for 3 months and then left for 1 month without treatment, [3H]CP 55940 binding was not different in the nucleus accumbens (100.5±22.2 vs. 100.9±25.4 fmol/mg ete; P>0.10). By contrast, there were significant increases in accumbal [3H]CP 55940 binding in rats treated with haloperidol (136.5±14.2 fmol/mg ete; P<0.05), chlorpromazine (137.4±12.7 fmol/mg ete; P<0.05) and olanzapine (144.7±10.1 fmol/mg ete; P<0.01). These data indicate that in the nucleus accumbens clozapine differs from other antipsychotic drugs in its effects on [3H]CP 55940 binding. If these results can be extrapolated into humans, then this effect of clozapine on the CB1 receptor may be a mechanism that makes it uniquely effective in schizophrenia and comorbid cannabis use. [ABSTRACT FROM AUTHOR]

Rationale: Recent studies have suggested that the salutary actions of clozapine in schizophrenia may be due to selective activation of M1 muscarinic receptors by clozapine and/or its major active metabolite N-desmethylclozapine. Objective: We systematically tested this hypothesis by screening a large number of psychoactive compounds, including many atypical antipsychotic drugs, for agonist activity at cloned, human M1, M3 and M5 muscarinic receptors. Results: Only three of the 14 atypical antipsychotic drugs we tested were found to possess partial agonist actions at M1 muscarinic receptors (fluperlapine, JL13, clozapine). A few additional miscellaneous compounds had a modest degree of M1 agonist actions. Only carbachol and N-desmethylclozapine had appreciable M3 muscarinic agonism at M3 muscarinic receptors, although several were M5 partial agonists including MK-212, N-desmethylclozapine and xanomeline. Conclusion: Although M1 muscarinic receptor-selective partial agonists have shown promise in some preclinical antipsychotic drug models, these studies indicate that it is unlikely that the salutary actions of clozapine and similar atypical antipsychotic drugs are mediated solely by M1 muscarinic receptor activation. It is possible, however, that the M1 agonism of N-desmethylclozapine contributes to the uniquely beneficial actions of clozapine. Thus, these results are consistent with the notion that a balanced degree of activity at multiple biogenic amine receptors, including M1 muscarinic agonism, is responsible for the uniquely beneficial actions of clozapine. [ABSTRACT FROM AUTHOR]

Examines highly specific antibodies against conjugated antigens determined by haptens based on benzodiazepines. Synthesis of conjugated antigens; Development of enzyme-linked immunosorbent assay procedure specific to compounds of the 1,4-benzodiazepine group; Ultraviolet absorption spectra of bovine serum albumin-based conjugated antigens determined by gidazepam and gidazepam metabolite.

Clozapine is an atypical antipsychotic agent showing therapeutic efficacy superior to that of classical neuroleptics. Clozapine has strong sedative effects, but detailed studies on the drug influencing sleep in rodents are lacking. We studied the effects of clozapine on sleep and body temperature in rats. Clozapine (0, 2.5, and 7.5 mg/kg) was given i.p. to male Wistar rats at the beginning of the rest period. After administration of 7.5 mg/kg clozapine, animals were significantly more awake during the first 2 h postinjection. In parallel, the slow-wave activity (SWA) was suppressed. In the following 2 h non-REM sleep was markedly increased, whereas the SWA returned to baseline. At both doses clozapine decreased overall wakefulness and increased non-REM sleep on the first treatment day, which was associated with prolonged non-REM sleep episodes. These effects were transiently present even after subchronic treatment (7 days). After acute treatment, 7.5 mg/kg clozapine significantly reduced REM sleep and pre-REM sleep due to an increase in REM sleep latency and a reduction in the number of REM sleep episodes. Furthermore, clozapine produced a transient decrease in brain temperature that was followed by a moderate, but long-lasting elevation. To conclude, clozapine affected sleep-wake behavior in a way comparable to its effects in humans, suggesting that the rat is a suitable model for further studies on the underlying mechanisms. [ABSTRACT FROM AUTHOR]

A one-pot synthetic approach to the novel 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines by thermal cyclization of 4-acylhydrazino-2,3-dihydro-1H-1,5-benzodiazepines is described. [ABSTRACT FROM AUTHOR]

An easy and convenient synthetic procedure for the preparation of benzodiazepines by coupling microwaves with the solvent technique have been elaborated. [ABSTRACT FROM AUTHOR]

Purpose. AMPA receptor-mediated excitotoxicity is thought to be a critical process in diseases accompanied by neuronal cell loss following a hypoxic/anoxic state of the central nervous system. It has been suggested that blockade of AMPA receptors might result in significant protection of neurons against cellular damage. For testing the hypothesis, in vitro efficacy and in vivo neuroprotective action of new 2,3-benzodiazepine (2,3BDZ) AMPA antagonists have been compared. Methods. 2,3BDZs were tested on kainate-evoked whole-cell currents in cultured neurons as well as on population spikes (PS) in rat hippocampal slices. Data were correlated with those obtained from the spreading depression (SD) experiments in chicken retina. Compounds were also examined in the gerbil bilateral carotid occlusion model (BCO), where percentage decrease of ischemia-related hypermotility (HM), impaired spatial memory (SA), and hypoxia-induced hippocampal CA1 neuronal cell death (CA1) were evaluated. Results. Certain structural modifications of classical 2,3BDZs resulted in increased in vitro activity and improved in vivo efficacy. In particular, the halogen-substituted compounds EGIS-9879 and EGIS-9883 showed the highest neuroprotecfive efficacy (84% and 47% protection in CA1, 71% and 82% decrease in HM, respectively; 4 × 5 mg/kg i.p.) in BCO. PS and SD were correlated to the decrease of neuronal loss in the CA1 area. Lack of significant correlation was found between PS and CA1 (r = 0.437, p = 0.079) or SD and CA1 (r = 0.380, p = 0.146). Conclusions. Several new 2,3BDZ AMPA receptor antagonists have been synthesized at EGIS Pharmaceuticals characterized by remarkable in vitro and corresponding in vivo neuroprotective properties. [ABSTRACT FROM AUTHOR]

Objective. To study how the various 25 subtests and observations of the Norwegian clinical test for impairment related to the blood benzodiazepine concentrations of apprehended drivers suspected of driving under the influence of benzodiazepines. The impact of single-dose intake in non-daily users of benzodiazepines on the clinical picture of inebriation was also studied. Methods. Included in the study were 818 drivers suspected of driving under the influence of non-alcoholic drugs with blood samples containing only one benzodiazepine. We determined which of the 25 subtests and observations of the clinical test for impairment related significantly to the blood benzodiazepine concentrations. Results. Significantly related to blood benzodiazepine concentrations were 13 subtests and observations. Of these, 9 withstood adjustment for a variety of background variables. Singledose intake in non-daily users only influenced 3 subtests and observations after adjustment for blood benzodiazepine concentration and background variables. Romberg's test, 1 observation concerning alertness (oriented for time and place), 4 tests on motor and coordination (walk and turn on line, finger-to-nose and finger-to-finger tests), 2 observations on speech (articulation and content) and 1 observation regarding appearance (general conduct) were related to blood benzodiazepine concentrations. Conclusion. Many of these simple clinical tests are included in the standardized field sobriety test and are of value in revealing benzodiazepine impairment. The present study offered some possible additions. Combinations of these robust tests can also be used to reveal benzodiazepine inebriation in other contexts. [ABSTRACT FROM AUTHOR]

Sexual assaults under benzodiazepine submission have been described, since use of benzodiazepine enables non consensual sexual activity but rarely fully reported. An accurate evaluation of the phenomenon has seemed interesting. Files of 23 adult males and females examined at the Emergency Forensic Unit of an University Teaching Hospital near Paris were reviewed. All the victims had complained from sexual assault under drug submission, in the years 1996 and 1997. A complete examination for sexual assault was realised linked to clinical examination of drug intoxication. Every victim of rape under drug submission was sampled for urine screening (mean delay of 17.5 h after sexual assault) and blood alcohol level quantification. Urine was screened for benzodiazepines, cocaine, opiates and cannabinoids with qualitative immunochromatographic test. Traumatic lesions of sexual penetration were retrieved in 10 victims and sperm in 5. Clinical signs of benzodiazepine intoxication were retrieved in 12 out of 23 victims. Urine benzodiazepine screening was positive, over the cut-off values (300 ng/mL)when sampled less than 20 h after the facts. In 6 out of 23 victims, drugs of abuse and alcohol were associated to benzodiazepines. A reinforced attention can be brought to the rape under drug submission including the need of a proper examination and samplings shortly after the alleged facts to ascertain the diagnosis and to help the victim facing the Justice inquiry. [ABSTRACT FROM AUTHOR]

Clozapine, the prototype for the new generation of atypical antipsychotics, has demonstrated efficacy in treating schizophrenia, particularly in patients with symptoms that are refractory to traditional antipsychotics. Unfortunately, clozapine is associated with agranulocytosis in a small but significant minority of patients. Reliable predictors of response, whether therapeutic or adverse, to clozapine would assist clinicians in using this drug more effectively. This article reviews some of the proposed mechanisms of action of clozapine, and surveys current research on potential predictors of favourable and adverse outcomes to clozapine treatment. Demographic factors, plasma clozapine concentrations, neurochemical measures at baseline, response to pharmacological challenges, neuroimaging and molecular genetics have all been considered. Although conclusive, sensitive and specific predictors of response to clozapine have yet to be identified, significant associations have been found for predictors of both favourable response and adverse effects. [ABSTRACT FROM AUTHOR]

The article discusses a study concerning the epoxidation of bicyclo (2.2.1)hept-2-en-exo-5-5 and -endo-5-ylmethanamine derivatives by the action of peroxypthalic acid. The product structure was confirmed by IR and 1H and 13C NMR spectroscopy, including homo-(COSY) and 1H-13C heteronuclear correlation techniques. The IR spectra were recoreded in KBR on a UR-20 spectrometer.

The article offers information in the study that examines the impact of chronic drugs. The researchers have studies the missing link connecting to benzodiazepines to the dopaminergenic circuitry, which is a select group of GABAA receptors. It also mentions that the researchers obtain the result of the benzodiazepines to the dopaminergenic with the zolpidem, which binds predominantly to GABAA. In addition, the interneurons ordinarily inhibit the activity of dopaminergic neurons in the ventral tegmental area.

The article focuses on the findings of a study concerning the impact of translocator protein (18 kD) on humans without the undesirable effects of benzodiazepines. It mentions that the translocator protein (18 kD) is located on the outer mitochondrial membrane, where it facilitates cholesterol transport into the organelle and neurosteroid biosynthesis. Moreover, researchers found that the main current alternative treatment for anxiety disorders, take several weeks to have an effect.

It is well established that omeprazole influences the catabolismof several benzodiazepines resulting in potentially acuteintoxication (1-3). No fatal long-term sequelae of successiveapplication of omeprazole after therapy with benzodiazepineshas yet been reported, however. [ABSTRACT FROM AUTHOR]

Focuses on the use of clozapine in the prevention of suicide in patients with schizophrenia or schizoaffective disorder. Statistics of patients with schizophrenia who will commit suicide; Dosage and administration; Pharmacokinetic profile of clozapine after oral administration.

Focuses on a study which examined the effects of clozapine on the bone marrow. Background on the atypical antipsychotic drug; Adverse effects of the drugs; Methodology used in the study; Indications of the research findings.