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Abstract Benzodiazepines (BDZ), which potentiate the action of GABA at four subtypes of GABA A receptors (α1, α2, α3, and α5GABA A Rs), are highly effective against anxiety disorders, but also cause severe side effects greatly limiting their clinical application. Both, preclinical studies in genetically engineered mice, and preclinical and clinical trials with subtype-selective compounds indicate that undesired effects can in principle be avoided by targeting specific GABA A R subtypes. While there is general consensus that activity at α1GABA A Rs should be avoided, controversy exists as to whether α2 or α3GABA A Rs need to be targeted for anxiolysis. While previous experiments in GABA A R point-mutated mice demonstrated a critical role of α2GABA A Rs, studies solely relying on pharmacological approaches suggested a dominant contribution of α3GABA A Rs. As most α1GABA A R-sparing BDZ site agonists discriminate little between α2 and α3GABA A Rs, these claims rest almost exclusively on a single compound, TP003, that has been reported to be a selective α3GABA A R modulator. Here, we have revisited the in vitro pharmacological profile of TP003 and, in addition, tested TP003 in GABA A R triple point-mutated mice, in which only either α1, α2, or α3GABA A Rs were left BDZ sensitive. These experiments revealed that TP003 behaves as a partial, rather non-selective BDZ site agonist in vitro that acts in vivo through α1, α2, and α3GABA A Rs (α5GABA A R-mediated effects were not tested). With respect to anxiolysis, our results support a critical contribution of α2GABA A Rs, but not of α3GABA A Rs. TP003 should therefore not be considered an α3GABA A R selective agent. Previously published studies using TP003 should be interpreted with caution. Highlights • TP003 has been claimed to be an α3GABA A receptor selective modulator. • Based on TP003, claims were made that anxiolysis occurs through α3GABA A receptors. • Here, TP003 potentiated all four benzodiazepine sensitive GABA A receptor subtypes. • In vivo , it exerted anxiolysis through α2 but not α3GABA A receptors. [ABSTRACT FROM AUTHOR]

For a signed graph Γ, let e ( Γ ) denote the number of edges and S k ( Γ ) denote the sum of the k largest eigenvalues of the Laplacian matrix of Γ. We conjecture that for any signed graph Γ with n vertices, S k ( Γ ) ≤ e ( Γ ) + ( k + 1 2 ) + 1 holds for k = 1 , … , n . We prove the conjecture for any signed graph when k = 2 , and prove that this conjecture is true for unicyclic and bicyclic signed graphs. [ABSTRACT FROM AUTHOR]

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]

Background: Little is known about risk factors for repeated opioid overdose and fatal opioid overdose in the first year following nonfatal opioid overdose.Methods: We identified a national retrospective longitudinal cohort of patients aged 18-64 years in the Medicaid program who received a clinical diagnosis of nonfatal opioid overdose. Repeated overdoses and fatal opioid overdoses were measured with the Medicaid record and the National Death Index. Rates of repeat overdose per 1000 person-years and fatal overdose per 100,000 person-years were determined. Hazard ratios of repeated opioid overdose and fatal opioid overdose were estimated by Cox proportional hazards.Results: Nearly two-thirds (64.8%) of the patients with nonfatal overdoses (total n = 75,556) had filled opioid prescriptions in the 180 days before initial overdose. During the 12 months after nonfatal overdose, the rate of repeat overdose was 295.0 per 1000 person-years and that of fatal opioid overdose was 1154 per 100,000 person-years. After controlling for age, sex, race/ethnicity, and region, the hazard of fatal opioid overdose was increased for patients who had filled a benzodiazepine prescription in the 180 days prior to their initial overdose (HR = 1.71, 95%CI: 1.46-1.99), whose initial overdose involved heroin (HR = 1.57, 95%CI:1.30-1.89), or who required mechanical ventilation at the initial overdose (HR = 1.86, 95%CI = 1.50-2.31).Conclusions: Adults treated for opioid overdose frequently have repeated opioid overdoses in the following year. They are also at high risk of fatal opioid overdose throughout this period, which underscores the importance of efforts to engage and maintain patients in evidence-based opioid treatments following nonfatal overdose. [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]

An iterative cross-coupling approach to conjugated trienes was explored as part of a planned stereoselective synthesis of bicyclic terpenes. Using a bifunctional bromoboronate building block, sequential Suzuki coupling reactions were employed to provide a conjugated trienone target containing a tetrasubstituted alkene. During the final cross-coupling step, an unexpected alkene isomerization was observed to give less hindered trans products. Examination of different substrates determined that conjugation to a ketone withdrawing group was responsible for isomerization, rather than steric hindrance of the tetrasubstituted alkene. [ABSTRACT FROM AUTHOR]

Objective There is some evidence that clozapine is significantly underutilised. Also, clozapine use is thought to vary by country, but so far no international study has assessed trends in clozapine prescribing. Therefore, this study aimed to assess clozapine use trends on an international scale, using standardised criteria for data analysis. Method A repeated cross-sectional design was applied to data extracts (2005-2014) from 17 countries worldwide. Results In 2014, overall clozapine use prevalence was greatest in Finland (189.2/100 000 persons) and in New Zealand (116.3/100 000), and lowest in the Japanese cohort (0.6/100 000), and in the privately insured US cohort (14.0/100 000). From 2005 to 2014, clozapine use increased in almost all studied countries (relative increase: 7.8-197.2%). In most countries, clozapine use was highest in 40-59-year-olds (range: 0.6/100 000 (Japan) to 344.8/100 000 (Finland)). In youths (10-19 years), clozapine use was highest in Finland (24.7/100 000) and in the publicly insured US cohort (15.5/100 000). Conclusion While clozapine use has increased in most studied countries over recent years, clozapine is still underutilised in many countries, with clozapine utilisation patterns differing significantly between countries. Future research should address the implementation of interventions designed to facilitate increased clozapine utilisation. [ABSTRACT FROM AUTHOR]

• Risk factors for violence in the ED include overcrowding, prolonged stays in the ED, increasing numbers of patients with mental health disorders (especially without proper facilities for them), understaffing, inadequate training, rising rates of substance abuse, absence of a pre-existing relationship between staff and patients, and the lack of privacy. • Cues to escalating behavior include yelling or cursing and aggressive verbal and physical behavior. Pacing, avoiding eye contact, and being destructive to their space suggest escalating behavior. • Sedation may be necessary. Commonly used drugs include benzodiazepines, haloperidol/droperidol, and ketamine. • Sedated patients may require intubation. Clearly, all patients given sedation who do not respond easily may require monitoring. • Chemical restraints are preferable to physical restraints. [ABSTRACT FROM AUTHOR]

A new ultra high performance liquid chromatography with electrospray ionization time of flight mass spectrometry method for the selective and sensitive separation, identification, and determination of selected designer benzodiazepines (namely, pyrazolam, phenazepam, etizolam, flubromazepam, diclazepam, deschloroetizolam, bentazepam, nimetazepam, and flubromazolam) in human serum was developed. The separation of the studied designer benzodiazepines was achieved on C18 chromatographic column using gradient elution within 6 min without any significant matrix interferences. Liquid-liquid extraction with butyl acetate was applied for serum samples cleanup and preconcentration of studied designer benzodiazepines. The method was validated in terms of linearity, limit of detection, limit of quantification, matrix effects, specificity, precision, accuracy, recovery, and sample stability. The limit of detection values were 0.10-0.15 ng/mL. The method was applied to a spiked serum sample to demonstrate its applicability for systematic toxicology analysis. Furthermore, a capillary chromatographic method with micellar electrokinetic chromatography was used for the estimation of partition coefficients of studied designer benzodiazepines as important parameters to evaluate their pharmacological and toxicological properties. [ABSTRACT FROM AUTHOR]

The 2-amino-4′-flouro-benzophenone ( 1) that was reacted with chloroacetylchloride to afford 2-chloro- N-(2-(4′-fluorobenzoyl) phenyl)acetamide ( 2) was subsequently converted to 1,4-benzodiazepines ( 3) by the modification of the known hexamethylenetetramine based reaction developed by Blazevic and Kajfez. Thus, obtained product ( 3) was reacted with a variety of alkyl halide using KOH in DMF to give 1-substituted-5-(4-fluorophenyl)-1 H-benzo[e][1,4]diazepin-2(3 H)-one ( 4a, 4b). To achieve 1, 3-disubstituted 1, 4-benzodiazepines ( 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m, 5n, 5o, 5p, 5q, 5r, 5s, 5t), 1-substituted-5-(4-fluorophenyl)-1 H-benzo[e][1,4]diazepin-2(3 H)-one ( 4a, 4b) was treated with various aromatic aldehydes in the presence of KOH in toluene. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare benzodiazepine (bzd) prescriptions for adults and older adults regarding appropriate use indicator. It is a cross-sectional study for collecting data on patients treated at the City's Mental Health Clinic in Sorocaba/SP, between March and December 2013. Appropriate use indicators were used: appropriate drug, with adequate posology and period of use; as well as the use of a single bzd, as anxiolytic for less than 3 months in depression treatment with antidepressants, use for less than 2 months if associated to an antidepressant and no use of long-acting bzd in older adults. From the 330 participants, most were women, with a family history of mental disorders and bzd use, without monitoring of a psychologist and using other psychotropic and polypharmacy (p>0.05).The minority of prescriptions had indication for the use of bzd (37.5% for older adults and 32.4% for adults) (p>0.05). Only 5.8% of the prescriptions for older adults and 1.9 for adults were rational (p>0.05). The chronic use was observed in all adults and older adults with depressive and anxiety disorders (p>0.05). A minority of prescriptions for adults and older adults was appropriate. [ABSTRACT FROM AUTHOR]

NS11821 is a partial GABAA agonist with relatively dominant α2,3 and α5 subtype efficacy but negligible α1 agonism. This first-in-human study was performed in healthy male subjects using a single-dose, parallel, double blind, placebo-controlled, randomized, dose-escalation study design. In total six cohorts (N=48) were enrolled. The eight subjects of each cohort received NS11821 (10 mg, 30 mg, 75 mg, 150 mg, 300 mg or 600 mg) or placebo in a 6:2 ratio. At low dose levels, NS11821 had a relatively low exposure and a more-than-proportional increase of the area under the curve and maximum plasma concentrations, probably due to poor solubility. Saccadic peak velocity decreased in a dose-related manner while limited impairments were seen on body sway and the visual analogue scale for alertness. The most common adverse events were somnolence and dizziness, which were more prominent with the higher doses. Although no positive control was used in this study, the results were compared post hoc with a Centre for Human Drug Research dataset for lorazepam 2 mg. The maximum saccadic peak velocity effects seemed comparable to the typical effects of lorazepam, whereas the other central nervous system effects were smaller. These results support the pharmacological selectivity of NS11821 and show that pharmacodynamic effective doses of NS11821 were safe and well tolerated in healthy subjects. [ABSTRACT FROM AUTHOR]

Clozapine is the only antipsychotic medication that has definitely shown to be effective in treating refractory schizophrenia. Clozapine is typically the medication of choice in schizophrenic patients with a partial response to treatment. When clozapine fails to elicit a full treatment response, augmentation strategies are then explored. It is important to note, however, that in treatment resistant schizophrenic patients, the addition of a second antipsychotic is frequently preferred as an augmentation method. Consistent positive results could not be obtained with previous augmentation strategies. Paliperidone is a risperidone metabolite that has proven effective in treating schizophrenia. Although most effects of paliperidone on the central nervous system are similar to risperidone, there are some noteworthy differences. In this case series, the treatment of five schizophrenic patients presenting with symptoms, excluding clozapine treatment, were augmented with paliperidone during six months of follow up. This augmentation was tolerated well by the patients, and resulted in a reduction of both positive and negative symptoms. The addition of paliperidone resulted in a remarkable improvement of negative symptoms in our patients. Further evaluation of paliperidone's effects on negative symptoms in schizophrenic patients with a partial response to clozapine treatment may provide another viable treatment choice. [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]

Reactions of triarylphosphines with fluoroantimony(III) triflates give phosphine antimony(III) complexes, which undergo spontaneous reductive elimination of fluorophosphonium cations. The resulting phosphine antimony(I) complexes catenate to give the first examples of cationic antimony bicyclic compounds, [(R3P)4Sb6]4+, featuring a bicyclo[3.1.0]hexastibine framework stabilized by four phosphine ligands. The unprecedented 14-electron redox process illustrates the generality of the reductive catenation method. [ABSTRACT FROM AUTHOR]

Benzodiazepines (BDZs) are widely used as tranquilizers and antidepressive drugs in common clinical practice. However, their ready availability and their synergistic effects with alcohol make them attractive for criminal intentions. To prove criminal action for legal reasons, it is often necessary to analyze beverage residues from a crime scene. Milk-based alcoholic drinks (whiskey creams) are gaining popularity due to their lower alcohol content pleasant taste. However, the complexity of this sample, containing proteins and fatty acids, can mask the presence of drugs or other substances in standard analysis methods. These characteristics make whiskey creams highly suitable for illicit purposes. In this study, eight BDZs, including diazepam, chlordiazepoxide, clobazam, flunitrazepam, bromazepam, flurazepam, nitrazepam and clonazepam, were extracted from whiskey cream using the Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) method and analyzed using GC-MS. The QuEChERS protocol can efficiently separate most of the matrix from the target compounds while maintaining acceptable recoveries. The presented method is simple and rapid and has been validated in terms of precision, accuracy and recoveries. Limits of detection and limits of quantitationwere in the range of 0.02-0.1 and 0.1-0.5 µg/mL, respectively. Whiskey cream beverages, fortified with commercial drugs at 20 µg/mL, were extracted and analyzed demonstrating the applicability of the method in forensic analysis. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy and safety of clozapine for treatment-resistant bipolar disorder (TRBD). Methods A systematic review of randomized controlled studies, open-label prospective studies, and retrospective studies of patients with TRBD was carried out. Interventions included clozapine monotherapy or clozapine combined with other medications. Outcome measures were efficacy and adverse drug reactions (ADRs). Results Fifteen clinical trials with a total sample of 1,044 patients met the inclusion criteria. Clozapine monotherapy or clozapine combined with other treatments for TRBD was associated with improvement in: (i) symptoms of mania, depression, rapid cycling, and psychotic symptoms, with many patients with TRBD achieving a remission or response; (ii) the number and duration of hospitalizations, the number of psychotropic co-medications, and the number of hospital visits for somatic reasons for intentional self-harm/overdose; (iii) suicidal ideation and aggressive behavior; and (iv) social functioning. In addition, patients with TRBD showed greater clinical improvement in long-term follow-up when compared with published schizophrenia data. Sedation (12%), constipation (5.0%), sialorrhea (5.2%), weight gain (4%), and body ache/pain (2%) were the commonly reported ADRs; however, these symptoms but did not usually require drug discontinuation. The percentage of severe ADRs reported, such as leukopenia (2%), agranulocytosis (0.3%), and seizure (0.5%), appeared to be lower than those reported in the published schizophrenia literature. Conclusion The limited current evidence supports the concept that clozapine may be both an effective and a relatively safe medication for TRBD. [ABSTRACT FROM AUTHOR]

A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects. [ABSTRACT FROM AUTHOR]

The relative and absolute configurations of phaeosphaeride A have been established via the first total synthesis of ent-phaeosphaeride A. The three contiguous stereogenic centers were installed by Sharpless asymmetric dihydroxylation and a stereoselective intramolecular vinyl anion aldol reaction. This synthesis has altered the originally proposed structure of natural phaeosphaeride A. [ABSTRACT FROM AUTHOR]

• The efficient and convenient methods for selective synthesis of 5-member and 7-member N -heterocycle compounds such as benzimidazoles and benzodiazepines have been developed. • The versatile binary-catalysis system of organometallic Lewis acid and Brønsted acid/base have been designed and applied in the condensation and cyclization between aldehyde or ketone and o -phenylenediamine. • Mechanism study on true catalytic species elicited that the combination of Ti Lewis acid with Brønsted acid / base was responsible for selective transformation of aldehyde and ketone with o -phenylenediamine into benzimidazole and benzodiazepine. Benzimidazoles and benzodiazepines were selectively synthesized from o -phenylenediamine and carbonyl compounds by Brønsted acid/base assisted titanocene dichloride. Mechanism research including NMR and ESI-MS analyses and control experiments elucidated the new catalytic species formed by Cp 2 TiCl 2 and the combination of titanocene Lewis acid with Brønsted acid/base was responsible for selective transformations of aldehyde and ketone with o -phenylenediamine into benzimidazole and benzodiazepine. [Display omitted] Selective Synthesis of Benzimidazoles and Benzodiazepines Catalyzed by Brønsted Acid/ Base-Cooperative Titanocene Dichloride [ABSTRACT FROM AUTHOR]

A general method for the formation of fused dihydroazepine derivatives from 1-sulfonyl-1,2,3-triazoles bearing a tethered diene is reported. The process involves an intramolecular cyclopropanation of an α-imino rhodium(II) carbenoid, leading to a transient 1-imino-2-vinylcyclopropane intermediate which rapidly undergoes a 1-aza-Cope rearrangement to generate fused dihydroazepine derivatives in moderate to excellent yields. The reaction proceeds with similar efficiency on gram scale. The use of catalyst-free conditions leads to the formation of a novel [4.4.0] bicyclic heterocycle. [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]

A rapid high performance liquid chromatography method, using a monolithic column, was developed for quantitative determinations of benzodiazepines (diazepam, clonazepam, lorazepam, midazolam) in whole blood. A liquid-liquid extraction step with n-chlorobutane isolates the drugs from alkalinized blood. The separation was carried out in reversed phase conditions using a Chromolith Performance (RP-18 100x4.6 mm) column. For the mobile phase, a mixture of a phosphate buffer (pH= 2.5)/acetonitrile (65/35 v/v), in isocratic mode at 2 mL/min. An ultraviolet spectrophotometer was used as the detector at the wavelength of 220 nm. The total run time of the analytical method is less than 4-6 minutes. The calibration curves showed linearity and the correlation coefficient of each individual curve was greater than 0.995. The method was linear over a concentration range of 0.03-0.6 μg/mL for clonazepam, lorazepam and midazolam. For diazepam of linearity was over the range 0.04-5.0μg/mL. Quantification limits ranged from 0.03-0.04μg/mL and the accuracy were from 80% to 105% for the recovery test. The results indicate that this analytical method is simple, specific, accuracy, sensitive, demonstrating from the validation data and a higher robustness. The proposed method is applied routinely in forensic toxicological analysis involving blood. [ABSTRACT FROM AUTHOR]

BACKGROUND: Borderline personality disorder (BPD) is a serious mental disorder that is difficult to treat. Possible targets for pharmacotherapy include affective symptoms, cognitive disturbances, and impulsive, self-injurious behaviors. Although many of the medications tested for treatment of BPD have been demonstrated to be useful, no clear pharmacologic treatment has emerged. Clozapine is one of the medications that has been evaluated for the treatment of severe BPD. The aim of this review is to summarize the evidence examining the effectiveness of clozapine in the treatment of BPD. METHODS: A comprehensive search of the health science databases PubMed, EMBASE, CINAHL, PsycINFO, Web of Science, Cochrane Library, and Google Scholar was performed for studies describing the use of clozapine in the treatment of BPD. RESULTS: After the initial search, no randomized controlled trials evaluating the effectiveness of clozapine in BPD were identified. Therefore, case reports and case series were reviewed, with 12 articles selected for final review. CONCLUSIONS: This review suggests that clozapine may be a beneficial treatment option for BPD especially in controlling symptom severity, psychotic symptoms, impulsivity, self-mutilation, number of days on enhanced observation, use of restraint, and overall functioning. [ABSTRACT FROM AUTHOR]

BACKGROUND: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis was formally described in 2007 and includes a range of psychiatric and neurologic symptoms. Most patients with anti-NMDAR encephalitis initially present to psychiatrists for diagnosis and treatment. However, there is limited literature summarizing treatment strategies for psychiatric symptoms. In an effort to improve identification and treatment, this review article provides an overview of anti-NMDAR encephalitis, with a focus on psychopharmacologic treatment strategies. Two case reports provide a clinical context for the literature review. METHODS: The authors conducted a PubMed search. RESULTS: Prominent psychiatric symptoms of anti-NMDAR encephalitis include psychosis, agitation, insomnia, and catatonia. Neuroleptics may be helpful for managing psychosis and agitation, but may exacerbate movement abnormalities. Diphenhydramine and benzodiazepines are helpful for agitation and insomnia. In addition, the anticholinergic affinity of diphenhydramine can improve dystonia or rigidity attributable to anti-NMDAR encephalitis, while benzodiazepines and electroconvulsive therapy have been used for catatonia associated with this condition. CONCLUSIONS: Psychiatrists play an important role in the diagnosis and treatment of anti-NMDAR encephalitis. Recognizing the typical clinical progression and closely monitoring for accompanying neurologic symptoms will facilitate diagnosis and timely treatment. Careful selection of psychopharmacological interventions may reduce suffering. [ABSTRACT FROM AUTHOR]

The prion diseases are rare neurodegenerative conditions that cause complex and highly variable neuropsychiatric syndromes, often with remarkably rapid progression. Prominent behavioral and psychiatric symptoms have been recognized since these diseases were first described. While research on such symptoms in common dementias has led to major changes in the way these symptoms are managed, evidence to guide the care of patients with prion disease is scarce. The authors review the published research and draw on more than 10 years' experience at the U.K. National Prion Clinic, including two large prospective clinical research studies in which more than 300 patients with prion disease have been followed up from diagnosis to death, with detailed observational data gathered on symptomatology and symptomatic treatments. The authors group behavioral and psychiatric symptoms into psychotic features, agitated features, and mood disorder and describe their natural history, showing that they spontaneously improve or resolve in many patients and are short-lived in many others because of rapid progression of global neurological disability. Diagnostic category, disease severity, age, gender, and genetic variation are or may be predictive factors. The authors review the observational data on pharmacological treatment of these symptoms in the U.K. clinical studies and make cautious recommendations for clinical practice. While nonpharmacological measures should be the first-line interventions for these symptoms, the authors conclude that there is a role for judicious use of pharmacological agents in some patients: antipsychotics for severe psychosis or agitation; benzodiazepines, particularly in the late stages of disease; and antidepressants for mood disorder. [ABSTRACT FROM AUTHOR]

SPE combined with dispersive liquid-liquid microextration was used for the extraction of ultra-trace amounts of benzodiazepines ( BZPs) including, diazepam, midazolam, and alprazolam, from ultra-pure water, tap water, fruit juices, and urine samples. The analytes were adsorbed from large volume samples (60 mL) onto octadecyl silica SPE columns. After the elution of the desired compounds from sorbents with 2.0 mL acetone, 0.5 mL of eluent containing 40.0 μL chloroform was injected rapidly into 4.5 mL pure water. After extraction and centrifugation, 2 μL of the sedimented phase was injected into a GC equipped with a flame ionization detector. Several parameters affecting this process were investigated and optimized. Under the optimal conditions, LODs ranged from 0.02 to 0.05 μg/L, a linear dynamic range of 0.1-100 μg/L and relative SDs in the range of 4.4-10.7% were attained. Very high preconcentration factors ranging from 3895-7222 were achieved. The applicability of the method for the extraction of BZPs from different types of complicated matrices, such as tap water, fruit juices, and urine samples, was studied. The obtained results reveal that the proposed method is a good technique for the extraction and determination of BZPs in complex matrices. [ABSTRACT FROM AUTHOR]

Background: Clozapine has been used widely in the management of treatment-resistant schizophrenia. The present study aims at determining whether pre-treatment electroencephalography (EEG) abnormalities would serve as a marker for response to clozapine treatment. Subjects and Methods: This was a cross-sectional study done in a tertiary care center in Mumbai where patients diagnosed with schizophrenia using DSM-IV criteria and resistant schizophrenia using Kane criteria were assessed using EEG prior to starting clozapine treatment. They were rated for symptomatic improvement using the Positive and Negative Syndrome Scale (PANSS) along with Clinical Global Improvement for Severity (CGI-S). The results were statistically analysed and presented. Results: 55 out of the 80 patients in the study showed baseline EEG abnormalities. The mean duration of illness in the patients were 2.65 years. Slow wave and background EEG abnormalities were common in pre-treatment EEG. 36.4% patients in the study showed clinical response. Patients with negative symptoms and baseline EEG abnormalities showed better response. Conclusions: The study was circumscribed and had many limitations due to a small sample size. The relation between pre-treatment EEG abnormalities and clozapine response could not be statistically correlated and it could not be ascertained to be a marker for response to clozapine therapy. [ABSTRACT FROM AUTHOR]

Aims: Our aim was to investigate the practicalities and success rate of clozapine titration in the community in a large sample of patients referred to three crisis teams in a defined geographical area. Methods: We collected data retrospectively of all the referrals for clozapine initiation to three crisis teams across Manchester during a three year period. Results: Out of a total of 6542 referrals, 66 were for clozapine initiation. From these referrals only 54 patients started clozapine, as the others declined the treatment. After commencing clozapine, a total of 46 patients (86.2%) completed the titration successfully. The main reason for discontinuing the clozapine titration in the community was withdrawal of patients' consent. Only one patient was unable to physically tolerate the titration and was admitted to hospital. Conclusions: Clozapine can be safely started in the community. Patients' adherence to the treatment and to the physical monitoring is the key element of a successful outcome. Crisis teams are in an ideal position to support patients undergoing initiation of clozapine at home. [ABSTRACT FROM AUTHOR]

The prevalence of the metabolic syndrome (MetS) is higher among patients receiving atypical antipsychotics (AAPs) treatment, and even among AAPs, treatment with clozapine has been shown to be associated with a higher long-term incidence rate of MetS. Likewise, brain-derived neurotrophic factor (BDNF) deficiency has been reported to result in metabolic traits, such as increased food intake, hyperphagia and obesity, etc. In this study, we hypothesized that a functional polymorphism (Val66Met) in the BDNF gene may confer susceptibility to clozapine-induced MetS, potentially in a sex-specific manner, since an interaction between Val66Met polymorphism and sex was observed in our previous studies. A total of 199 schizophrenia patients being treated with clozapine were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program's Adult Treatment Panel III. We genotyped the Val66Met polymorphism, and measured the serum levels of fasting glucose (GLU), triglyceride (TG) and high density lipoprotein cholesterol (HDL). There was a trend indicating a significant association between the homozygous Met/Met genotype and MetS in male patients (OR = 2.39; 95% CI: 1.05–5.41; p = 0.039; corrected p = 0.078). Among the six risk factors listed in the ATPIII criteria, we found a significant association between fasting GLU levels and Val66Met polymorphism in males (p = 0.005; corrected p = 0.03), but not in females (p = 0.65). Post-hoc analysis in males revealed that the Met/Met carriers had significant higher levels of fasting GLU than those with Val/Val or Val/Met genotypes (p = 0.007; corrected p = 0.042 and p = 0.002; corrected p = 0.012, respectively). In conclusion, we observed a weak association between the Val66Met polymorphism and clozapine-induced MetS in a sex-specific manner. While preliminary, such findings prompt further, large-scale longitudinal studies to replicate these findings. [ABSTRACT FROM AUTHOR]

A broad forensic screening method for 256 analytes in whole blood based on a fully automated SPE robotic extraction and ultra-high-performance liquid chromatography (UHPLC) with TOF- MS with data-independent acquisition has been developed. The limit of identification was evaluated for all 256 compounds and 95 of these compounds were validated with regard to matrix effects, extraction recovery, and process efficiency. The limit of identification ranged from 0.001 to 0.1 mg/kg, and the process efficiency exceeded 50% for 73 of the 95 analytes. As an example of application, 1335 forensic traffic cases were analyzed with the presented screening method. Of these, 992 cases (74%) were positive for one or more traffic-relevant drugs above the Danish legal limits. Commonly abused drugs such as amphetamine, cocaine, and frequent types of benzodiazepines were the major findings. Nineteen less frequently encountered drugs were detected e.g. buprenorphine, butylone, cathine, fentanyl, lysergic acid diethylamide, m-chlorophenylpiperazine, 3,4-methylenedioxypyrovalerone, mephedrone, 4-methylamphetamine, p-fluoroamphetamine, and p-methoxy- N-methylamphetamine. In conclusion, using UHPLC- TOF- MS screening with data-independent acquisition resulted in the detection of common drugs of abuse as well as new designer drugs and more rarely occurring drugs. Thus, TOF- MS screening of blood samples constitutes a practical way for screening traffic cases, with the exception of δ-9-tetrahydrocannabinol, which should be handled in a separate method. [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]

Background: The neurotrophic factor, S100B, is released primarily from astrocytes, with serum and CSF levels of S100B reported as altered in schizophrenia. However, many of these reports are contradictory. Here, serum levels of S100B in schizophrenia and influence of age, gender, medication and illness severity were examined. Methods: Serum S100B levels were measured in patients with schizophrenia treated with clozapine. Lifestyle, metabolic and illness severity parameters were correlated with S100B concentrations. Results: Data showed raised serum levels of S100B in schizophrenia female patients, but not male patients, compared to controls. Correlation analysis demonstrated a positive association between S100B serum concentrations and BMI. Conclusions: This study supports previous findings that adipocytes may contribute to S100B serum concentrations in females, in addition to astrocytes. This study also supports the hypothesis that metabolic effects of medication, lifestyle choices and the illness itself, may be contributing factors to altered levels of S100B. [ABSTRACT FROM AUTHOR]

Introduction: An increased risk for metabolic syndrome has been described for patients with psychotic disorders. Antipsychotic drugs possibly contribute to metabolic changes. Methods: Haloperidol or clozapine was orally fed to male and female Sprague Dawley rats for 12 weeks, and body weight gain, food and water intake were measured. The serum levels of fasting glucose, HbA1c, triglycerides, cholesterol, HDL and LDL, insulin, leptin, adiponectin and ghrelin were determined. Gonadal and perirenal fat pads were removed and weighed. Results: We found increased body weight in the male clozapine group, but decreased ones in the male haloperidol group. Clozapine-treated male and female animals had higher fasting glucose, adiponectin, leptin, ghrelin, cholesterol, HDL and LDL levels, whereas haloperidol caused increased levels of insulin and decreased values of HbA1c, cholesterol, HDL and LDL. Conclusion: Both antipsychotic drugs cause sex-dependent metabolic changes, which are risk factors for the metabolic syndrome, be it hyperinsulinemia under haloperidol treatment or hyperglycemia, hyperleptinemia and hyperlipidemia under clozapine. [ABSTRACT FROM AUTHOR]

Pentylenetetrazole (PTZ) is a common convulsant agent used in animal models to investigate the mechanisms of seizures. Although adult zebrafish have been recently used to study epileptic seizures, a thorough characterization of the PTZinduced seizures in this animal model is missing. The goal of this study was to perform a detailed temporal behavior profile characterization of PTZ-induced seizure in adult zebrafish. The behavioral profile during 20 min of PTZ immersion (5, 7.5, 10, and 15 mM) was characterized by stages defined as scores: (0) short swim, (1) increased swimming activity and high frequency of opercular movement, (2) erratic movements, (3) circular movements, (4) clonic seizure-like behavior, (5) fall to the bottom of the tank and tonic seizure-like behavior, (6) death. Animals exposed to distinct PTZ concentrations presented different seizure profiles, intensities and latencies to reach all scores. Only animals immersed into 15 mM PTZ showed an increased time to return to the normal behavior (score 0), after exposure. Total mortality rate at 10 and 15 mM were 33% and 50%, respectively. Considering all behavioral parameters, 5, 7.5, 10, and 15 mM PTZ, induced seizures with low, intermediate, and high severity, respectively. Pretreatment with diazepam (DZP) significantly attenuated seizure severity. Finally, the brain PTZ levels in adult zebrafish immersed into the chemoconvulsant solution at 5 and 10 mM were comparable to those described for the rodent model, with a peak after a 20-min of exposure. The PTZ brain levels observed after 2.5-min PTZ exposure and after 60-min removal from exposure were similar. Altogether, our results showed a detailed temporal behavioral characterization of a PTZ epileptic seizure model in adult zebrafish. These behavioral analyses and the simple method for PTZ quantification could be considered as important tools for future investigations and translational research. [ABSTRACT FROM AUTHOR]

There is a considerable disparity between clinical practice and recommendations based on meta-analyses of antipsychotic polypharmacy in clozapine resistant schizophrenia. For this reason, we investigated the clinical response to reducing the use olanzapine that had been previously added on clozapine treatment among seriously ill hospitalized patients. In a randomized controlled trial with crossover design, we studied volunteer patients (N=15) who had olanzapine added on to clozapine in a state mental hospital. Clozapine monotherapy was just as effective as clozapine-olanzapine therapy, according to results from Clinical Global Impression Scale and Global Assessment of Functioning as primary outcome measures. Polypharmacy is widely used in treating schizophrenia, and usually, add-on medications are started because of worsening of the clinical state. A major confounding feature of these add-ons is whether observed improvements are caused by the medication or explained by the natural fluctuating course of the disorder. The present study, in spite of its small size, indicates the necessity of reconsidering the value of polypharmacy in treating schizophrenia [ABSTRACT FROM AUTHOR]

A series of amido-substituted triazolopyrrolo[2,1-c][1,4]benzodiazepine (PBDT) derivatives was synthesized from isatoic anhydride, and their cytotoxicity against the MRC-5 and Mahlavu cell lines was evaluated. The results suggest that compound PBDT-7i with the meta-trifluoromethylbenzoyl substituent can selectively inhibit the growth of Mahlavu cells and has low toxicity towards MRC-5 cells. [ABSTRACT FROM AUTHOR]

The inherent morbidity and mortality caused by schistosomiasis is a serious public health problem in developing countries. Praziquantel is the only drug in therapeutic use, leading to a permanent risk of parasite resistance. In search for new schistosomicidal drugs, meclonazepam, the 3-methyl-derivative of clonazepam, is still considered an interesting lead-candidate because it has a proven schistosomicidal effect in humans but adverse effects on the central nervous system did not allow its clinical use. Herein, the synthesis, in vitro biological evaluation, and molecular modeling of clonazepam, meclonazepam, and analogues are reported to establish the first structure-activity relationship for schistosomicidal benzodiazepines. Our findings indicate that the amide moiety [N1H-C2(=O)] is the principal pharmacophoric unit of 1,4-benzodiazepine schistosomicidal compounds and that substitution on the amide nitrogen atom ( N1 position) is not tolerated. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE The molecular substrates underlying the respiratory changes associated with benzodiazepine sedation are unknown. We examined the effects of different doses of diazepam and alprazolam on resting breathing in wild-type (WT) mice and clarified the contribution of α1- and α2-GABAA receptors, which mediate the sedative and muscle relaxant action of diazepam, respectively, to these drug effects using point-mutated mice possessing either α1H101R- or α2H101R-GABAA receptors insensitive to benzodiazepine. EXPERIMENTAL APPROACH Room air breathing was monitored using whole-body plethysmography. Different groups of WT mice were injected i.p. with diazepam (1-100 mg·kg−1), alprazolam (0.3, 1 or 3 mg·kg−1) or vehicle. α1H101R and α2H101R mice received 1 or 10 mg·kg−1 diazepam or 0.3 or 3 mg·kg−1 alprazolam. Respiratory frequency, tidal volume, time of expiration and time of inspiration before and 20 min after drug injection were analysed. KEY RESULTS Diazepam (10 mg·kg−1) decreased the time of expiration, thereby increasing the resting respiratory frequency, in WT and α2H101R mice, but not in α1H101R mice. The time of inspiration was shortened in WT and α1H101R mice, but not in α2H101R mice. Alprazolam (1-3 mg·kg−1) stimulated the respiratory frequency by shortening expiration and inspiration duration in WT mice. This tachypnoeic effect was partially conserved in α1H101R mice while absent in α2H101R mice. CONCLUSIONS AND IMPLICATIONS These results identify a specific role for α1-GABAA receptors and α2-GABAA receptors in mediating the shortening by benzodiazepines of the expiratory and inspiratory phase of resting breathing respectively. [ABSTRACT FROM AUTHOR]

2,3-Benzodiazepine (2,3-BDZ) compounds are a group of AMPA receptor inhibitors and are drug candidates for treating neurological diseases involving excessive AMPA receptor activity. We investigated the mechanism by which GluA2Qflip receptor channel opening is inhibited by two 2,3-BDZ derivatives, Le., 1-(4-aminophenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one (2,3-BDZ-11-2) and its 1-(4-amino-3-chlorophenyl) analogue (2,3-BDZ-11-4). Both compounds have a 7,8-ethylenedioxy moiety instead of the 7,8-methyienedioxy feature present in the structure of GYKI S2466, the prototypic 2,3-BDZ compound. Using a laser-pulse photolysis approach with a time resolution of ∼60 μs and a rapid solution flow technique, we characterized the effect of the two compounds on the channel opening process of the homomeric GluA2Qflip receptor. We found that both 2,3-BDZ-11-2 and 2,3-BDZ-11-4 are noncompetitive inhibitors with specificity for the closed-channel conformation of the GluA2Qflip receptor. However, 2,3-BDZ-11-4 is ∼10-fold stronger, defined by its inhibition constant for the closed-channel conformation (i.e.( K, - 2 μM), than 2,3-BDZ-11-2. From double-inhibitor experiments, we determined that both compounds bind to the same site, but this site is different from two other known, noncompetitive binding sites on the GluA2Qflip receptor previously reported. Our results provide both mechanistic clues to improve our understanding of AMPA receptor regulation and a structure-activity relationship for designing more potent 2,3-BDZ compounds with predictable properties for this new noncompetitive site. [ABSTRACT FROM AUTHOR]

A strategy featuring a multicomponent assembly process fallowed by an intra molecular azide-alkyne dipolar (Huisgen) cycloaddition was implemented for the facile synthesis of three diiferent l,2,3-triazoIa-i,4-benzodiaz-epine scaffolds. A diverse library of 170 compounds derived from these scaffolds was then created through N-functionali/a-tians, palladium-catalyzed cross-coupling reactions, and several applications of a-aminonitrile cbemistr [ABSTRACT FROM AUTHOR]

Condensation of 2-methyl-/2-ethyl- and 2-phenyl-/p-tolyl-4-arylidene-/heterylmethylidene-2-oxazolin-5-ones (γ-azlactones) 2 with o-aminobenzamide 1 in acetic acid resulted in the formation of two entirely different heterocyclic systems, differently substituted quinazoline compounds, 2-methyl-/2-ethyl-3-α-carboxy-α-styryl-/β-heteryl-α-carboxyvinyl-quinazolin-4(3 H)-ones 3a-3e and 3′a-3′e and differently substituted 1,4-benzodiazepine compounds, 3-arylidene-/heteryl methylidene-4-aroyl-1 H-[1,4]benzodiazepine-2,5(3 H,4 H)-diones 7a-7e and 7′a-7′e. Compounds 3a-3e and 3′a-3′e have been converted into compounds, 4a-4e and 4′a-4′e; 5a-5e, and 5′a-5′e; and 6a-6e and 6′a-6′e through different transformations. Benzodiazepines, 7a-7e and 7′a-7′e, on condensation with o-phenylenediamine have generated three novel heterocyclic systems 8a-8e and 8′a-8′e; 9a-9e and 9′a-9′e; and 10a-10e and 10′a-10′e. J. Heterocyclic Chem., (2012). [ABSTRACT FROM AUTHOR]

Background: Selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and benzodiazepine anxiolytics are used in the US to treat generalized anxiety disorder (GAD). While benzodiazepines typically provide rapid symptomatic relief, long-term use is not recommended due to risks of dependency, sedation, falls, and accidents. Methods: Using a US health insurance database, we identified all persons with GAD (ICD-9-CM diagnosis code 300.02) who began a long-term course of treatment (≥90 days) with a benzodiazepine anxiolytic between 1/1/2003 and 12/31/2007, We compared healthcare utilization and costs over the six-month periods preceding and following the date of treatment initiation ("pretreatment" and "post-treatment", respectively), and focused attention on accident-related encounters (e.g., for treatment of fractures) and care received for other reasons possibly related benzodiazepine use (e.g., sedation, dizziness). Results: A total of 866 patients met all study entry criteria; 25% of patients began treatment on an add-on basis (i.e., adjunctive to escitalopram, paroxetine, sertraline, or venlafaxine), while 75% of patients did not receive concomitant therapy. Mean total healthcare costs increased by $2334 between the pretreatment and post-treatment periods (from $4637 [SD=$9840] to $6971 [$17,002]; p<0.01); costs of accident-related encounters and other care that was possibly related to use of benzodiazepines increased by an average of $1099 ($1757 [$7656] vs $2856 [$14,836]; p=0.03). Conclusions: Healthcare costs increase in patients with GAD beginning long-term (≥90 days) treatment with a benzodiazepine anxiolytic; a substantial proportion of this increase is attributable to care associated with accidents and other known sequelae of long-term benzodiazepine use. [ABSTRACT FROM AUTHOR]

We describe a simple and novel protocol for the synthesis of tetrahydro-1,4-benzodiazepin-2-ones with three points of diversity, exploiting the acylating properties of the recently rediscovered Ugi-imide. The final compounds can be easily prepared in three synthetic steps using a multicomponent reaction, a Staudinger reduction, and an acylative protocol, with good to excellent yields for each synthetic step. [ABSTRACT FROM AUTHOR]

Abstract: A library of 1,4-benzodiazepines has been synthesized and evaluated against Trypanosoma brucei, a causative parasite of Human African trypanosomiasis. Benzodiazepines possessing a P2- transporter motif were found to have MIC values as low as 0.78μM. [Copyright &y& Elsevier]