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Purpose There is a lack of information on the compatibility of remimazolam with opioid analgesics, muscle relaxants, and other sedatives. This study aimed to evaluate the physical compatibility of remimazolam with these drug classes. Methods Remimazolam was combined with 1 or 2 target drugs (remifentanil, fentanyl, rocuronium, vecuronium, dexmedetomidine, and midazolam). Ten physical compatibility tests were conducted, including four 3-drug compatibility tests. Remimazolam was dissolved in 0.9% sodium chloride injection to a final concentration of 5 mg/mL. Other medications were diluted in 0.9% sodium chloride injection to obtain clinically relevant concentrations. Compatibility tests were conducted with 3 test solutions, wherein remimazolam and the target drugs were compounded at equal volume ratios (1:1 or 1:1:1). Visual appearance was assessed and testing of Tyndall effect, turbidity, and pH was performed immediately after mixing and then again 1 hour and 4 hours after mixing. Appearance and turbidity were evaluated by comparison with the control solution of each target drug diluted with 0.9% sodium chloride injection to the same concentration as the test solution. Results All drugs tested were determined to be compatible with remimazolam. The drug combination with the highest change of turbidity was remimazolam and vecuronium (a mean increase of 0.16 NTU relative to the remimazolam control solution), 4 hours after mixing. The combination with the highest pH was remimazolam, fentanyl, and vecuronium (mean [SD], 3.76 [0.01]), 4 hours after mixing. The combination of remimazolam and fentanyl showed a larger change in pH at 4 hours after mixing (a mean increase of 2.6%) than immediately after mixing. Conclusion Remifentanil, fentanyl, rocuronium, vecuronium, dexmedetomidine, and midazolam are physically compatible with remimazolam during simulated Y-site administration. [ABSTRACT FROM AUTHOR]

The emergence of benzodiazepine-type new psychoactive substances (NPSs) are a growing international public health concern, with increasing detections in drug seizures and clinical and coronial casework. This study describes the patterns and nature of benzodiazepine-type NPS detections extracted from the Emerging Drugs Network of Australia – Victoria (EDNAV) project, to better characterise benzodiazepine-type NPS exposures within an Australian context. EDNAV is a state-wide illicit drug toxicosurveillance project collecting data from patients presenting to an emergency department with illicit drug-related toxicity. Patient blood samples were screened for illicit, pharmaceutical and NPSs utilising liquid chromatography-tandem mass spectrometry. Demographic, clinical, and analytical data was extracted from the centralised registry for cases with an analytical confirmation of a benzodiazepine-type NPS(s) between September 2020–August 2022. A benzodiazepine-type NPS was detected in 16.5 % of the EDNAV cohort (n = 183/1112). Benzodiazepine-type NPS positive patients were predominately male (69.4 %, n = 127), with a median age of 24 (range 16-68) years. Twelve different benzodiazepine-type NPSs were detected over the two-year period, most commonly clonazolam (n = 82, 44.8 %), etizolam (n = 62, 33.9 %), clobromazolam (n = 43, 23.5 %), flualprazolam (n = 42, 23.0 %), and phenazepam (n = 31, 16.9 %). Two or more benzodiazepine-type NPSs were detected in 47.0 % of benzodiazepine-type NPS positive patients. No patient referenced the use of a benzodiazepine-type NPS by name or reported the possibility of heterogenous product content. Non-prescription benzodiazepine use may be an emerging concern in Australia, particularly amongst young males. The large variety of benzodiazepine-type NPS combinations suggest that consumers may not be aware of product heterogeneity upon purchase or use. Continued monitoring efforts are paramount to inform harm reduction opportunities. [ABSTRACT FROM AUTHOR]

Aims To search for pharmaceutical additives in illicit alcoholic beverages referred to the laboratory of Legal Medicine Organization in Iran in 2017. Methods Hundred beverages were sampled. Ethanol content was determined by gas chromatography with flame ionization detection (GC–FID) and then a liquid-liquid extraction combined with reversed-phase high performance liquid chromatography equipped with a photodiode array detector (PAD) was employed for the qualitative analysis. The analysis was confirmed using gas chromatography coupled with mass spectroscopy (GC/MS). Results In 15% either one or more of the following were detected: tramadol, methadone, diazepam, oxazepam, flurazepam and alprazolam. Tramadol was found with highest frequency. Conclusions The wide availability of addictive pharmaceutical is leading to fortification of alcoholic beverages on some countries. The addition of such depressant additives should be better known because of the potentially fatal consequences of the combination with ethanol, as well as the potential for adverse effects on behavior. [ABSTRACT FROM AUTHOR]

Hair, larvae and cardiac muscle, the only biological samples present on a skeletonized human body found in a rural area, were used for forensic toxicological analyses in order to determine possible causes of death. Since no information about the victim or the circumstances of death was available (except for the place where the corpse was found, known to be a gathering place for drug addicts), the first approach for the analysis of non-conventional matrices involved the screening of different classes of active principles, using a chemiluminescence-based screening assay designed for whole blood. The immunoassay test results showed positivity to amphetamines, cocaine and opiates on water/methanol extract from cardiac tissue, larvae and hair samples. Gas chromatography-mass spectrometry (GC/MS) analyses confirmed the immunoassay results, except for amphetamines. The minimal sample preparation (hydration and extraction in an ultrasonic bath), the reduced sample volume required for the analyses, together with the correctness of results as confirmed by GC/MS, showed the suitability of the screening test for forensic applications on non-conventional matrices. Quantitative analyses in GC/MS allowed the cause of death to be ascertained on the basis of the ratio between parent drugs and metabolites. [ABSTRACT FROM AUTHOR]

Nardostachys jatamansi has profound applications against pharmacological interventions and is categorized as a hypno-sedative drug according to Ayurveda. In the present study probable mechanism of anxiolytic action of Nardostachys jatamansi extract (NJE) was studied using behavioral anxiolytic tests (Elevated plus maze, Open field test, Light dark box test, and Vogel’s conflict test) in mice. Mice were treated orally with NJE (250 mg/kg) for 3, 7 and 14 days or diazepam (1 mg/kg) followed by behavioral assessment and estimation of monoamine neurotransmitters, GABA, and antioxidant enzymes. Treatment of mice for 7 days caused an increase in time spent in open arms in elevated plus maze, number of line crossings in open field test, increased time spent in lit compartment of light-dark box test, an increase in number of licks made and shocks accepted in Vogel’s conflict test, with results comparable to diazepam and this treatment also caused a significant increase in monoamine neurotransmitters and GABA in brain and tissue antioxidant parameters. Co-treatment of NJE with flumazenil (GABA-benzodiazepine antagonist; 0.5 mg/kg i.p) or picrotoxin (GABAA gated chloride channel blocker; 1 mg/kg i.p) caused a blockage/antagonised anxiolytic actions of NJE by causing a significant reduction in time spent in open arms of elevated plus maze, an decrease in number of line crossing in open field test and also number of shocks and licks accepted in Vogel’s conflict test. Further, NJE was radiolabelled with technetium99m at their hydroxyl groups following which purity as well as in vivo and in vitro stability of radiolabelled formulations was evaluated. The blood kinetics and in vivo bio-distribution studies were carried out in rabbits and mice respectively. Labeled formulation was found to be stable in vitro (96 to 93% stability) and in vivo (96 to 92% stability). The labeled compound was cleared rapidly from blood (within 24 h) and accumulated majorly in kidneys (11.65 ± 1.33), liver (6.07 ± 0.94), and blood (4.03 ± 0.63) after 1 h. However, a small amount was observed in brain (0.1 ± 0.02) probably because of its inability to cross blood-brain barrier. These results highlight biodistribution pattern of NJE, and also indicated that a 7-day treatment with NJE produced significant anxiolytic effects in mice and also a significant increase in brain monoamine and GABA neurotransmitter levels and suggests that anxiolytic effects of NJE are primarily and plausibly mediated by activating GABAergic receptor complex. [ABSTRACT FROM AUTHOR]

In this study, a molecularly imprinted polymer based chemiluminescence array capable of simultaneous determining phenothiazines and benzodiazepines was first reported. Two polymers were coated in different wells of the conventional 96-well microtiter plate as the recognition reagents, and the added analytes competed with a horseradish peroxidase-labeled bi-hapten conjugate to bind the recognition reagents. The light signal was induced by using a highly effective luminol-H 2 O 2 -IMP system. The assay procedure consisted of only one sample-loading step prior to data acquisition. Then, the array was used to determine 4 phenothiazines and 5 benzodiazepines in pork simultaneously. The limits of detection for the 9 drugs were in a range of 0.001–0.01 ng/mL, and the recoveries from the fortified blank pork were in a range of 63.5%–94.1%. Furthermore, the array could be reused for 8 times. The detection results for some real pork samples were consistent with an ultra performance liquid chromatography method. [ABSTRACT FROM AUTHOR]

In this paper, novel univariate and multivariate regression model updating methods were developed and validated for the simultaneous determination of ternary mixture of bromazepam, diazepam and clonazepam. The univariate methods used are the mean centering of ratio spectrophotometric method and iso-absorptive point coupled with ratio-subtraction and ratio difference spectrophotometric method. Linearity, ranges, precision and accuracy of these methods were determined. The multivariate methods adopted are the principal component regression and partial least-squares. These models were estimated using nineteen mixtures as calibration set and six mixtures as validation set. The minimum root square error of predication were 0.1215 and 0.0568 for BMZ, 0.0598 and 0.0712 for DIZ and 0.0867 and 0.0753 for CNP by PLS and PCR respectively. PCR and PLS methods were successfully applied for the analysis of BMZ, DIZ and CNP in their dosage forms. Content uniformity testing of the studied pharmaceutical tablets by PLS and PCR was also determined. MCR, IPRSRD and PLS model updating enabled the determination of BMZ, DIZ and CNP in spiked human urine. Moreover, PLS model updating was applied to drug-dissolution rate testing of BMZ and DIZ in their commercial tablets. The obtained results were statistically compared with those obtained by reported methods giving a conclusion that there is no significant difference regarding accuracy and precision. [ABSTRACT FROM AUTHOR]

A new series of 4-benzodiazepinyl-2-( substituted phenyl)-1,5-benzothiazepines (3a-3f) and 4-benzodiazepinyl-2-(substituted phenyl)-1,5-benzoxazepines (4a-4f) were synthesised and evaluated for their anticonvulsant activity. All these compounds were screened in vivo, for their anticonvulsant activity and acute toxicity. Compound 4-benzodiazepinyl-2-(p-methoxy phenyl)-1,5-benzothiazepine 4b, was found to be most potent compoundof this series, more potent than standard drug phenytoin sodium. The homogeneity of all the compounds was checked by TLC. The structures of these compounds have been established by elemental analysis, IR and 1H NMR spectroscopy. [ABSTRACT FROM AUTHOR]

Pentameric ligand-gated ion channels (pLGICs) constitute a widespread class of ion channels, present in archaea, bacteria, and eukaryotes. Upon binding of their agonists in the extracellular domain, the transmembrane pore opens, allowing ions to go through, via a gating mechanism that can be modulated by a number of drugs. Even though high-resolution structural information on pLGICs has increased in a spectacular way in recent years, both in bacterial and in eukaryotic systems, the structure of the open channel conformation of some intensively studied receptors whose structures are known in a nonactive (closed) form, such as Erwinia chrysanthemi pLGIC (ELIC), is still lacking. Here we describe a gammaproteobacterial pLGIC from an endo-symbiont of Tevnia jerichonana (sTeLIC), whose sequence is closely related to the pLGIC from ELIC with 28% identity. We provide an X-ray crystallographic structure at 2.3 Å in an active conformation, where the pore is found to be more open than any current conformation found for pLGICs. In addition, two charged restriction rings are present in the vestibule. Functional characterization shows sTeLIC to be a cationic channel activated at alkaline pH. It is inhibited by divalent cations, but not by quaternary ammonium ions, such as tetramethylammonium. Additionally, we found that sTeLIC is allosterically potentiated by aromatic amino acids Phe and Trp, as well as their derivatives, such as 4-bromo-cinnamate, whose cocrystal structure reveals a vestibular binding site equivalent to, but more deeply buried than, the one already described for benzodiazepines in ELIC. [ABSTRACT FROM AUTHOR]

Introduction: Fever and the use of drugs such as benzodiazepines (GABAA agonists) and ketamine (NMDA antagonist) occur relatively frequently in anesthesiology. Breathing is a pattern generated in the brain stem, product of a complex ponto-medullary networks, which control the respiratory motoneurons thanks to the interaction of the inspiratory neurons of the pre-Bötzinger complex and the espiratory ones of the Bötzinger complex. These neurons have membrane receptors of the GABAA and NMDA type, which show high thermo-dependence, however, the changes in the pattern of neuronal discharge induced by these drugs and changes in body temperature are unknown. Materials and methods: A validated model of pre-inspiratory neuron (pre-Bötzinger complex) was generated, increasing the synaptic GABAA weight equivalent to the effect of benzodiazepines or reducing the NMDA synaptic weight equivalent to the effect of ketamine in hypo- (35°C), normo- (37°C) or hyperthermia (40°C) quantifying the number and amplitude of neuronal discharges. Results: Increase in GABAA or reduction of NMDA synaptic weights at temperatures of 35°C, 37°C or 40°C proportionally reduced the number of spikes and the amplitude of the action potential of the Pre-I neuronal, showing dose-response 2nd order polynomial curves with increased slopes at 35°C and 40°C. Conclusion: benzodiazepines or ketamine through its receptors GABAA and NMDA modify in silico the discharge pattern of Pre-I neuron from Pre-Bötzinger nucleus, showing more gabaergic effect and higher thermo-dependence in the dose-response curves during hypo and hyperthermia which are relevant for clinical practice. [ABSTRACT FROM AUTHOR]

Cancer chemotherapy has several limitations such as often insufficient differentiation between malign tissue and benign tissue. The clinical utility of the pyrrolo[2,1- c ][1,4]benzodiazepines (PBDs) are inadequate because of the lack of selectivity for tumor tissues, high reactivity of the pharmacophoric imine functionality, low water solubility, and stability. To address these limitations two new β-glucoside prodrugs of PBDs have been synthesized and evaluated for their potential use in selective therapy of solid tumors by ADEPT. The preliminary studies reveal the prodrugs are much less toxic compared to the parent moieties. These prodrugs are activated by β-glucosidase to produce the active cytotoxic moiety signifying their utility in ADEPT of cancer. The prodrugs 1a and 1b were evaluated for their cytotoxic activity in three human cancer cell lines, i.e., A375, MCF-7 and HT-29 by employing MTT assay. The results reveal that the prodrugs have shown significant cytotoxic activity in the presence of enzyme. Another important property of these molecules is their enhanced water solubility and stability, which are essential for a molecule to be an effective drug. [ABSTRACT FROM AUTHOR]

Objective: Clinical guidelines suggest that benzodiazepines (BZDs) and non-BZD hypnotics (NBHs) be used on a short-term basis. The authors examined trends in long-term BZD and NBH use from 1999 to 2014.Methods: Data included 82,091 respondents in the 1999-2014 waves of the National Health and Nutrition Examination Survey (NHANES). NHANES recorded medications used in the past 30 days on the basis of prescription bottles, and participants reported use duration. BZD and NBH use were categorized as short, medium, and long term, and time trends in use were assessed.Results: BZD and NBH use increased from 1999 to 2014, driven by increases in medium- and long-term use, even after adjustment for age and race-ethnicity. In most years, only a fifth of current BZD or NBH users reported short-term use.Conclusions: Long-term BZD and NBH use has grown independent of U.S. demographic shifts. Monitoring of use is needed to prevent adverse outcomes. [ABSTRACT FROM AUTHOR]

A novel non-aqueous capillary electrophoresis - tandem mass spectrometry method for the simultaneous separation, identification and quantification of nine designer benzodiazepines (bentazepam, etizolam, deschloroetizolam, diclazepam, flubromazepam, flubromazolam, nimetazepam, phenazepam, and pyrazolam) was developed. A non-aqueous running electrolyte consisting of 25 mM ammonium acetate with 100 mM trifluoroacetic acid in acetonitrile was used. The separation was carried out using a semipermanent coated capillary (successive multiple ionic-polymer coating) with a strong anodic electroosmotic flow at a negative separation voltage within twelve minutes. Electrospray ionization with a triple quadrupole mass spectrometry was utilized for the identification and quantification of selected designer benzodiazepines in a positive ionization mode. The developed method was validated and applied on the analysis of spiked serum sample following a simple liquid-liquid extraction. The LODs of the designer benzodiazepines were between 1.5 and 15.0 ng mL −1 . [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the correlation between histories of zolpidem and benzodiazepines use and their concentrations in hair as determined by segmental hair analysis, that is, by analyzing hair samples taken 0-1, 1-2, 2-3, 3-4, 4-5, and 5-6cm etc. and 0-3cm from the scalp, and whole hair. Of the 23 hair samples examined, 18 were collected from patients in a rehabilitation program and five were from patients that had taken zolpidem only once by prescription. All 23 patients provided written informed consent after reviewing the research plan, described their zolpidem and benzodiazepines use histories accurately, and provided hair samples, which were weighed, washed, cut into lengths of <1mm, and extracted in 100% methanol for 16h (diazepam-d5 was used as an internal standard). Extracts were evaporated under reduced pressure and reconstituted with aqueous methanol (1:1 v/v). These extracts (10μL) were analyzed by Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS). The method used was validated by determining LOD, LOQ, calibration curves, intra- and inter-accuracies, precisions, matrix effects, process efficiencies, extraction efficiencies, and processed sample stabilities. Five hundred and ninety-five 1cm hair segments showed 61.59% positive probability and 86.71% negative probability of quality correlation between zolpidem and benzodiazepines use and concentrations in hair. Good qualitative correlations were observed between drug use and detection in hair. False positivity and false negativity were very low. Of the hair samples taken from patients in a rehabilitation program, subject nos. 4, 5, and 12 had correlation coefficients of 0.68, 0.54 and 0.71, respectively, for relationships between zolpidem use and concentration of zolpidem in hair. For the 5 patients taking only a single dose of zolpidem (10mg), the average zolpidem concentrations in hair were 20, 15 and 40pg/mg after 5, 30 and 60 days, respectively. This study shows a relationship between history of zolpidem and benzodiazepines use and their concentrations in 1cm hair segment. [ABSTRACT FROM AUTHOR]

The objective of this work was to establish an analytical method for the analysis of 7 Benzodiazepines (diazepam, oxazepam, temazepam, nordiazepam, desalkylflurazepam, alprazolam and α-hydroxyalprazolam) in urine specimens taken from drivers suspected of driving under the influence of drugs. The specimen, calibrator and control preparation involved hydrolysis of conjugated benzodiazepines using β-glucuronidase in sodium acetate buffer, with incubation at 60 °C for 2 h. Specimens were then centrifuged, before being diluted 1 in 5 (total dilution 1 in 10), with 10% acetonitrile in water. Specimens were analysed using a Shimadzu Prominence UPLC coupled to an AB Sciex 4000 QTrap LC–MS-MS. The chromatographic column was a Shim-pack XR ODS 2.2 μm. 3.0 × 50 mm column and the mobile phase was a binary gradient system comprising of mobile phase A which was an ammonium formate/formic acid buffer dissolved in water and mobile phase B which was an ammonium formate/formic acid buffer dissolved in Acetonitrile. APCI was selected as the ionisation technique and the MS was operated in MRM mode, monitoring 2 transitions per analyte. The validation of the method is described. The method was found to be linear, accurate and precise (within day and between day) for diazepam, oxazepam, temazepam, nordiazepam, desalkylflurazepam, alprazolam and α-hydroxyalprazolam. The results of 480 cases are reviewed and show that alprazolam use was found in 35% of cases. Use of benzodiazepines resulting in oxazepam, nordiazepam or temazepam were found ca. 70% of cases analysed. [ABSTRACT FROM AUTHOR]

Introduction: An in vitro study on authentic positive samples was carried out, aiming the evaluation of the effect of chlorinated water on benzodiazepines in hair. Two subjects exposed to chlorinated water for several consecutive times were also investigated.Method: Seven hair samples collected from autopsy cases, previously tested positive for benzodiazepines, were washed with dichloromethane and methanol. They were longitudinally divided in six aliquots of about 30mg. An aliquot was processed without treatment while other five ones were soaked in chlorinated water (0.1% sodium dichloroisocyanurate and 0,1M sulfuric acid at pH 5.5) for 4, 20, 24 and 30h respectively. Hair samples were then processed following a fully validated and previously published method. Briefly hair samples were sonicated in 600 microliters methanol containing halazepam (IS) up to two hours. Ten microliters were injected in a liquid chromatographic tandem mass spectrometric (LC-MS/MS) system. Analytes were eluted from a C18 reversed-phased column. Two transitions on multiple reaction monitoring and positive ionization mode were monitored for each compound.Result and Discussions: Six compounds among benzodiazepines and metabolites were identified and quantified in the seven hair samples: diazepam (575pg/mg), desmethyldiazepam (562pg/mg), chlordesmethyldiazepam (173pg/mg), desalkylflurazepam (320pg/mg), clonazepam (three cases-195, 119 and 111pg/mg respectively), lormetazepam (two cases-182 and 416pg/mg respectively). Traces of 7-aminoclonazepam were identified into 2 samples. Stability of benzodiazepines in water was evaluated by soaking an aliquot of hair for up to 30h in deionized water. No significant degradation was observed. Samples soaked in chlorinated water showed considerable decreasing from the initial concentration even after the 4-h treatment: the fastest degradation was provided by clonazepam that showed a 61% loss. The greatest loss was measured for diazepam (86% loss after 30-h soaking).Conclusion: To the best of our knowledge this is the first in vitro study that evaluated benzodiazepines stability in hair after prolonged exposure to chlorinated water. The results showed that the longer the exposure the higher the degradation. Prolonged exposure to chlorinated water and sunlight must be always taken into account as possible causes of false negative results. [ABSTRACT FROM AUTHOR]

Dried matrix spot (DMS) technique as alternative sampling strategy, especially dried urine spots (DUS), might be an alternative for drug screening. So far only particular drugs or drug classes were covered in DMS screenings. Therefore, workup of DUS for a broad comprehensive library-based LC-MS n screening was developed. It consisted of enzymatic on-spot deconjugation followed by liquid extraction and LC-MS n analysis. This workup was compared to established urine precipitation (UP) and validated according to international guidelines for qualitative approaches, using exemplary compounds of several drug classes (antidepressants, benzodiazepines, cardiovascular drugs, neuroleptics, opioids, stimulants, etc.) with a broad range of (physico-)chemical properties and chromatographic behaviors. On-spot conjugate cleavage and liquid extraction was sufficient for most compounds and the validation results comparable to those obtained after simple UP. For demonstrating the applicability, 103 authentic urine samples, six rat urine samples after low dose substance administrations, and two proficiency tests for systematic toxicological urinalysis were worked up with the new DUS approach or by UP without or with conjugate cleavage. In the authentic urine samples, 112 different drugs out of 43 categories plus metabolites were identified via the used LC-MS n library. With the new DUS approach, 5% less positive hits could be found compared to the UP approach and 15% less than the latter after conjugate cleavage. The differences should be caused mainly by smaller urine volumes used for DUS. In the two proficiency tests, all 15 drugs could be detected. Unfortunately, all three approaches were not able to detect very low-dosed substances in rat urine samples. However, they could be detected using a more sensitive LC-high resolution-MS/MS approach showing that the DUS workup was also suitable for those. In conclusion, DUS might be an alternative sampling technique for comprehensive drug testing or adherence monitoring. [ABSTRACT FROM AUTHOR]

Background: Non-benzodiazepine hypnotics (Z-drugs) are advocated to be safer than benzodiazepines (BZDs). This study comprehensively investigated the association of BZD and Z-drug usage with the risk of hospitalisation for fall-related injuries in older people.Methods: This study used the Taiwan National Health Insurance Database with a nested matched case-control design. We identified 2238 elderly patients who had been hospitalised for fall-related injuries between 2003 and 2012. They were individually matched (1:4) with a comparison group by age, sex, and index year. Conditional logistic regression was used to determine independent effects of drug characteristics (type of exposure, dosage, half-life, and polypharmacy) on older people.Results: Older people hospitalisation for fall-related injuries were significantly associated with current use of BZDs (adjusted odds ratio [AOR] = 1.32, 95% confidential interval [CI] = 1.17-1.50) and Z-drugs (AOR = 1.24, 95%CI = 1.05-1.48). At all dose levels of BZDs, high dose levels of Z-drugs, long-acting BZD, and short-acting BZD use were all significantly increased the risk of fall-related injuries requiring hospitalisation. Polypharmacy, the use of two or more kinds of BZDs, one kind of BZD plus Z-drugs and two or more kinds of BZDs plus Z-drugs, also significantly increased the risk (AOR = 1.61, 95% CI = 1.38-1.89; AOR = 1.65, 95% CI = 1.08-2.50, and AOR = 1.58, 95% CI = 1.21-2.07).Conclusions: Different dose levels and half-lives of BZDs, a high dose of Z-drugs, and polypharmacy with BZDs and Z-drugs were associated with an increased risk of fall-related injury requiring hospitalisation in older people. Physicians should balance the risks and benefits when prescribing these drug regimens to older people considering the risk of falls. [ABSTRACT FROM AUTHOR]

The article reports on the Soyka's multifaceted approach in treatment of symptoms of withdrawal from and dependence on benzodiazepines. It is also mentioned that according to the author counters the view that benzodiazepines should not be used for the long term and also that certain conditions may require the sustained use of these agents.

A novel microextraction technique based on ultrasound-assisted low-density solvent dispersive liquid–liquid microextraction (UA-LDS-DLLME) had been applied for the determination of 4 designer benzodiazepines (phenazepam, diclazepam, flubromazepam and etizolam) in urine samples by gas chromatography- triple quadrupole mass spectrometry (GC-QQQ-MS). Ethyl acetate (168 μL) was added into the urine samples after adjusting pH to 11.3. The samples were sonicated in an ultrasonic bath for 5.5 min to form a cloudy suspension. After centrifugation at 10000 rpm for 3 min, the supernatant extractant was withdrawn and injected into the GC-QQQ-MS for analysis. Parameters affecting the extraction efficiency have been investigated and optimized by means of single factor experiment and response surface methodology (Box-Behnken design). Under the optimum extraction conditions, a recovery of 73.8–85.5% were obtained for all analytes. The analytical method was linear for all analytes in the range from 0.003 to 10 μg/mL with the correlation coefficient ranging from 0.9978 to 0.9990. The LODs were estimated to be 1–3 ng/mL. The accuracy (expressed as mean relative error MRE) was within ±5.8% and the precision (expressed as relative standard error RSD) was less than 5.9%. UA-LDS-DLLME technique has the advantages of shorter extraction time and is suitable for simultaneous pretreatment of samples in batches. The combination of UA-LDS-DLLME with GC–QQQ–MS offers an alternative analytical approach for the sensitive detection of these designer benzodiazepines in urine matrix for clinical and medico-legal purposes. [ABSTRACT FROM AUTHOR]

Remimazolam is a new chemical entity belonging to the benzodiazepine class of sedative drugs, which shows faster-acting onset and recovery than currently available short-acting sedatives. In the present study, ultra high performance liquid chromatography with synapt high-definition mass spectrometry method combined with MassLynx software was established to characterize metabolites of remimazolam in human plasma and urine. In total, 5 human metabolites were detected, including 3 phase I and 2 phase II metabolites. There was no novel human metabolite detected compared to that in rat. Hydrolysis, glucuronidation and oxidation were the major metabolic reactions. To our knowledge, this is the first report of the human metabolic profile of remimazolam. [ABSTRACT FROM AUTHOR]

During the optimization of process, eight impurities (CLB Imp-A to CLB Imp-H) were detected in few of the laboratory batches of clobazam, used as anxiolytic agent, in the range of 0.02–0.12% using gradient HPLC method with UV detection. On the basis of co-spiking analysis, six impurities (CLB Imp-A to -F) enumerated by European Pharmacopoeia, however, not reported in the earlier literature, have been harmonized and found to be two impurities are completely unknown (CLB Imp-G and -H). These two new impurities structures were presumed based on LC-ESI/MS n study as 8-chloro-1-methyl-5-phenyl-1,5-dihydro-3 H -1,5-benzodiazepine-2,4-dione (CLB Imp-G) and 5-chloro-1-methyl-3-phenyl-1 H -benzo[ d ]imidazol-2(3 H )-one (CLB Imp-H). The presumed impurities structures were confirmed by their synthesis followed by the complete spectral analysis such as ESI–MS, 1D NMR ( 1 H, 13 C and DEPT), 2D NMR (HSQC, HMBC and COSY) and IR, and chromatographic retention time profile. Identification, synthesis, structural characterization, prospects to the formation and controlling of these new impurities were described in detail and reported first in this paper. [ABSTRACT FROM AUTHOR]

A sensitive microextraction method based on a new poly(methacrylic acid-ethylene glycol dimethacrylate- N-vinylcarbazole) monolithic capillary column, coupled with gas chromatography and electron capture detection, was established for the determination of three benzodiazepines (estazolam, alprazolam, and triazolam) in urine and beer samples. Owing to the abundant π electrons and polar surface of N-vinylcarbazole, N-vinylcarbazole-incorporated monolith showed a higher extraction performance than neat poly(methacrylic acid-ethylene glycol dimethacrylate) because of the enhanced π-π stacking interactions derived from the π-electron-rich benzene groups from N-vinylcarbazole. The monolith exhibited a homogeneous and continuous structure, good permeability, and a long lifetime. Factors affecting the extraction such as solution pH, salt concentration, sample volume, desorption solvent, and desorption volume were investigated. Under the optimized conditions, limits of detection of 0.011-0.026 ng/mL were obtained. The one-column and column-to-column precision values were ≤7.2 and ≤9.8%, respectively. The real samples were first diluted with deionized water and then treated by the monolith microextraction before gas chromatography analysis. The recoveries were 81.4-93.3 and 83.3-94.7% for the spiked samples, with relative standard deviations of 4.1-8.1 and 3.8-8.5%, respectively. This method provides an accurate, simple, and sensitive detection platform for drug analysis. [ABSTRACT FROM AUTHOR]

Introduction Current guidelines for brain PET imaging advice against the injection of diazepam prior to brain FDG-PET examination in order to avoid possible interactions of benzodiazepines with the radiotracer uptake. Nevertheless, many patients undergoing PET studies are likely to be under chronic treatment with benzodiazepines, for example due to the use of different medications such as sleeping pills. Animal studies may provide an extensive and accurate estimation of the effect of benzodiazepines on brain metabolism in a well-defined and controlled framework. Aim This study aims at evaluating the impact of benzodiazepines on brain FDG uptake after single-dose administration and chronic treatment in rats. Methods Twelve Sprague–Dawley healthy rats were randomly divided into two groups, one treated with diazepam and the other used as control group. Both groups underwent PET/CT examinations after single-dose and chronic administration of diazepam (treated) or saline (controls) during twenty-eight days. Different atlas-based quantification methods were used to explore differences on the total uptake and uptake patterns of FDG between both groups. Results Our analysis revealed a significant reduction of global FDG uptake after acute (−16.2%) and chronic (−23.2%) administration of diazepam. Moreover, a strong trend pointing to differences between acute and chronic administrations (p < 0.08) was also observed. Uptake levels returned to normal after interrupting the administration of diazepam. On the other hand, patterns of FDG uptake were not affected by the administration of diazepam. Conclusions The administration of diazepam causes a progressive decrease of the FDG global uptake in the rat brain, but it does not change local patterns within the brain. Under these conditions, visual assessment and quantification methods based on regional differences such as asymmetry indexes or SPM statistical analysis would still be valid when administrating this medication. [ABSTRACT FROM AUTHOR]

Background: While acute detrimental effects of benzodiazepine (BDZ), and BDZ and related z-substance (BDZR) use on cognition and memory are known, the association of BDZR use and risk of dementia in the elderly is controversially discussed. Previous studies on cohort or claims data mostly show an increased risk for dementia with the use of BDZs or BDZRs. For Germany, analyses on large population-based data sets are missing.Objective: To evaluate the association between regular BDZR use and incident any dementia in a large German claims data set.Methods: Using longitudinal German public health insurance data from 2004 to 2011 we analyzed the association between regular BDZR use (versus no BDZR use) and incident dementia in a case-control design. We examined patient samples aged≥60 years that were free of dementia at baseline. To address potential protopathic bias we introduced a lag time between BDZR prescription and dementia diagnosis. Odds ratios were calculated applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy.Results: The regular use of BDZRs was associated with a significant increased risk of incident dementia for patients aged≥60 years (adjusted odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13-1.29). The association was slightly stronger for long-acting substances than for short-acting ones. A trend for increased risk for dementia with higher exposure was observed.Conclusion: The restricted use of BDZRs may contribute to dementia prevention in the elderly. [ABSTRACT FROM AUTHOR]

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A poly( N -vinylcarbazole- co -divinylbenzene) (NVC/DVB) monolithic column was successfully prepared in a silanized capillary for microextraction of six benzodiazepines (BZPs) in complex samples. The polymerization was optimized primarily by changing the ratio of porogen content. The optimized polymer monolith had a homogeneous and continuous column bed, good permeability and mechanical stability. Poly(NVC/DVB) had good affinity to BZPs because of its through-pore structure and strong π-π stacking interactions derived from the rich benzene functional groups in the polymer. Potential factors that affect the extraction efficiency were studied in detail. In the optimized method, 3 mL of sample (pH 2) was extracted with the polymer monolithic column and eluted with 80 μL of methanol, and the eluent was analysed with ultra-high-performance liquid chromatography and quadrupole high resolution Orbitrap mass spectrometry (UHPLC/Q-Orbitrap MS). Under these conditions, the developed method gave the linear range of 0.005–0.5 ng/mL for most of the six BZPs, whereas 0.05–0.5 ng/mL for nitrazepam, 0.01–0.5 ng/mL for lorazepam, respectively, with coefficients of determination (R 2 ) ≥ 0.9991. The detection limits (LODs) were 1.08–6.04 ng/L, and the quantification limits (LOQs) were 3.60–20.1 ng/L. The method repeatability was investigated in terms of intra- and inter-day precision, which were indicated by relative standard deviations (RSDs) of ≤8.3% and ≤9.9%, respectively. Finally, the proposed method was successfully applied to detect BZPs in beer and human urine samples. The percentages of extraction recovery were 80.4–94.2% for beer and 79.6–95.2% for urine. [ABSTRACT FROM AUTHOR]

A new pretreatment method termed solid-phase extraction (SPE) which is combined with dispersive liquid-liquid microextraction (SPE-DLLME) has been developed for the determination of oxazepam, alprazolam and diazepam in urine and plasma samples. The analytes were extracted from biological samples using SPE followed by DLLME. Various parameters that affect the efficiency of the two extraction techniques have been optimized. The calibration plots were linear in the range of 2.5-500 μg L-1 for oxazepam, alprazolam and 1.0-500 μg L-1 for diazepam with detection limits of 0.7 μg L-1 for oxazepam, alprazolam and 0.4 μg L-1 for diazepam in plasma sample. The results confirm the suitability of the SPE-DLLME-HPLC-UV as a sensitive method for the analysis of the targeted analytes in urine and plasma samples. [ABSTRACT FROM AUTHOR]

Purpose: To develop a simple, fast and sensitive spectrophotometric method for the determination of tofisopam in tablet dosage form. Methods: Tofisopam as n-electron donor was reacted with two p-acceptors, namely, chloranilic acid (ChA), and 7,7,8,8 tetracyanoquinodimethane (TCNQ) to form charge transfer complexes. The complexes were evaluated spectrophotometrically at 520 and 824 nm for ChA and TCNQ, respectively. The optimum conditions for the reaction were determined and optimized. The developed method was compared with Japanese Pharmacopeia method. Results: The calibration curve was linear in the ranges 25 - 125 and 30 - 150 µg/mL for ChA and TCNQ, respectively. The lower limit of detection was 8.0 and 10.0 µg/mL for ChA and TCNQ, respectively while the slope and intercept of the calibration curves were 0.0025 and 0.011 and 0.0115 and -0.237, for ChA and TCNQ, respectively. Conclusion: The developed methods for tofisopam have good accuracy and precision, and comparable to a standard pharmacopeial method. The methods can be applied for routine analysis and in quality control. [ABSTRACT FROM AUTHOR]

Sulfo-functionalized iron oxide magnetic nanobeads were employed as an adsorbent for magnetic solid-phase extraction of benzodiazepines in beef. The analytes were determined by high performance liquid chromatography–mass spectrometry. The sulfo-functionalized iron oxide magnetic nanobeads were characterized by transmission electron microscopy and infrared spectroscopy. The optimal pH, ionic strength, volume of sulfo-functionalized iron oxide magnetic nanobeads, and elution solvent were investigated for the isolation procedure. Under the optimized conditions, the limits of detection for diazepam, oxzepam, triazolam, and chlordiazepoxide were 0.79, 0.22, 0.13, and 0.23 ng/kg, respectively. The method was employed for the determination of the analytes in beef. Compared with established methods, magnetic solid phase extraction and high-performance liquid chromatography–tandem mass spectrometry method exhibited high sensitivity, rapid separation, and low cost. [ABSTRACT FROM PUBLISHER]

Background: Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE.Methods: We did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2.5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35.Findings: Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference -10.3%, 95% CI -24.0 to 3.4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group.Interpretation: The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment.Funding: UCB Pharma. [ABSTRACT FROM AUTHOR]

The potential for postmortem redistribution of olanzapine was investigated in beagle dogs. Olanzapine pamoate monohydrate was administered once every 14 days by intramuscular injection for 3 months to fed male dogs (n=15) at a dose of 20 mg/kg olanzapine (equivalent to 46 mg/kg olanzapine pamoate monohydrate). Blood samples were collected after the fifth (Day 57) and sixth (Day 71) doses to determine olanzapine and N-oxide olanzapine concentrations. On Day 71 at 72 h postdose, dogs were euthanized and placed on their backs without additional manipulation and held for postmortem blood, urine, and tissue collection at room temperature for up to 168 h postdose (96 h after euthanasia). Concentrations of olanzapine and N-oxide olanzapine were determined by liquid chromatography-mass spectroscopy/mass spectroscopy (LC-MS/MS). Postmortem olanzapine concentrations in blood increased up to seven-fold compared to the last quantified antemortem blood concentration. Olanzapine concentrations in vein tissue samples (surrogates for peripheral blood) also increased, whereas other tissue concentrations, such as myocardium, lung, liver, and kidney decreased over the postmortem period. An increase in blood concentration of olanzapine after death was observed in all but one animal, suggesting that postmortem redistribution may occur in dogs following biweekly intramuscular administration of olanzapine pamoate monohydrate. The rise in olanzapine concentrations in blood after death in this study may potentially be attributed to diffusion from multiple tissues to blood and, to a lesser extent, reduction of the N-oxide olanzapine metabolite back to olanzapine. However, the generalizability of these results to humans cannot be confirmed by the present study. [ABSTRACT FROM AUTHOR]

Quazepam (QZP) is a long-acting benzodiazepine-type hypnotic. We searched for novel QZP metabolites in bile and determined their structures by liquid chromatography-ion trap time-of-flight mass spectrometry (LC-IT-TOF MS). The metabolites were extracted with ethyl acetate after β-glucuronidase treatment. First, a single MS spectrum was acquired. Second, MS(n) spectra were acquired for peaks that consisted of ions with the isotope pattern corresponding to molecules bearing one chlorine atom. The novel QZP metabolites found in this study were hydroxyquazepam, hydroxy-methoxyquazepam, hydroxy-oxoquazepam, and hydroxy-methoxy-oxoquazepam, which have the hydroxy and methoxy groups on the fluorophenyl group, and dihydroxy-oxoquazepam and dihydroxy-methoxy-oxoquazepam, which have one hydroxy group at the 3-position of the seven-membered ring and the other hydroxy group and the methoxy group on the fluorophenyl group. We demonstrated that LC-IT-TOF MS was a useful tool for determining the structure of the metabolites. However, the exact locations of the hydroxy and methoxy groups on the fluorophenyl group could not be identified. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to investigate the possible association between benzodiazepine ( BZD) use and risk of incident stroke by utilizing data from 2000 to 2003 from the National Health Insurance system of Taiwan. Methods Study subjects consisted of 38 671 patients with new BZD use and 38 663 people without BZD use who were frequency-matched for age, sex and baseline comorbidity with BZD users. All subjects had no history of stroke. Each study patient's case was followed until a new diagnosis of stroke was made or until the patient was censored by loss to follow up, death, or termination of insurance. The study lasted until the end of 2009. A Cox proportional hazards regression model was used to estimate the incidences and hazard ratios ( HR) of stroke. Results The HR of hemorrhagic stroke was significantly lower in the BZD group when compared with the non- BZD group. For patients aged 20-39 years, the HR of ischemic stroke was significantly higher in the BZD group when compared with the non- BZD group. Compared to the non- BZD group, patients with a lower annual dosage (<1 g) or duration (<30 days) of BZD use had a lower risk of stroke in the elder group ( P < 0.0001) and patients with a higher annual dosage (≥ 4 g) or duration (≥ 95 days) of BZD use had a higher risk of stroke in all age groups ( P < 0.0001). Conclusions Our findings may suggest neuroprotection under lower-dosage BZD use and neurotoxicity under higher-dosage BZD use. [ABSTRACT FROM AUTHOR]

The American College of Medical Toxicology and the National Association of Medical Examiners convened an expert panel to generate evidence-based recommendations for the practice of death investigation and autopsy, toxicological analysis, interpretation of toxicology findings, and death certification to improve the precision of death certificate data available for public health surveillance. The panel finds the following: 1. A complete autopsy is necessary for optimal interpretation of toxicology results, which must also be considered in the context of the circumstances surrounding death, medical history, and scene findings. 2. A complete scene investigation extends to reconciliation of prescription information and pill counts. 3. Blood, urine, and vitreous humor, when available, should be retained in all cases. Blood from the femoral vein is preferable to blood from other sites. 4. A toxicological panel should be comprehensive and include opioid and benzodiazepine analytes, as well as other potent depressant, stimulant, and anti-depressant medications. 5. Interpretation of postmortem opioid concentrations requires correlation with medical history, scene investigation, and autopsy findings. 6. If death is attributed to any drug or combination of drugs (whether as cause or contributing factor), the certifier should list all the responsible substances by generic name in the autopsy report and on the death certificate. 7. The best classification for manner of death in deaths due to the misuse or abuse of opioids without any apparent intent of self-harm is 'accident.' Reserve 'undetermined' as the manner for the rare cases in which evidence exists to support more than one possible determination. [ABSTRACT FROM AUTHOR]

For the first time, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) multi-analyte approach based on a simple liquid-liquid extraction was developed and validated for fast target screening and quantification of benzodiazepines and Z-drugs in case of driving ability and crime responsibility in the three most important biosamples whole blood, plasma, and serum. Whole blood, plasma, and serum (500 μL each) were extracted twice at pH 7.4 and at pH 10 with ether/ethyl acetate (1:1). Separation, detection, and quantification were performed using LC-MS/MS with electrospray ionization in positive mode. The method was validated with respect to selectivity, ion suppression/enhancement of co-eluting analytes, matrix effects, recovery, process efficiency, accuracy and precision, stabilities, and limits of detection and quantification. For accuracy and precision, full calibration was performed with ranges from subtherapeutic to toxic concentrations. The presented LC-MS/MS approach as part of a universal multi-analyte concept for over 100 drugs was applicable for selective detection as well as accurate and precise quantification in whole blood, plasma, and serum. The approach was selective, sensitive, accurate, and precise for 16 of the 19 tested drugs in whole blood, 18 in plasma, and 17 in serum. Only semiquantitative results could be obtained for zopiclone because of its instability in all tested biosamples. [ABSTRACT FROM AUTHOR]

The article offers information on the research related to the use of benzodiazepines as a protective factor for community-acquired pneumonia (CAP) in ≤60 year old subjects by Obiora and colleagues. It discusses the effect of the effect of benzodiazepines (BZs) on the risk of CAP. It mentions that the study was based on data from a large database which could have made a misclassification both in disease codification and drug exposure.

Objectives: The purpose of this study was to describe, from a health care system perspective, potentially inappropriate benzodiazepine prescribing among elderly persons in a publicly funded health system in Canada as well as health service use and costs associated with such pre- scriptions and the related drug interactions. Methods: The sample (N=2,320) was representative of Quebec's community-dwelling elderly population (≧65 years) and consisted of respondents to the 2006 ESA survey (Enquete sur la Sante des Ames, or Survey on the Health of the Elderly). The definition of potentially inappropriate benzodiazepine prescription was based on Beers criteria and on the potential for benzodiazepine-related drug interactions. Using a retrospective design, logistic regressions tested the association between inappropriate prescribing and health service use incurred over 12 months. The cost analysis used a generalized linear model with a gamma distribution. Results: Thirty-two percent (N= 744) had received a benzodiazepine prescription, and 44% of this group received at least one potentially inappropriate prescription. Participants susceptible to benzodiazepine-related drug interactions, unlike those with inappropriate prescriptions according to Beers criteria, had a greater risk of hospitalizations and of emergency department and outpatient visits and higher health care costs ($3,076 higher per year, p<.001) than those with appropriate prescriptions. Conclusions: Use of administrative and survey data permitted control for several factors, and a significant association between benzodiazepine- related drug interactions and health care costs among elderly persons was found. Research should further examine this association and evaluate the potential of shared medical electronic databases to decrease life-threatening drug interactions affecting this population. [ABSTRACT FROM AUTHOR]

Abstract: Subjects with mild cognitive impairment (MCI) have “prodromal or incipient” dementia with neuropathological changes. Peripheral benzodiazepine receptor (PBR) binding was shown to reflect activated microglia, one of the predictive biomarkers of conversion to dementia. We sought to evaluate PBR binding in MCI subjects using positron emission tomography (PET). PET scans with [11C]DAA1106, a potent and selective ligand for PBR, were performed on seven MCI subjects, 10 patients with Alzheimer''s disease (AD) and 10 age-matched control subjects. PBR binding in the regions of interest was quantified by binding potential (BP). Five MCI subjects were clinically followed for 5years after their initial PET scans. [11C]DAA1106 binding to PBR was significantly increased in widespread areas in MCI subjects when compared to healthy controls. We found no significant difference in BP between MCI and AD patients. MCI subjects with [11C]DAA1106 binding values higher than the control mean +0.5 standard deviation (S.D.) developed dementia within 5years. Our finding of higher DAA binding in MCI subjects indicated that microglial activation may occur before the onset of dementia. In vivo detection of microglial activation may provide useful prognostic information with respect to stratifying MCI subjects at increased risk of dementia. [Copyright &y& Elsevier]

Benzodiazepines have a various behavioral effects in addition to their anxiolytic action. There is every reason to believe that the BZ/GABA receptor complex is involved in these effects, since GABAmimetic manipulations modify the effect of BZ in tests of convulsive activity, motor function, and appetitive behavior. 1,5-Benzodiazepines are biologically important molecules and are extensively used clinically as analgesic, hypnotic, sedative, and antidepressive agents. Hence, 1,5-Benzodiazepines were synthesized by condensation of o-phenylenediamine and ketones, for example, cyclohexanone and acetone in presence of sulfated zirconia (catalyst). Mannich bases were synthesized with acetophenone, p-nitroacetophenone, p-chloroacetophenone, and formaldehyde. Schiff bases were synthesized using Mannich base of 1,5-benzodiazepines with p-chloroaniline and p-chlorophenylsemicarbazide in the presence of glacial acetic acid. All the synthesized compounds were characterized by 1H NMR and IR spectral analyses. All the synthesized derivatives were evaluated at the dose of 30mg/kg b.w for anticonvulsant activity by isoniazid induced convulsion model, and the compounds NBZD-3 and NBZD-8 were found to be the most active among all compounds. Among all the synthesized derivatives, compounds NBZD-13 and NBZD-17 were found to be the most active among all compounds using thiosemicarbazide induced model. Although NBZD-8, NBZD-10, and NBZD-18 are the compounds which had shown good anticonvulsant activity and have an advantage over that, they were not sedative. [ABSTRACT FROM AUTHOR]

The applicability of micellar electrokinetic capillary chromatography (MEKC) for the separation of benzodiazepine (BZD) derivates with different structural characteristics has been studied. Efforts were first focused on the optimization of the analytical conditions, on the effects of buffer concentration, surfactant concentration and buffer pH on the separation. To manipulate selectivity of the separation β-cyclodextrin (CD) was added to the buffer solution, and urea was used to improve the solubility of the CD in water. The CD-modified MEKC separation of the eight BZDs was achieved within 15 minutes using 25 mmol dm-3 natrium tetraborate-50 mmol dm-3 sodium dodecyl sulphate-15 mmol dm β-CD-2 mol dm-3 urea (pH 9.3) as the running buffer. The proposed separation method was evaluated on the basis of precision, linearity and limit of detection. [ABSTRACT FROM AUTHOR]

Phenazepam and etizolam were the first uncontrolled benzodiazepines available for sale in the UK. Pyrazolam, flubromazepam and diclazepam are not used medicinally anywhere in the world; they are produced exclusively for the uncontrolled, recreational market. It is important to know whether potentially abused drugs like these can be detected in routine toxicological screening tests. The purpose of this study was to evaluate whether the Immunalysis® Benzodiazepines ELISA kit could detect phenazepam, etizolam, pyrazolam, flubromazepam, diclazepam and its metabolite delorazepam. Their cross-reactivity was assessed by comparing the absorbance of the drug with that of oxazepam, the reference standard. This study found that these uncontrolled benzodiazepines cross-react sufficiently to produce a positive result with the Immunalysis® Benzodiazepine ELISA kit. Cross-reactivity ranged from 79 to 107% for phenazepam, etizolam, pyrazolam, flubromazepam, diclazepam and delorazepam fortified into blood. The results show that it is possible to detect these newer benzodiazepines with traditional forensic toxicology laboratory tools and it is important to include these benzodiazepines in the confirmation tests. [ABSTRACT FROM AUTHOR]

Abstract: Olanzapine has been shown to cause or have a contributory role in the development of hyperglycemia and diabetes mellitus. Without careful monitoring for the development of these conditions and control of the resulting adverse effects, patients receiving olanzapine may be at risk of developing fatal ketoacidosis. A review of post-mortem toxicological reports has revealed an increase in the incidence of post-mortem findings of acetone in decedents who were taking olanzapine over the past decade. A review of the current literature and a comprehensive review of case histories and toxicological findings were conducted at the Centre of Forensic Sciences (Toronto, Ontario). Olanzapine concentrations ranging from <62.5 to 858ng/mL and acetone concentrations as high as 95mg/dL were detected concurrently. Due to the unstable nature of olanzapine, in several instances quantitation was not possible despite elevated responses during qualitative screening procedures. Five cases suggesting olanzapine-induced ketoacidosis were identified based on the case history and toxicological findings. These data have been compiled and examined with respect to acetone concentrations following olanzapine use and the forensic relevance of post-mortem olanzapine and acetone concentrations are discussed. [Copyright &y& Elsevier]

At the request of the Service des Haras, our laboratory works on the toxicological problems of the sport-horse. These studies have resulted in the setting up of an anti-doping control for equestrian competitions of various types, not only flat racing. During events, horses, must be calm and docile to the riders' order. Frequently, the latter use tranquillizers to try and win events. The analytical method for the research and identification of these compounds is described. The technique involves successively: 1. alkalinisation of the sample - saliva, blood or urine after enzymatic hydrolysis. 2. extraction with diethyl ether - the recovery is 70% to 90% depending upon the drug. 3. determination by gas-liquid chromatography with use of a retention index for qualitative analysis. We can detect up to fifteen tranquillizers in any one sample, even when present at such low concentrations as found in saliva. The use of the retention index is a reliable method for qualitative analysis. For example, the method has been used for three years, during which period the rentention index of acetylpromazine remained at 3240 +/- 7. The chromatographic analysis was performed on 3% OV-17 at 290 degrees. The chromatographic analysis has been performed by three columns of different polarity (OV-1; OV-17; SP-2250). If on the three columns, the retention index of one peak is the same as that of the tranquilizer, a further confirmation is made with the use of a thermionic detector specific for nitrogenous drugs. In conclusion, this method which is sufficiently precise and specific has been used for anti-doping control. [ABSTRACT FROM PUBLISHER]

The introduction of new psychoactive substances (NPS) on the illicit drug market has led to major challenges for the analytical laboratories. Keeping screening methods up to date with all relevant drugs is hard to achieve and the risk of missing important findings in biological samples is a matter of concern. Aiming for an extended retrospective data analysis, diagnostic fragment ions from synthetic cannabinoids (n=251), synthetic opioids (n=88) and designer benzodiazepines (n=26) not included in our original analytical method were obtained from the crowdsourced database HighResNPS.com and converted to a personalized library in a format compatible with the analytical instrumentation. Data files from the analysis of 1314 forensic post mortem samples with an Agilent 6540 ultra high pressure liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) performed in our laboratory from January 2014 to December 2018 were retrieved and retrospectively processed with the new personalized library. Potentially positive findings were grouped in two: The most confident findings contained MS/MS data for library match (category 1) whereas the less confident findings lacked such data (category 2). Five new category 1 findings were identified: Flubromazepam in two data files from 2015 and 2016, respectively, phenibut (4-amino-3-phenylbutyric acid) in one data file from 2015, fluorofentanyl in one data file from 2016 and cyclopropylfentanyl in one data file from 2018. Retention time matches with reference standards further strengthened these findings. A list of 35 presumably positive category 2 findings was generated. Of these, only one finding of phenibut was considered plausible after checking retention times and signal-to-noise ratios. This study shows that new compounds can be detected retrospectively in data files from QTOF-MS using an updated library containing diagnostic fragment ions. Automatic screening procedures can be useful, but a manual re-evaluation of positive findings will always be necessary. [ABSTRACT FROM AUTHOR]

The article focuses on a research related to the role of benzodiazepines in causing dementia in elderly people. It mentions that the use of benzodiazepines increases the risk of Dementia by approximately 50 percent in elderly people. Further, it discusses the therapeutic benefits of Omega-3 fatty acids and Ginkgo biloba.

The article focuses on quantitative analysis of benzodiazepines in whole blood using the approach Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) and liquid chromatography-mass spectrometry. Topics include use of benzodiazepine, a psychoactive drug, for treatment of diseases such as insomnia and alcohol withdrawal; a chart showing relative standard deviations for compounds such as Alprazolam and Diazepam; and advantages of QuEChERS such as removal of undesired matrix interferences.