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Benzodiazepine ingestion is frequent in patients admitted to ICU for intoxications. Generally, a supportive approach by securing the airway, breathing, and circulation is sufficient. Flumazenil is a well-known antidote for benzodiazepines but does not influence its elimination. Following preclinical data, we applied for the first time in humans a hemadsorption filter in a patient with a bromazepam intoxication. This technique proved to be effective in eliminating bromazepam in a patient with CHILD-C cirrhosis. We conclude that hemadsorption is a viable option to reduce length of ICU stay or intubation in slow metabolizers without contraindications. [ABSTRACT FROM AUTHOR]

Similar to the antibiotic mixing strategies, which depend on reducing the worth of diffusion of the resistant bacteria to new host, in this contribution, we explicit new mixed‐ligand complexes of the type [M(SMZ)2(BZM)] (M = Co(II), Ni(II) and Cu(II)) based on two drugs: sulfamethazine (SMZ) and bromazepam (BZM). The novelty aspect of the present work relies on combining two drugs in a single molecule via the synthesis of the ternary complexes. The ternary complexes were characterized by spectroscopic and analytical tools with the aid of the quantum chemical calculations. Copper(II) complex has the highest DNA intrinsic binding constant (2.20 × 105 M−1), induces extensively DNA cleavage compared to the other complexes, and exhibits the highest cytotoxicity (IC50 = 0.67 μM) against human liver cancer cell line (HepG2). Exciting, Cu(II) compound exhibits no toxicity to the nonmalignant human foetal lung fibroblast (WI‐38). Alternatively, the low cytotoxicity of the Co(II) complex correlates well with the high affinity of the compound to human serum albumin (Kb = 4.58 × 105) compared to 1.93 × 105 and 2.14 × 105 M−1 for Ni (II) and Cu (II) complexes, respectively. [ABSTRACT FROM AUTHOR]

Aim: To assess the effects of chronic evening oral administration of bromazepam alone or in combination with propranolol on ambulatory blood pressure (BP) and heart rate (HR) in mild hypertensive subjects. Methods: Thirty-seven mild hypertensive patients after a 2-week placebo period were randomized to bromazepam 3 mg, propranolol 40 mg, bromazepam 3 mg plus propranolol 40 mg or placebo for 2 weeks according to a double-blind, double dummy, cross-over design. After each treatment period, 24-h BP and HR ambulatory monitoring was performed by using a non-invasive device. Results: Ambulatory monitoring showed that during night-time SBP and DBP values were unaffected by bromazepam as compared to placebo, whereas SBP was significantly reduced by propranolol both when taken alone and in combination with bromazepam. HR nocturnal values were significantly reduced by propranolol, whereas they were significantly increased by bromazepan both when taken alone (+11.5%, p < 0.05 vs. placebo) and in combination with propranolol (+12.8%, p < 0.05 vs. propranolol). No significant difference in day-time values of SBP, DBP and HR was observed among the 4 treatment groups. Conclusions: In mild hypertensive patients, evening consumption of bromazepam for a 2-week period did not affect BP, while it increased nocturnal HR. Such an increase was observed both when bromazepam was taken alone and in combination with propranolol, which suggests that it depends on a bromazepam mediated decrease in vagal tone. Whatever the mechanism, the HR nocturnal increase might be of clinical relevance, due to the role of high HR as cardiovascular risk factor, particularly in already at risk hypertensive subjects. [ABSTRACT FROM AUTHOR]

Bromazepam is a psychoactive drug belonging to class of benzodiazepines with well-known hypnotic and sedative effects. It acts on the central neural system as an inhibitor of the neurotransmitter gamma aminobutyric acid. It is frequently prescribed for treatment of severe anxiety, to reduce tension, agitation and depression. Dissolution testing (the process by which a solid solute enters in to a solution) is a requirement for all solid oral dosage forms and is used in all phases of research and development for product release and stability testing. Tablet dissolution test is a standardized method for measuring the rate of drug release from a dosage form and it simulates the percentage of active substance that can be absorbed into the blood circulation. The direct determination of Bromazepam in pharmaceutical dosage forms using HPLC with UV detector to carry out dissolution test, have not yet been described. Development of HPLC method with UV detection for direct determination of in-vitro dissolution test of Bromazepam tablets, which can be used in the same time as method for determination of assay of Bromazepam in Bromazepam tablets, can make analytical procedure easier and quicker. A simple, selective, linear, precise and accurate RP-HPLC method has been developed and validated for assay and in-vitro dissolution test of Bromazepam tablets. The method was validated according to the guidelines set by the International Conference of Harmonization for validation of analytical procedures. The chromatographic separation was carried out using reversed phase HPLC LiChrospher RP Select B column (125 x 4.0 mm i.d.; 5μm) at temperature of 50oC. Mobile phase was consisting of the mixture of methanol, acetonitrile and potassium dihydrogen phosphate buffer (pH 7.0, adjusted with 0.5M Potassium hydroxide), with the ratio of 45:5:50 (v/v/v) and flow rate of 1.0 ml/min. The detection was carried out at 239 nm. System suitability tests were performed through evaluation of different parameters (retention time, tailing factor, retention factor and selectivity) on freshly prepared standard solution of bromazepam. The retention time of bromazepam in 0,1M HCl was 3.5 min. High percentage of recovery shows that the method is free from the interferences from excipients in test samples. Linearity of response was calculated as a ratio of peak areas of bromazepam vs. concentration in 0,1M HCl and spiked tablets in the concentration range of 0.0018 – 0.016 mgmL-1. The response was linear over the concentration range of 0.0018 – 0.016 mgmL-1 and coefficient of correlation was greater than 0.99. Good linearity shows that the proposed method may be useful for quickly and routinely determination of the percentage of dissolved bromazepam from bromazepam tablets and it can be a method of choice for assay determination in the same time. [ABSTRACT FROM AUTHOR]

Context: Prior works demonstrates an increased risk of death when opioid analgesics and benzodiazepines are used concomitantly to gain a high. Using poison center data, we described trends in abuse or misuse of benzodiazepines and opioid analgesics. We quantified mortality risk associated with abuse or misuse of benzodiazepines, opioid analgesics and the combination of opioid analgesics and benzodiazepines. Methods: This was a retrospective chart review of data from the National Poison Data System which collects information from 55 poison centers located across the United States. We identified reported cases of "intentional abuse or misuse" of benzodiazepine and/or opioid analgesic exposures. Poisson regression was used to compare the number of cases from each year between 2001 and 2014 to the year 2000. Logistic regression was used to determine whether cases exposed to both benzodiazepines and opioids had greater odds of death relative to cases exposed to opioid analgesics alone. Results: From 2000 to 2014, there were 125,485 benzodiazepine exposures and 84,627 opioid exposures among "intentional abuse or misuse" cases. Of the benzodiazepine exposures, 17.3% (n = 21,660) also involved an opioid. In 2010, exposures involving both opioids and benzodiazepines were 4.26-fold (95% CI: 3.87-4.70; p < .001) higher than in 2000. The risk of death was 1.55 (95% CI: 1.01-2.37; p = .04) times greater among those who used both an opioid and a benzodiazepine compared to opioids alone. This association held after adjusting for gender and age. Conclusion: Intentional abuse or misuse of benzodiazepines and opioids in combination increased significantly from 2000 to 2014. Benzodiazepine abuse or misuse far exceeded cases of opioid abuse or misuse. Death was greater with co-abuse or misuse of benzodiazepines and opioids. Population-level campaigns to inform the public about the risk of death with co-abuse or misuse of benzodiazepines and opioids are urgently needed to address this overdose epidemic. [ABSTRACT FROM AUTHOR]

Diversion of prescription drugs is difficult to assess in quality and quantity. This study aimed to characterize diversion of prescription drugs in France through a comparative analysis of falsified prescriptions collected during three periods from 2001 to 2012. The data recorded in a national program which records all falsified prescriptions presented to community pharmacies were studied. Included data regarded: subjects, prescription forms, and drugs. Description of the dataset in three periods (2001-2004, 2005-2008, and 2009-2012) was completed with clustering analyses to characterize profiles of prescriptions and subjects associated with the most reported drugs. The 4469 falsified prescriptions concerned most often females (51.6%). Average age was 46.5 years. Zolpidem, bromazepam, and buprenorphine were the most frequent drugs. Alone, 13 drugs (1.7%, 13/772) represented more than 40% of the total reports (3055/7272). They were associated with three diversion profiles: (i) buprenorphine, flunitrazepam, and morphine were mentioned on overlapping secure prescription forms presented by young men; (ii) alprazolam, bromazepam, zolpidem, codeine/acetaminophen were mentioned on simple prescription forms presented by experienced women; and (iii) acetaminophen and lorazepam were mentioned on modified prescription forms presented by elderly subjects. Clonazepam, clorazepate, dextropropoxyphene, zopiclone moved between those profiles. The patterns of falsified prescriptions provided in this study contribute to enhance the scientific knowledge on the most diverted prescription drugs. The latter follow distinct trajectories across time depending on their pharmacology (including their abuse/addiction potential) and on their regulation's history. The close and continuous analysis of falsified prescriptions is an excellent way to monitor prescription drug diversion. [ABSTRACT FROM AUTHOR]

The reaction of bromazepam (7-bromo-1,3-dihydro-5-(2-pyridyl)-2 H-1,4-benzodiazepin-2-one, BZM) with Cr(III) ( 1), Fe(III) ( 2) and Ru(III) ( 3) salts gives complexes of the type [M(BZM)3]⋅3X (X = Cl or NO3). Structural characterization was extensively carried out using various analytical and spectral tools such as infrared, 1H NMR and UV-visible spectroscopies and magnetic, conductance, elemental and thermal analyses. BZM is a bidentate ligand and interacts with the metal ions via the pyridine and benzodiazepin-2-one nitrogen atoms. The magnetic and electronic properties of 2 and 3 are consistent with low-spin octahedral complexes. The three BZM molecules are non-isoenergetically coordinated to the metal ions and this is reflected in the values of the second-order interaction energy. The antibacterial activity was studied using Staphylococcus aureus and Escherichia coli. Coordination of BZM to Cr(III) or Ru(III) ions leads to a marked increase in toxicity with respect to the inactive Fe(III) complex 2. [ABSTRACT FROM AUTHOR]

Two new photoactivatable carbon monoxide-releasing molecules (CORMs), fac-[Mn(CO)3(BZM)Br] ( 1) and [RuCl2(BZM)(CO)2] ( 2), derived from the anti-anxiety drug bromazepam (BZM) and capable of rapid release of CO upon the illumination with light-emitting diode (LED) source light (470-525 nm) have been synthesized and characterized. The photo-delivery of CO to myoglobin solution could be achieved via the illumination of 1 at 525 nm for 10 min or at 470 nm for 1 min. The addition of water to a dimethylsulfoxide (DMSO) solution of 1 increases its stability, but it decreases the rate of the CO-releasing process. CORM 2 behaves as a good visible photoCORM, whereby its two CO molecules are released within 10 min upon exposure to LED light source at 470 nm in DMSO. The illumination profile of 2 was also examined using solution . The cis/ trans stereochemistry around the Ru(II) ion was determined using quantum chemical calculations. The formation of photoCORMs leads to an improvement in the toxicity of BZM against tested microbes. [ABSTRACT FROM AUTHOR]

Rationale: Several model organisms have been employed to study the impacts of stress on biological systems. Different models of unpredictable chronic stress (UCS) have been established in rodents; however, these protocols are expensive, long-lasting, and require a large physical structure. Our group has recently reported an UCS protocol in zebrafish with several advantages compared to rodent models. We observed that UCS induced behavioral, biochemical, and molecular changes similar to those observed in depressed patients, supporting the translational relevance of the protocol. Objectives: Considering that a pharmacological assessment is lacking in this zebrafish model, our aim was to evaluate the effects of anxiolytic (bromazepam) and antidepressant drugs (fluoxetine and nortriptyline) on behavioral (novel tank test), biochemical (whole-body cortisol), and molecular parameters ( cox-2, tnf-α, il-6, and il-10 gene expression) in zebrafish subjected to UCS. Results: We replicated previous data showing that UCS induces behavioral and neuroendocrine alterations in zebrafish, and we show for the first time that anxiolytic and antidepressant drugs are able to prevent such effects. Furthermore, we extended the molecular characterization of the model, revealing that UCS increases expression of the pro-inflammatory markers cox-2 and il-6, which was also prevented by the drugs tested. Conclusions: This study reinforces the use of zebrafish as a model organism to study the behavioral and physiological effects of stress. The UCS protocol may also serve as a screening tool for evaluating new drugs that can be used to treat psychiatric disorders with stress-related etiologies. [ABSTRACT FROM AUTHOR]

Background The majority of infertile women are young and healthy but exhibit stress, anxiety, and other psychological disorders associated with infertility. This anxiety should be attenuated with appropriate drugs during premedication. Moreover, after the procedure, patients report visceral pain resulting from cervical manipulation, which should be relieved with appropriate analgesia. Objectives The aim of this study was to evaluate and compare the clinical efficacy of oral premedication with pregabalin and bromazepam for sedation in terms of effectiveness and postoperative analgesia in patients undergoing embryo transfer during in-vitro fertilization (IVF). Patients and methods A total of 60 healthy infertile consented female patients younger than 39 years with ASA physical status I or II who were scheduled for embryo transfer during IVF were randomized to receive either pregabalin (300 mg) (group A), bromazepam (3 mg) (group B), or placebo (folic acid 0.5 mg) (group C) 90 min before surgery as oral premedication. The Ramsay sedation scale was used to evaluate preoperative sedation. Hemodynamic data were recorded before premedication, just after induction, after recovery, and 2 and 4 h postoperatively. Severity of postoperative pain was assessed using a visual analogue scale ( VAS). Results Perioperative sedation levels were lighter in the pregabalin group than in the bromazepam group, as there were statistically significant differences in terms of attenuation in mean arterial blood pressure and heart rate. Moreover, VAS score was significantly lower in the pregabalin group at induction, recovery, and 2 and 4 h after surgery. Conclusion This study showed that the use of pregabalin 300 mg or bromazepam 3 mg causes good preoperative sedation with hemodynamic stability intraoperatively together with decreasing postoperative pain in embryo transfer during IVF procedure. [ABSTRACT FROM AUTHOR]

Kinetics of the acid hydrolysis of bromazepam (Bz) has been investigated in micelles, reverse micelles, and microemulcions of cetyltrimethylammonium bromide (CTAB) by spectrophotometric method. The rate of the acid hydrolysis of Bz was found to be enhanced both below and above the critical micelle concentration (CMC) of CTAB in aqueous solution. The pseudo-first-order rate constant (k′) shows an initial decrease for both low and high H+ concentrations. With further increase in [CTAB], at low [H+], the k′ attains an almost constant value, while, at high [H+], the k′ passes through a maximum and then decreases. The kinetic data for catalysis by micelles of CTAB was interpreted with the pseudophase ion exchange (PIE) model. In CTAB/cyclohexane/1-butanol/water microemulsions, as the water to surfactant ratio (wo) increases, the physicochemical properties and droplet sizes of microemulsions significantly change and distinct changes in reaction environment can be marked. The rate of the hydrolysis reaction exhibits excellent correlation with the physicochemical properties and droplet sizes of the microemulsions and reverse micelles of CTAB. At [H+] = 0.001 M, in reverse micelles and microemulsions of CTAB, the k′ of the acid hydrolysis of Bz decreases sharply followed by a slight increase with increasing wo. [ABSTRACT FROM AUTHOR]

Herein, we report a case of an assisted suicide committed by application of 34 matrix-based fentanyl-containing transdermal therapeutic systems (TTS) with different release rates. The TTS were supplied by the husband but administered by the deceased herself. Besides routine systematic toxicological analysis (STA), the concentrations of fentanyl and norfentanyl were determined in the blood (femoral and heart), urine, stomach content, brain, lung tissue, musculus iliopsoas, liver, kidney, bile and in some of the used TTS by LC-MS/MS. Blood levels of fentanyl were 60.6 μg/L in femoral blood and 94.1 μg/L in heart blood. These concentrations are in good concordance with levels described in cases with accidental or lethal suicidal fentanyl patch application. The organ distribution indicates an influence of post-mortem redistribution. The levels of residual fentanyl in the TTS were also determined. STA furthermore revealed supratherapeutic levels of bromazepam. Thus, the cause of death was a combination of fentanyl and bromazepam intoxication. However, considering the determined levels of fentanyl and norfentanyl in the entire set of specimens and the high toxicity in comparison to bromazepam, fentanyl was the leading toxic noxa. [ABSTRACT FROM AUTHOR]

Vibratory angioedema is a rare form of physical urticaria, hereditary or acquired, which occurs at body sites exposed to vibrations. Pathogenic mechanisms of disease are not completely clear and, consequently, current pharmacological treatment is sometimes unsatisfactory. We report the case of a horn player affected by acquired vibratory angioedema, relapsing after prolonged use of the instrument and resistant to systemic antihistamines and corticosteroids, which successfully responded to therapy with low doses of amitriptyline and bromazepam. A neuroinflammatory mechanism can be likely implicated in the pathogenesis of vibratory angioedema, in line with many different cutaneous/mucosal diseases involving a complex interplay of homeostatic/allostatic systems. Furthermore, in mucosal diseases, such as vibratory angioedema, physical/psychological stressors have a relevant role. In such cases, because of the complex interplay between nervous and immune system, the pharmacological activity of benzodiazepines and typical antidepressants may downregulate neuroinflammation. [ABSTRACT FROM AUTHOR]

The efficacy and safety of Axamon were studied in patients aged 65-88 years with motor and cognitive disorders during the residual period of stroke: 25 patients received basal treatment and Axamon prescribed for 12 weeks at a dose of 20 mg three times daily, while 25 patients of the control group received basal treatment only. Along with neurological studies, assessment of the efficacy and safety of complex therapy was performed using neuropsychological tests and scales. Decreases in the severity of cognitive and motor disorders were seen in patients given Axamon. Axamon promoted optimization of the rehabilitation potential of patients during the residual period of stroke. [ABSTRACT FROM AUTHOR]

This study evaluated the role of prodynorphin gene in the regulation of anxiety and associated molecular mechanisms. Emotional responses were assessed using the light—dark test, elevated plus maze and social interaction tests in prodynorphin knockout and wild-type mice. Corticotrophin releasing factor and proopiomelanocortin gene expressions in the hypothalamus were evaluated after restraint stress using in situ hybridization. The anxiolytic efficacy of bromazepam and GABA A receptor subunits gene expression in the amygdala were also assessed in both genotypes. The deletion of prodynorphin increased anxiety-like behaviours and proopiomelanocortin gene expression in the arcuate nucleus (two-fold). Moreover, the anxiolytic action of bromazepam was significantly attenuated in the mutant mice. Decreased GABAAγ2 and increased GABAAβ2 gene expression receptor subunits were found in the amygdala of prodynorphin knockout mice. These results indicate that deletion of prodynorphin gene is associated with increased anxiety-like behaviours, enhanced sensibility response to stress stimuli, reduced anxiolytic efficacy of bromazepam and altered expression of the GABAA receptor subunits. [ABSTRACT FROM PUBLISHER]

To characterize and compare the pharmacokinetic profiles of bromazepam, omeprazole and paracetamol when administered by the oral and nasogastric routes to the same healthy cohort of volunteers. In a prospective, monocentric, randomized crossover study, eight healthy volunteers received the three drugs by the oral (OR) and nasogastric routes (NT). Sequential plasma samples were analyzed by high-performance liquid chromatography–UV, pharmacokinetic parameters (Cmax, $${\text{AUC}}_{0 - \infty } $$, t½, ke, tmax) were compared statistically, and Cmax, $${\text{AUC}}_{0 - \infty } $$ and tmax were analyzed for bioequivalence. A statistically significant difference was seen in the $${\text{AUC}}_{0 - \infty } $$ of bromazepam, with nasogastric administration decreasing availability by about 25%: AUCOR = 2501 ng mL−1 h; AUCNT = 1855 ng mL−1 h ( p < 0.05); ratio (geometric mean) = 0.74 [90% confidence interval (CI) 0.64–0.87]. However, this does not appear to be clinically relevant given the usual dosage range and the drug’s half-life (approx. 30 h). A large interindividual variability in omeprazole parameters prevented any statistical conclusion from being drawn in terms of both modes of administration despite their similar average profile: AUCOR = 579 ng mL−1 h; AUCNT = 587 ng mL−1 h ( p > 0.05); ratio (geometric mean) = 1.01 (90% CI 0.64–1.61). An extended study with a larger number of subjects may possibly provide clearer answers. The narrow 90% confidence limits of paracetamol indicate bioequivalence: AUCOR = 37 μg mL−1 h; AUCNT = 41 μg mL−1 h( p > 0.05); ratio (geometric mean) = 1.12 (90% CI 0.98–1.28). The results of this study show that the nasogastric route of administration does not appear to cause marked, clinically unsuitable alterations in the bioavailability of the tested drugs. [ABSTRACT FROM AUTHOR]

The application of ion-selective electrodes (ISEs) in the detection and determination of environmental pollutants has become a very important mission in the last few years. Two selective and sensitive membrane electrodes were fabricated in the laboratory and intended to evaluate the electrochemical response of bromazepam (BRZ) using phosphotungstic acid (PTA) and sodium tetraphenylborate (TPB) as ion pairing agents. The linearity range of the fabricated electrodes was between 1 × 10−6 M to 1 × 10−3 M. Nernstian slopes of 54 mV/decade and 57 mV/decade were obtained for the BRZ-PTA and BRZ-TPB membrane electrodes, respectively. The performance of the fabricated membranes was optimum in the pH range of 3–6. Optimum electrochemical response was attained through the careful adjustment of all assay settings. The cited method was successfully applied for the selective determination of BRZ in either its pure form or real wastewater samples obtained from a pharmaceutical industrial plant. The main core of novelty in the suggested method lies in the application of the membranes for the sensitive, selective, and economic determination of BRZ in real wastewater effluents without the tedious sample pretreatment procedures. This can make the suggested method considered an eco-friendly method, as it minimizes the use of organic solvents and chemicals used in the pretreatment process. [ABSTRACT FROM AUTHOR]

Copyright of Revista da Faculdade de Ciências da Saúde is the property of Edicoes Universidade Fernando Pessoa and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A sensitive, fast, and accurate reversed phased High Performance Liquid Chromatographic method, coupled with UV/DAD set at 240 nm has been developed for the separation and quantification of six benzodiazepines (alprazolam, bromazepam, clonazepam, diazepam, flunitrazepam, lorazepam) in pharmaceutical and biological matrices after solid phase extraction. The separation was achieved within 10 min. on a Kromasill (C8-5 µm, 250×4 mm, 100) analytical column using a mobile phase consisting of CH3OH:0.05M, CH3COONH4:CH3CN delivered under a gradient program at a constant flow rate of 1.0 mL/min. Colchicine (4 ng/µL) was used as internal standard. The drug/internal standard peak area ratios were linked in quadratic relationships to its concentrations giving a linearity range of 0.20-15.00 ng/µL for each BDZ, except BRZ that of which was 0.1-18.0 ng/µL with correlation coefficients greater than 0.993. The precision and accuracy were evaluated at three concentrations. Validation was also performed in terms of selectivity, extraction recovery, stability, and robustness. Recoveries from pharmaceutical/biological samples were between 88-113% and intra-inter day RSD were 0.5-12%. The method was also applied to a real urine sample from a patient under treatment with alprazolam. [ABSTRACT FROM AUTHOR]

Bromazepam and omeprazole are frequently administered to hospitalized patients to decrease anxiety and prevent stress ulcers, respectively. In patients under enteral nutrition, these drugs are administered via a nasogastric feeding tube. However, this mode of administration renders their bioavailability highly variable, and calls for their therapeutic monitoring. Given the absence of published data on the compared bioavailability of the two drugs given orally or via a nasogastric feeding tube, we have developed a high performance liquid chromatography method with UV detection (HPLC-UV) suitable for their simultaneous monitoring in human plasma. The method involves solid phase extraction of 2 mL plasma samples. Linearity was demonstrated in a concentration range of 5-100 ng/mL and 20-2000 ng/mL for bromazepam and omeprazole, respectively. The lower limit of quantification was 5 ng/mL and 20 mg/mL for bromazepam and omeprazole, respectively. The method proved its worth in the simultaneous monitoring of bromazepam and omeprazole administered to healthy volunteers. [ABSTRACT FROM AUTHOR]

During our extensive routine analyses of drugs of abuse and other drugs such as benzodiazepines using both immunoassays and gas chromatography-mass spectrometry (GC-MS), we have noticed that the EMIT II benzodiazepine assays for urine samples sometimes gave false-negative results for bromazepam use or abuse. The negative benzodiazepine immunoassays and positive GC-MS results for bromazepam in urine could be explained by the absence (or below the detection limit) of 3-hydroxybromazepam (3HB) and the presence of 2-amino-3-hydroxy-5-bromobenzoylpyridine (AHBBP), which are the two major metabolites of bromazepam. 3HB cross-reacted with the antibody contained in the EMIT II, but AHBBP did not, due to their structural characteristics. To avoid such false-negative results for bromazepam, AHBBP screening by GC-MS is recommended. The false-negative results observed for bromazepam are probably not limited to the EMIT II kit; the same phenomena may be also true for other commercially available kits that are based on immunochemical reactions. [ABSTRACT FROM AUTHOR]

Bromazepam was isolated from plasma samples by simple protein precipitation with acetonitrile. A high throughput isocratic reversed phase separation between bromazepam and nitrazepam (IS) was achieved within 2 minutes on a rapid resolution cartridge column Zorbax SB-C18, using methanol/aqueous 0.1% formic acid 40/60 (v/v) as mobile phase. Detection was made by tandem mass spectrometry, using the multiple reaction monitoring mode (MRM). Both electrospray (ESI) and atmospheric pressure chemical (API) ionizations modes were considered, together with triple quadrupole (TQ) and ion trap (IT) mass analyzers. Ionization patterns are discussed; no major differences being observed between ESI and API. Higher sensitivity was obtained when using the TQ mass analyzer. Comparison between different ionization modes/mass analyzers types is made, based on bromazepam concentration/time profiles in real plasma samples. The best results were obtained in ESI/TQ conditions. Consequently, the method was fully validated, and then applied to a single dose (6 mg) open label, randomized, two period, two sequence, and crossover bioequivalence study of bromazepam in two commercially available tablet formulations. A low limit of quantification (LOQ) at 2.5 ng/mL level was obtained. Precision below 3% (expressed as relative standard deviation) and accuracy (expressed as % bias) within -7 and +11% were achieved. Pharmacokinetic parameters are presented, being in good accordance with literature data. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Chemistry is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Rationale and objective. Bromazepam, an anti-anxiety agent, has been reported to be metabolized by cytochrome P450 (CYP). However, the enzyme responsible for the metabolism of bromazepam has yet to be determined. The purpose of this study was to examine whether the inhibition of CYP3A4 produced by itraconazole alters the pharmacokinetics and pharmacodynamics of bromazepam. Methods. Eight healthy male volunteers participated in this randomized double-blind crossover study. The subjects received a 6-day treatment of itraconazole (200 mg daily) or its placebo. On day 4 of the treatment, each subject received a single oral dose of bromazepam (3 mg). Blood samplings for drug assay were performed up to 70 h after bromazepam administration. The time course of the pharmacodynamic effects of bromazepam on the central nervous system was assessed using a subjective rating of sedation, continuous number addition test and electroencephalography up to 21.5 h after bromazepam administration. Results. Itraconazole caused no significant changes in the pharmacokinetics and pharmacodynamics of bromazepam. The mean (±SD) values of area under the plasma concentration–time curve and elimination half-life for placebo versus itraconazole were 1328±330 ng h/ml versus 1445±419 ng h/ml and 32.1±9.3 h versus 31.1±8.4 h, respectively. Conclusion. The pharmacokinetics and pharmacodynamics of bromazepam were not affected by itraconazole, suggesting that CYP3A4 is not involved in the metabolism of bromazepam to a major extent. It is likely that bromazepam can be used in the usual doses for patients receiving itraconazole or other CYP3A4 inhibitors. [ABSTRACT FROM AUTHOR]

This study was designed to explore the effects on performance in stem-completion tasks of two benzodiazepines (BZ) in equipotent doses: lorazepam, a drug that atypically disrupts perceptual priming, and flunitrazepam, a compound with standard BZ effects. The study followed a placebo-controlled, double-blind, parallel-group design. Thirty-six young and healthy subjects carried out three completion tasks at theoretical peak-plasma concentrations of drugs: (a) indirect tasks, in which the subjects were instructed to complete stems with the first word that came to mind; (b) direct inclusion tasks/cued recall, in which the participants had to try to use words seen at study as completions; and (c) direct exclusion tasks, in which words seen at study were to be avoided. The PDP was applied to the results in the inclusion and exclusion tasks, to obtain indices of explicit/controlled (C ) and implicit/automatic (A ) memory. The C index was lowered by both BZs and A was equivalent in all treatments, confirming the general amnestic action of BZs. However, lorazepam led to decreases in completions in the indirect and inclusion tasks, while flunitrazepam impaired performance in the exclusion task. The qualitative differences between the drugs in their effects on performance suggest that these BZs may lead to differences in response bias. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Two new spectrophotometric procedures for determining trace amounts of bromazepam and clonazepam, 1,4-benzodiazepine derivatives in their pure and pharmaceutical dosage forms have been developed. The methods are based on forming C.T. complexes with chloranil in chloroform or ethanol at alkaline pH. The absorbance of the formed C.T. complexes were measured at λ = 330 nm and λ = 375 nm for bromazepam and clonazepam, respectively. Linear calibration curves were obtained in the ranges of 31.6-316.0 µg mL[sup -1] for bromazepam and of 63.2-316.0 µg mL[sup -1] for clonazepam. Average recoveries of 99.00-99.60% and 98.57-99.60% were obtained. These reflect 0.5-1.11% and 0.67-1.74% relative errors for bromazepam and clonazepam, respectively. The methods showed standard deviations of 0.6-2.00 and 0.75-1.11 with variance coefficients of 0.63-1.58% and 0.32-1.19% for bromazepam and clonazepam tablets, respectively. Student t-test and F-test statistical treatments were applied for the results obtained by the two methods. t-values indicated the absence of systematic errors at 95% confidence level. Comparing our methods with official HPLC method at 95% confidence level gave insignificant differences. This shows suitability of the two methods for safety, accurate and simple use for quality control analysis of investigated drugs in pure as well as in pharmaceutical preparations. [ABSTRACT FROM AUTHOR]

The article presents a clinical and laboratory data of one case of acute poisoning by methomy caused by inhalation and transdermal absorption, with no signs of ingestion of the agent. The development of poisoning and the fatal outcome are discussed in relation to the use of bromazepam, a mild anxiolytic drug. The study revealed that in cases of methomyl poisoning, oxime therapy neither contributes to the recovery of the poisoned patients nor leads to exacerbation of the cholinergic symptoms and thus can prove beneficial in cases of unknown or mixed pesticide poisoning.

A multicentre, double-blind, randomized trial compared the efficacy of a sustained-release formulation of alprazolam with bromazepam in the treatment of generalized anxiety. One hundred and twenty-one outpatients were randomly assigned to three weeks of active treatment with alprazolam SR (2 mg once daily) or bromazepam (3 mg three times daily), following a period of 3–7 days without medication. After treatment, doses were reduced by 50 per cent during a 1-week dosage-tapering period; patients were then followed for one additional week. There was no significant difference in the anxiolytic effects of alprazolam SR and bromazepam. The results in the two treatment groups were very similar and showed a rapid and statistically significant reduction in efficacy measures, including the total score on the Hamilton Anxiety Rating Scale and the Clinical Global Impression improvement and severity of illness scores. The mean changes from baseline scores were compared between treatments at each evaluation point and no statistically significant differences were observed. At week 3, more than 70 per cent of patients in the alprazolam SR and bromazepam groups were classified as responders. In conclusion, alprazolam SR, in a single daily dose, has a rapid onset of action and is effective in the treatment of generalized anxiety disorder. Its anxiolytic activity is similar to that of bromazepam taken in several daily doses and it has the advantage of enhancing patient compliance and reducing the potential for breakthrough anxiety. Copyright © 1999 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Using a double-blind procedure, 68 patients with putative benzodiazepine dependence were randomly allocated to one of three groups given lorazepam (n = 22), diazepam (n = 23) or bromazepam (n = 23) in doses equivalent to those of the patients' original benzodiazepine. After four weeks the dosage was reduced in 25% quantities until no further benzodiazepines were taken. A total of 23 patients dropped out during the study, ten on lorazepam (one of whom committed suicide), seven on diazepam and six on bromazepam. There were few differences in withdrawal symptoms between the three groups but, despite the higher dropout rate, these symptoms were somewhat less marked in the lorazepam group. Withdrawal symptoms were greater in patients who had taken a benzodiazepine for greater than 5 years and were most marked in those with personality disorders, predominantly dependent ones. [ABSTRACT FROM AUTHOR]

The interaction between metoprolol and bromazepam and lorazepam was studied in 12 healthy male volunteers aged 21-37 years. Metoprolol had no significant effect on the pharmacokinetics of bromazepam or lorazepam. However, bromazepam AUC was 35% higher in the presence of metoprolol. Bromazepam enhanced the effect of metoprolol on systolic blood pressure but not on diastolic blood pressure or pulse rate. Lorazepam had no effect on either blood pressure or pulse. Metoprolol did not enhance the effect of bromazepam on the psychomotor tests used in this study. Metoprolol caused a small increase in critical flicker fusion threshold with lorazepam but had no effect on the other tests. Lorazepam (2 mg) was more potent than bromazepam (6 mg) in the doses used in this study. The interaction of metoprolol with bromazepam and lorazepam is unlikely to be of clinical significance. No change in dose is necessary when using these drugs together. [ABSTRACT FROM AUTHOR]

The acute effects of bromazepam 1.5, 3, 6 and 12 mg on psychomotor skills were examined in 12 male volunteers. The two lower doses slightly improved psychomotor performance, probably due to reduction of tension. The 6 mg and especially the 12 mg dose impaired all the psychomotor factors tested. The impairment was roughly correlated with the increasing plasma levels 30, 90 and 150 min after administration of the drug. Psychomotor performance improved subsequently even if the plasma levels remained high. [ABSTRACT FROM AUTHOR]

Forty paid healthy male students participated in two subacute experiments of 6 weeks each. In the first trial 20 of them received bromazepam, thioridazine, and placebo double blind cross over for 2 weeks each, and in the second trial the active agents administered to the other 20 participants were chlorpromazine and sulpiride. The tests used were paired associate learning with nonsense syllables and digit memory span. Before testing the subjects took either an alcoholic or a nonalcoholic bitter drink. As in the the previous study from this laboratory, alcohol was found to impair learning capacity. Of the drugs used only bromazepam impaired learning significantly, and the combined effect of alcohol and bromazepam on learning capacity was very deleterious. The adrenolytic effect of drugs did not correlate with their effect on learning. Caution is necessary when prescribing bromazepam for active outpatients at least in doses used in this study. [ABSTRACT FROM AUTHOR]

Citicoline is an endogenous intermediate in the biosynthesis of brain phospholipids and acetylcholine used for the treatment of neurodegenerative processes associated with head trauma, stroke, brain aging, cerebrovascular pathology and Alzheimer's disease. In this study we have investigated the effects of citicoline on acquisition and retention in passive avoidance and spatial discriminative learning tasks in control rats and in bomazepam-treated animals. Interactions of citicoline with bromazepam on exploratory behaviour (anxiolytic/sedative activity) and motor co-ordination (myorelaxing activity) were also evaluated to test the specificity of the cognitive effects of citicoline. Our results indicate that citicoline reverses bromazepam-induced amnesia, improves retention in control rats, and has no significant effects on spontaneous activity and motor co-ordination when given alone or in combination with bromazepam. According to these results we conclude that citicoline acts as a promnesic and anti-amnesic drug with no sedative-myorelaxing activity in rats. Therefore, this compound might be of use for the specific treatment of cognitive impairments associated with the chronic use of benzodiazepines. © 1997 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: We describe a rare case of diffuse macroscopic discoloration and chemical gastritis due to chronic bromazepam intake. The chemical composition of pharmaceuticals has to be considered at endoscopy and it is evident that some chemical substances damage the epithelial tissue and lead to clinical symptoms. Case Presentation: Endoscopy was performed in an 82-year-old patient due to gastroesophageal reflux symptoms and epigastric pain. Gastroscopy showed a hiatal hernia and a scarred duodenal bulb. More striking was the yellow-brownish discoloration of the gastric and the duodenal mucosa. The gastric antrum and the duodenal bulb showed local discoloration that could not be rinsed off. The medical history indicated that bromazepam (6 mg) had been used daily as a sleeping aid in the previous two years. The histopathological findings showed appearances of chemical gastritis. Within the lamina propria and on the epithelial surface there were granules. There was no foreign body reaction to these granules. Corpus mucosa showed a mild chronic gastritis. Conclusions: If discoloration of the mucosa at endoscopy is seen, a careful drug history must be sought. This is the first case in literature that shows a chemical gastritis after bromazepam intake. [ABSTRACT FROM AUTHOR]

The following table contains an overview of first published case reports of adverse drug reactions (ADRs) identified in the international literature in recent weeks by the drug safety alerting service Reactions Weekly. Summarising information selected from over 1700 biomedical publications, this newsletter is produced by Adis International Limited and is available in a variety of formats. Please contact your nearest Adis office for subscription details. [ABSTRACT FROM AUTHOR]

A study which developed a reverse phase high-performance liquid chromatographic (HPLC) method for in vitro dissolution test for the determination of bromazepam and its release from pharmaceutical dosage form is presented.

The article presents a double-blind trial of bromazepam, medazem and chlordiazepoxide. It aims to evaluate the effectiveness of the new tranquilizer agent, bromazepam. Under the study, benzodiazepine, bromazepam was compared with medazepam and chlordiazepoxide in the treatment of patients suffering from neurotic anxiety. Result shows that medazepam and bromazepam are more likely successful than chlordiazepoxide in relieving anxiety. The study also found that each drug have big differences in effectiveness for individual patients.