Protracted deep coma after bromazepam poisoning.

BACKGROUND: Bromazepam intoxication is very common but surprisingly rarely reported. CASE DESCRIPTION: We describe the case of a 73-year-old woman who suffered from a prolonged coma after acute self poisoning with bromazepam (serum concentration of 2,000 ng/ml at admission, 2 - 10 hours after ingestion of up to 180 mg) and zolpidem (900 ng/ml at admission). Only the former lasted at toxic concentrations. Recovery of consciousness allowed extubation on Day 16. Repeat-dose activated charcoal (25 g every 6 h from Day 14 to 16) resulted in minimal effects on bromazepam grossly estimated kinetics. CONCLUSION: Despite its relatively low theoretic half-life, bromazepam may induce a prolonged life-threatening coma, even in the absence of renal or hepatic failure.

Efectos del bromacepam en el desarrollo de una actividad sensoriomotora: un estudio electroencefalográfico / The effects of bromazepan on the performance of a sensory-motor activity: an electroencephalographic study

Objetivos. Investigar los efectos del uso del bromacepam en la potencia relativa en alfa durante la realización de unatarea de mecanografía. Teniendo en cuenta las particularidades de cada hemisferio cerebral, nuestra hipótesis era que a travésde la medida de la potencia relativa sería posible investigar el efecto del bromacepam sobre áreas corticales específicas. Concretamente,se esperaba observar diferentes patrones de potencias en los procesos de atención, activación e integración sensoriomotora.Sujetos y métodos. La muestra estaba formada por 39 sujetos (15 hombres y 24 mujeres) con una media de edad de30 ± 10 años. Los grupos control (placebo) y experimental (bromacepam de 3 mg y 6 mg) fueron entrenados en la tarea de mecanografíacon un modelo doble ciego aleatorizado. Resultados. Mediante el ANOVA de tres vías y el test de Scheffé se comprobaroninteracciones entre los factores condición y momento y entre condición y sector. Conclusión. Las dosis empleadas en esteestudio facilitaron el desarrollo motor de la tarea de mecanografía. En este estudio, el uso del fármaco no impidió el aprendizajede la tarea, pero parece ser que concentró el esfuerzo mental sobre aspectos más restringidos y específicos de la mecanografía.Tuvo lugar una influencia sobre el ritmo y la eficacia de las operaciones ejecutadas durante mecanismos de codificacióny almacenamiento de nuevas informaciones. Asimismo, se comprobó un predominio de actividad en el área frontal izquierda(dominante) en el grupo bromacepam 3 mg, lo cual indica que esta dosis del fármaco permite al sujeto un mayor direccionamientode la actividad cortical para la planificación y la ejecución de la tarea(AU)

Aims. To investigate the effects of using bromazepam on the relative power in alpha while performing a typing task.Bearing in mind the particularities of each brain hemisphere, our hypothesis was that measuring the relative power wouldallow us to investigate the effects of bromazepam on specific areas of the cortex. More specifically, we expected to observedifferent patterns of powers in sensory-motor integration, attention and activation processes. Subjects and methods. The samplewas made up of 39 subjects (15 males and 24 females) with a mean age of 30 ± 10 years. The control (placebo) and experimental(3 mg and 6 mg of bromazepam) groups were trained in the typing task with a randomised double-blind model. Results. A threewayANOVA and Scheffé test were used to analyse interactions between the factors condition and moment, and betweencondition and sector. Conclusions. The doses used in this study facilitated motor performance of the typing task. In this study,the use of the drug did not prevent learning of the task, but it did appear to concentrate mental effort on more restricted andspecific aspects of typing. It also seemed to influence the rhythm and effectiveness of the operations performed duringmechanisms related to the encoding and storage of new information. Likewise, a predominance of activity was observed in theleft (dominant) frontal area in the 3 mg bromazepam group, which indicates that this dose of the drug affords the subject agreater degree of directionality of cortical activity for planning and performing the task(AU)

The bioavailability of bromazepam, omeprazole and paracetamol given by nasogastric feeding tube.

AIMS: 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. METHODS: 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, AUC(0-infinity), t(1/2), k(e), tmax) were compared statistically, and Cmax, AUC(0-infinity) and t(max) were analyzed for bioequivalence. RESULTS: A statistically significant difference was seen in the AUC(0-infinity) of bromazepam, with nasogastric administration decreasing availability by about 25%: AUC(OR) = 2501 ng mL(-1) h; AUC(NT) = 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: AUC(OR) = 579 ng mL(-1) h; AUC(NT) = 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: AUC(OR) = 37 microg mL(-1) h; AUC(NT) = 41 microg mL(-1) h(p > 0.05); ratio (geometric mean) = 1.12 (90% CI 0.98-1.28). CONCLUSION: 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.

Cardiac and peripheral blood similarities in the comparison of nordiazepam and bromazepam blood concentrations.

Concomitant heart and peripheral blood determinations were performed on 40 fatal cases involving nordiazepam (20 cases) and bromazepam (20 cases). The heart blood concentration for the two drugs (588 ng/mL for nordiazepam and 802 ng/mL for bromazepam) does not differ from the corresponding peripheral blood concentration (587 ng/mL for nordiazepam and 883 ng/mL for bromazepam). The mean ratios for the heart and peripheral blood concentrations were 0.95 for nordiazepam and 0.86 for bromazepam. No postmortem redistribution was observed for these two benzodiazepines. The authors thus suggest that corresponding heart blood can be proposed in the quantitative analysis of these drugs when peripheral blood is unavailable. The present study also shows the stability of the two drugs after a year of storage.

Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatrists.

Benzodiazepines are relatively well-tolerated medicines but can induce serious problems of addiction and that is why their use is regulated. However, in developing countries like Senegal, these products are used without clear indications on their prescription, their dispensation or their use. This work focuses on the prescription of these medicines with a view to make recommendations for their rational use. Benzodiazepine prescription was studied with psychiatrists or neurologists and generalists in 2003. Specialist doctors work in two Dakar university hospitals and generalists in the 11 health centres in Dakar. We did a survey by direct interview with 29 of 35 specialists and 23 of 25 generalists. All doctors were interviewed in their office. The questionnaire focused on benzodiazepine indications, their pharmacological properties, benzodiazepines prescribed in first intention against a given disease and the level of training in benzodiazepines by doctors. Comparisons between specialists and generalists were made by chi-square test. Benzodiazepines were essentially used for anxiety, insomnia and epilepsy. With these diseases, the most benzodiazepines prescribed are prazepam against anxiety and insomnia and diazepam against epilepsy. About 10% of doctors do not know that there is a limitation for the period of benzodiazepine use. The principal reasons of drugs choice are knowledge of the drugs, habit and low side effects of drugs. All generalists (100%) said that their training on benzodiazepines is poor vs. 62.1% of specialists, and doctors suggest seminars, journals adhesions and conferences to complete their training in this field. There are not many differences between specialists and generalists except the fact that specialists prefer prazepam in first intention in the insomnia treatment where generalists choose bromazepam. In addition, our survey showed that specialists' training in benzodiazepines is better than that of generalists. Overall, benzodiazepine prescription poses problems particularly in training, and national authorities must take urgent measures for rational use of these drugs.

On-line solid-phase extraction coupled with high-performance liquid chromatography and tandem mass spectrometry (SPE-HPLC-MS-MS) for quantification of bromazepam in human plasma: an automated method for bioequivalence studies.

A validated method for on-line solid-phase extraction coupled with high-performance liquid chromatography tandem mass spectrometry (SPE-HPLC-MS-MS) is described for the quantification of bromazepam in human plasma. The method involves a dilution of 300 muL of plasma with 100 muL of carbamazepine (2.5 ng/mL), used as internal standard, vortex-mixing, centrifugation, and injection of 100 muL of the supernate. The analytes were ionized using positive electrospray mass spectrometry then detected by multiple reaction monitoring (MRM). The m/z transitions 316-->182 (bromazepam) and 237-->194 (carbamazepine) were used for quantification. The calibration curve was linear from 1 ng/mL (limit of quantification) to 200 ng/mL. The retention times of bromazepam and carbamazepine were 2.6 and 3.2 minutes, respectively. The intraday and interday precisions were 3.43%-15.45% and 5.2%-17%, respectively. The intraday and interday accuracy was 94.00%-103.94%. This new automated method has been successfully applied in a bioequivalence study of 2 tablet formulations of 6 mg bromazepam: Lexotan(R) from Produtos Roche Químicos e Farmacêuticos SA, Rio de Janeiro, Brazil (reference) and test formulation from Laboratórios Biosintética Ltda, São Paulo, Brazil. Because the 90% CI of geometric mean ratios between reference and test were completely included in the 80%-125% interval, the 2 formulations were considered bioequivalent. The comparison of different experimental conditions for establishing a dissolution profile in vitro along with our bioavailability data further allowed us to propose rationally based experimental conditions for a dissolution test of bromazepam tablets, actually lacking a pharmacopeial monograph.

Determination of bromazepam in human plasma by high-performance liquid chromatography with electrospray ionization tandem mass spectrometric detection: application to a bioequivalence study.

A simple method using a one-step liquid-liquid extraction (LLE) followed by high-performance liquid chromatography (HPLC) with positive ion electrospray ionization tandem mass spectrometric (ESI-MS/MS) detection was developed for the determination of bromazepam in human plasma, using lorazepam as internal standard. The acquisition was performed in the multiple reaction monitoring mode, monitoring the transitions: m/z 316 > 182 for bromazepam and m/z 321 > 275 for lorazepam. The method was linear over the studied range (1-100 ng ml(-1)), with r(2) > 0.98, and the run time was 2.5 min. The intra- and inter-assay precisions were 2.7-14.6 and 4.1-17.3%, respectively and the intra- and inter-assay accuracies were 87-111 and 75.8-109.5%, respectively. The mean recovery was 73.7%, ranging from 64.5 to 79.7%. The limit of quantification was 1 ng ml(-1). At this concentration the mean intra- and inter-assay precisions were 14.6 and 7.1%, respectively, and the mean intra- and inter-assay accuracies were 102.5 and 104%, respectively. Bromazepam stability was evaluated and the results showed that the drug is stable in standard solution and in plasma samples under typical storage and processing conditions. The method was applied to a bioequivalence study in which 27 healthy adult volunteers (14 men) received single oral doses (6 mg) of reference and test bromazepam formulations, in an open, two-period, randomized, crossover protocol. The 90% confidence interval of the individual ratios (test formulation/reference formulation) for C(max) (peak plasma concentration), AUC(0-96) and AUC(0-inf) (area under the plasma concentration versus time curve from time zero to 96 h and to infinity, respectively) were within the range 80-125%, which supports the conclusion that the test formulation is bioequivalent to the reference formulation regarding the rate and extent of bromazepam absorption.

Bromazepam determination in human plasma by high-performance liquid chromatography coupled to tandem mass spectrometry: a highly sensitive and specific tool for bioequivalence studies.

A rapid, sensitive and specific method to quantify bromazepam in human plasma using diazepam as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by liquid-liquid extraction using diethyl ether-hexane (80 : 20, v/v). The extracts were analyzed by high-performance liquid chromatography (HPLC) coupled to electrospray tandem mass spectrometry (MS/MS). Chromatography was performed isocratically on a Genesis C(18) analytical column (100 x 2.1 mm i.d., film thickness 4 microm). The method had a chromatographic run time of 5.0 min and a linear calibration curve over the range 5.0-150 ng ml(-1) (r(2) > 0.9952). The limit of quantification was 5 ng ml(-1). This HPLC/MS/MS procedure was used to assess the bioequivalence of two bromazepam 6 mg tablet formulations (bromazepam from Medley SA Indústria Farmacêutica as the test formulation and Lexotan from Produtos Roche Químico e Farmacêutico SA as the reference formulation). A single 6 mg dose of each formulation was administered to 24 healthy volunteers (12 males and 12 females). The study was conducted using an open, randomized, two-period crossover design with a 3 week washout interval. Since the 90% CI for C(max), AUC(last), AUC(0-240 h) (linear) and AUC((0- infinity )) ratios were all inside the 80-125% interval proposed by the US Food and Drug Administration, it was concluded that the bromazepam formulation from Medley is bioequivalent to the Lexotan formulation for both the rate and the extent of absorption.

The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers.

RATIONALE AND OBJECTIVE: Bromazepam, an anti-anxiety agent, has been reported to be metabolized by cytochrome P(450) (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.

[Pharmacokinetics of bromazepam in 57 patients with acute drug intoxication].

Pharmacokinetic parameters of bromazepam were analyzed by 57 cases. The patients were admitted 7.3 +/- 8.9 hours (mean +/- S.D.) after ingestion of 88 +/- 127 mg bromazepam. Most patients had taken several drugs other than bromazepam and the number was 5.5 +/- 2.6 drugs. The serum bromazepam levels were 1,871 +/- 2,428 ng/ml and the elimination half-lives were 29 +/- 4 hours. Increased serum bromazepam levels were followed by extended elimination half-lives. There was no bromazepam toxic sign under 2,300 ng/ml. One case was treated with direct hemoperfusion and the therapy was effective.

Effect of fluconazole on the pharmacokinetics and pharmacodynamics of oral and rectal bromazepam: an application of electroencephalography as the pharmacodynamic method.

Quantitative analysis of electroencephalography (EEG) is used increasingly to evaluate the pharmacodynamics of benzodiazepines. The present study aimed to apply the EEG method as well as more traditional approaches to an interaction study of bromazepam and fluconazole. Twelve healthy male volunteers participated in a randomized, double-blind, four-way crossover study. The subjects received single oral or rectal doses of bromazepam (3 mg) after 4-day pretreatment of oral fluconazole (100 mg daily) or its placebo. Plasma bromazepam concentrations were measured before and 0.5, 1, 2, 3, 4, 6, 12, 22, 46, and 70 hours after bromazepam administration. Pharmacodynamic effects of bromazepam were assessed using self-rated drowsiness, continuous number addition test, and EEG. Fluconazole caused no significant changes in pharmacokinetics and pharmacodynamics of oral or rectal bromazepam. Rectal administration significantly increased AUC (1.7-fold, p < 0.0001) and Cmax (1.6-fold, p < 0.0001) of bromazepam. These changes following rectal dose may be due to avoidance of degradation occurring in the gastrointestinal tract. Rectal bromazepam also increased the area under the effect curves assessed by EEG (p < 0.05) and subjective drowsiness (p < 0.05). EEG effects were closely correlated with mean plasma bromazepam concentrations (r = 0.92, p < 0.001 for placebo; r = 0.89, p < 0.0001 for fluconazole). Thus, the EEG method provided pharmacodynamic data that clearly reflected the pharmacokinetics of bromazepam.

Comparative bioavailability of two oral formulations of bromazepam in healthy volunteers.

The aim of this study was to assess the pharmacokinetic profile of two bromazepam (CAS 1812-30-2) formulations in 24 healthy volunteers. An open, randomised clinical trial designed as two-period crossover with 14-day washout between doses was employed. Plasma samples for assessments of their bromazepam concentration by HPLC-UV were obtained over 96 h after administration. No adverse effect was reported for any of the formulations administered. The following pharmacokinetics parameters were calculated: AUC(0-96 h), AUCinf, Cmax, Tmax, Ke and T1/2. The 90% confidence intervals (CI) for the mean test/reference individual ratios were 81-109 for AUC and 84-116 for Cmax. Since the 90% CI for both, AUC and Cmax ratios were within the 80-125% interval proposed by the Food and Drug Administration, it is concluded that the new bromazepam slow-release formulation is therapeutic equivalent to the conventional formulation for both, the extent and the rate of absorption after single dose administration in healthy volunteers.

Sensitive determination of bromazepam in human tissues using capillary gas chromatography-mass spectrometry.

A reliable and sensitive gas chromatographic-mass spectrometric method was devised to determine the levels of bromazepam in human tissues. Bromazepam was extracted from body tissues using a three-step solvent extraction procedure. N-Desmethyldiazepam served as the internal standard. Selected ion monitoring with m/z 317 for bromazepam and m/z 270 for internal standard was used for quantitation. Calibration curves in all body tissues were linear over the concentration range from 50-500 ng/g. The lower detection limit in body tissues was 2-5 ng/g and the absolute recovery in body tissues was 27.8-68.0%. This method was used to determine the levels of bromazepam in tissues of an autopsied individual who had been prescribed psychotropic drugs and who was found dead in a car.

Considerable cost savings through the analysis of pooled plasma samples in bioequivalence studies that fail to show bioequivalence.

A major part of the cost of bioequivalence studies is due to the drug assays of the individual plasma samples collected from each volunteer. Considerable savings in manpower, time, and especially costs could be achieved if it could be determined before the individual plasma samples are assayed that bioequivalence can not be shown. Such information can in fact be obtained through the analysis of pooled plasma samples. We propose an approach where pooled plasma samples are assayed and the resulting pooled drug concentration profiles for the test and reference product are compared. If this comparison indicates that one will not be able to show bioequivalence in the statistical analysis of the individual data, the individual plasma samples are not assayed. Thus more than 40% of the cost of a bioequivalence study that fails to show bioequivalence can be saved.

Interaction of metoprolol with lorazepam and bromazepam.

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.

Effect of food on the bioavailability of bromazepam following oral administration in healthy volunteers.

The effect of food on the rate and extent of bioavailability of bromazepam was examined in seven normal volunteers following a single oral dose of 10 mg bromazepam with 200 ml of water in the fasting and non-fasting states. Plasma concentrations of bromazepam were measured by high pressure liquid chromatography. A tmax value in a non-fasting state was prolonged from 2.3 +/- 0.3 (mean +/- S.E.M.) to 2.8 +/- 0.6 h but not significantly different (p greater than 0.05) whereas a Cmax value was significantly (p less than 0.05) decreased from 259 +/- 12.7 (mean +/- S.E.M.) to 169 +/- 13.9 ng/ml. The area under the plasma concentration-time curve in the non-fasting state was also significantly (p less than 0.05) decreased from 1844 +/- 145 (mean +/- S.E.M.) to 1233 +/- 98.1 ng.h/ml after oral administration of bromazepam.

[Determination of the optimal dose of bromazepam in the elderly]. / Recherche d'une posologie optimale du bromazépam chez le sujet âgé.

The aim of our study was to determine in patients over 70 years, the optimal dose of Bromazepam. Seven patients were administered a unique dose of Bromazepam (3 mg), then repeated doses (1.5 mg) every 12 hours for 9 days. Cmax was 42.5 +/- 12 ng/ml in Tmax ranged from 2 to 12 hours after the first dose-concentrations of Bromazepam at steady-state were between 79 and 157 ng/ml. Half life was 30.5 +/- 14.7 hrs for the unique and the repeated doses. Sleeping was noted for concentrations over 40 ng/ml. The dose of 1.5 mg bid is recommended in old patients.

Acute effects of bromazepam on signal detection performance, digit symbol substitution test and smooth pursuit eye movements.

Effects of 6 and 12 mg bromazepam on reaction time, stimulus sensitivity and response bias in a 1-hour visual attention task, on smooth pursuit eye movements, and on performance in the digit symbol substitution test (DSST) were investigated in 12 healthy male volunteers. It was a placebo-controlled, double-blind, crossover study that used repeated measures. Three saliva samples and a blood sample were taken for correlating drug concentration and performance. Bromazepam lowered stimulus sensitivity dose-dependently. Response times for hits and response bias were affected by the 12-mg dose only. DSST performance decreased dose-dependently. Smooth pursuit was equally impaired by 6 and 12 mg. Concentrations in serum correlated with concentrations in saliva, but serum and saliva concentrations did not correlate with task performance.