Assessing the cumulative effects of exposure to selected benzodiazepines on the risk of fall-related injuries in the elderly.

BACKGROUND: The use of benzodiazepines is associated with increased risk of fall-related injuries in the elderly. However, it is unclear if the risks vary across the products and how they depend on the pattern of use and dosage. Specifically, the possibility of cumulative effects of past benzodiazepine use has not been thoroughly investigated. METHODS: We used the administrative database for a cohort of 23,765 new users of benzodiazepines, aged 65 years and older, in Quebec, Canada, between 1990 and 1994. The associations between the use of seven benzodiazepines and the risk of fall-related injuries were assessed using several statistical models, including a novel weighted cumulative exposure model. That model assigns to each dose taken in the past a weight that represents the importance of that dose in explaining the current risk of fall. RESULTS: For flurazepam, the best-fitting model indicated a cumulative effect of doses taken in the last two weeks. Uninterrupted use of flurazepam in the past months was associated with a highly significant increase in the risk of fall-related injuries (HR = 2.83, 95% CI: 1.45-4.34). The cumulative effect of a 30-day exposure to alprazolam was 1.27 (1.13-1.42). For temazepam, the results suggested a potential withdrawal effect. CONCLUSIONS: Mechanisms affecting the risk of falls differ across benzodiazepines, and may include cumulative effects of use in the previous few weeks. Thus, benzodiazepine-specific analyses that account for individual patterns of use should be preferred over simpler analyses that group different benzodiazepines together and limit exposure to current use or current dose.

Chemical gastritis after chronic bromazepam intake: a case report.

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.

[Anxiety level and addiction to first-time prescriptions of anxiolytics: a psychometric study]. / Niveau d'anxiété et de dépendance des primoconsommants d'anxiolytiques: une étude de psychométrie.

CONTEXT: The anxiety epidemic and its corollary, the widespread prescription of anxiolytics, present a public health problem in view of the risk of addiction to these drugs. OBJECTIVE: To assess the level of anxiety and addiction in the borderline population at risk of addiction. DESIGN: The study analyzed a series of patients in the third month of their first prescription for anxiolytics. It used two validated scales: the Hospital Anxiety and Depression scale (HAD), and a French scale measuring addiction (the "Echelle Cognitive d'Attachement aux Benzodiazepines" or ECAB). RESULT: 83% of patients were still anxious at the third month of treatment. 23% had become addicted. DISCUSSION: There is a contradiction between the prolonged prescription and use of anxiolytics, which are associated with a risk of addiction, and professional guidelines that recommend short treatment for outpatients using these drugs for the first time.

[Drug-facilitated crime and sexual abuse: a pediatric observation]. / Soumission chimique et agression sexuelle chez l'enfant: à propos d'une observation.

Drug-facilitated crime in sexual assault situations remains insufficiently recognized by physicians. In the possible context of an assault and in front of recent neuropsychicological disturbances in a child, such an issue has to be considered. The quality of sampling, the use of ultra-sensitive and specific toxicologic methods and a clinical-biological collaboration allow to recognize this form of delinquency whose consequences are both medical and legal.

[Fixed drug eruption : about 13 cases]. / Erytheme pigmente fixe. A travers une serie hospitaliere de 13 cas.

AIM: To discuss, through a retrospective study, the epidemiological and clinical aspects and the causative agents of fixed drug eruption. METHODS: Thirteen cases were collected retrospectively during 11 years. There were 10 females and 3 males with a mean age of 44 years. RESULTS: The lesions correspond to erythematous plaques which fade to leave slate-brawn macules in all cases. The most frequent localizations were limbs (12 cases), trunk (6 cases), face (3 cases) ans external genitals (3 cases). Sulfonamides were the most frequent responsible drugs in our series (7 cases). CONCLUSION: Fixed drug eruption is characterized by one or more erythematous plaques which recur in the same places after challenge. Sulfonamides are actually the most frequent causative drugs in the different series.

[Treatment of hydroxychloroquine poisoning with extracorporeal circulation]. / Traitement d'une intoxication à l'hydroxychloroquine par circulation extracorporelle.

We report a case of massive overdose of hydroxychloroquine treated with circulatory assistance by peripheral extracorporeal circulation (ECC). We expose the case of a 39-year-old woman who ingested 12 g of hydroxychloroquine with bromazepam, paroxetine, and zolpidem, in a suicide attempt. Patient has developed central nervous system depression, hemodynamic failure, life-threatening ventricular arrhythmias, and serious hypokalemia. Initially the patient has received conventional treatment with gastric lavage and activated charcoal for gastrointestinal decontamination, blood volume expansion and vasopressive drugs, intubation and mechanical ventilation, high dose of diazepam, and potassium replacement. A ventricular fibrillation was treated with external cardiac massage. In spite of this treatment, cardiogenic shock was uncontrolled, and imposed circulatory assistance. After extracorporeal circulation, we observed a spectacular improvement of hemodynamic parameters and electrocardiographic normalization at day one. Extracorporeal circulation could be used as a rescue treatment of cardiotrope and hydroxychloroquine overdoses.

[The effects of bromazepam on contingent negative variation and reaction time in a visuomotor task]. / Efectos del bromacepam sobre la variación negativa contingente y el tiempo de reacción en una tarea visuomotora.

INTRODUCTION: Bromazepam is the second most commonly used benzodiazepine in Brazil. Psychophysiological research on this substance is still in its early stages. AIM: To determine the neurotoxicity of bromazepam by examining reaction times (RT) and contingent negative variations (CNV). SUBJECTS AND METHODS: Using a videogame produced in our laboratory for psychophysiological research purposes (Car Acquisition), 14 healthy volunteers (9 males) aged between 23 and 42 drove a vehicle along a road full of curves (i.e. distractors) while they had to respond to imperative stimuli (i.e. orders to press the button on the joystick) that were preceded by warnings (S1-S2-RM paradigm with distractor). We compared RT, amplitudes and latencies of the CNV at each of the three electrodes on the median line (Fz, Cz and Pz) one hour after random, double-blind and crossed administration of placebo (P), 3 mg of bromazepam (B3) or 6 mg of bromazepam (B6) on different days. STATISTICS: one-way ANOVA and Post Hoc Scheffé. RESULTS: No significant differences were observed in the RT. At Pz, the CNV amplitudes displayed significant differences for P, B3 and B6 (p = 0.006), and also for B3 and B6 (p = 0.018), with B6 > B3 = P. At Fz, a non-significant tendency (p = 0.074) suggested a difference between the latencies, shorter in B6 than in B3 (p = 0.098), both equivalent to placebo. The mean amplitudes ranged between 2.4 and 5.9 microV. CONCLUSIONS: Behavioural and neurophysiological neurotoxicity was insignificant one hour after administration of a single 3 or 6 mg dose of bromazepam in healthy young adults. Low mean amplitudes were compatible with the interference from distractors and did not result in floor effect.

Methcathinone: a new postindustrial drug.

Methcathinone, a methyl derivative of cathinone, is an illicit drug also known as ephedrone. It is a stimulant found in the "khat" plant, Catha edulis, which can easily be synthesized from pseudoephedrine. Its intoxication is difficult to diagnose and cure properly for two reasons: (i) target consumers are usually "well-educated people" aware of the risks and precautionary measures and (ii) intoxication by cathinone derivatives of synthetic or natural (derived from the khat) origin induce misleading symptoms. As a result, documented reports of methcathinone intoxication that are based on reliable analyses are rare. This paper describes a case of reiterated coma due to an overdose of methcathinone dissolved in alcohol that was taken with bromazepam. A 29-year-old woman was admitted to an emergency department for a coma of toxic origin. Medical files showed that it was her second such episode to occur that month. Moreover, the family indicated signs of depression, incoherent behaviour and intake of "amphetamine-like" drugs. Clinical examination revealed a Glasgow coma score of 9, symmetrical reactive pupils with mydriasis and no convulsions. The patient presented with rapid respirations and her blood pressure was 93/53 mmHg. The ionogram and the blood gas analyses were normal, while the blood alcohol level was 0.167 g/dL. Urinalysis revealed the presence of benzodiazepines and a high concentration of amphetamines (methcathinone: 17.24 mg/L, ephedrine: 11.60 mg/L and methylephedrine: 11.10 mg/L). In addition, serum analysis revealed bromazepam (8.89 mg/L), methcathinone (0.50 mg/L) and methylephedrine (0.19 mg/L). This case showed that the consumption of bromazepam and alcohol altered the typical clinical symptoms of cathinone derivative intoxication, namely hypertension and convulsions. Methylephedrine, an impurity resulting from the alkylation of a primary amine, can be considered a chemical tag indicating fraudulent synthetic origin of the drug. This case describes a documented example of new addictive behaviour of "well-educated" people involving the intake of methcathinone, a postindustrial psychostimulant intentionally combined with an anticonvulsant benzodiazepine. However, this specific case suggests that in spite of a very high bromazepam concentration in presence of the potentiator alcohol, the vital respiratory function would be probably maintained, thanks to the association with methcathinone.

Impaired hypothalamic-pituitary-adrenocortical (HPA) system is related to severity of benzodiazepine withdrawal in patients with depression.

A concatenation of data indicates that the pathogenesis of depression is related to an increased production and secretion of corticotropin-releasing hormone (CRH). Benzodiazepines profoundly suppress the basal and stress-related activation of the hypothalamic-pituitary-adrenocortical (HPA) system and discontinuation of these drugs results in rebound activation. We therefore investigated whether the extent of HPA system dysregulation is related to the severity of benzodiazepine withdrawal in patients with depression. We performed the combined dexamethasone/CRH test before benzodiazepine discontinuation (taper-off max. 5 mg diazepam-equivalents/week) in 14 depressed patients (13 f, 1 m, mean age 54.6 +/- 14.6) who responded to the antidepressant treatment. The severity of withdrawal symptoms was measured using the Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) questionnaire. The depressive psychopathology was monitored using the Hamilton Depression Rating Scale, Montgomery Asberg Depression Rating Scale and Beck Depression Inventory. Patients with more severe benzodiazepine withdrawal (CIWA-B-increase > 14 pts; n = 7) showed a significant higher cortisol and ACTH response in the dexamethasone/CRH test preceding the discontinuation of benzodiazepines than patients displaying less severe withdrawal symptoms (CIWA-B-increase <14 pts.; n = 7) (ANCOVA, p < 0.05). Both groups did not differ in the pre-taper psychopathology ratings and their basal neuroendocrine activity. In view of the GABAergic inhibition of HPA system activity and the anxiogenic effect of CRH, benzodiazepine withdrawal symptoms may be partly due to a disinhibition of the HPA system during discontinuation of benzodiazepines.

Drug-induced sweat gland necrosis in a non-comatose patient: a case presentation.

BACKGROUND: Coma-induced bullae and sweat gland necrosis is a rare clinicopathological entity often associated with drug-induced coma. SUBJECT: We report a case with clinical and histopathologic findings characteristic of blisters and sweat gland necrosis occurring in a non-comatose patient. CONCLUSIONS: Skin blisters with underlying sweat gland necrosis is an entity previously reported to occur in comatose patients, our findings open new questions about the role of the drugs in the pathogenesis of those conditions.

[A case of Parkinson syndrome secondary to combined amineptine and bromazepam abuse]. / Un cas de syndrome parkinsonien secondaire à la surconsommation d'amineptine et de bromazépam.

A case report of parkinsonism secondary to chronic abuse of amineptine (3 gr/day) and bromazepam (35 mg/day) in a patient diagnosed of borderline personality disorder is presented. The patient did not take any other drugs and he was not recently on neuroleptic treatment; he recognized the abuse of amineptine, as a stimulant, and the bromazepam abuse, looking for a relief to the excessive anxiety secondary to amineptine. The parkinsonism improved after removing both drugs and taking biperiden and diazepam; lastly the patient was discharged without any medication. The patient did not suffer from other complications associated with amineptine or bromazepam abuse. There are some cases reported of parkinsonism secondary to benzodiazepines but there is none secondary to amineptine. We present a short review of the possible responsible mechanisms, thinking on a complex interaction of both drugs on dopamine and its modulatory systems.

[Comparative study for assessing quality of life of patients with exogenous sleep disorders (temporary sleep onset and sleep interruption disorders) treated with a hops-valarian preparation and a benzodiazepine drug]. / Vergleichsstudie zur Untersuchung der Lebensqualität von Patienten mit exogenen Schlafstörungen (vorübergehenden Ein- und Durchschlafstörungen) unter Therapie mit einem Hopfen-Baldrian-Präparat und einem Benzodiazepin-Präparat.

This randomized, double-blind, controlled clinical trial in parallel group design demonstrated equivalent efficacy and tolerability of a hop-valerian preparation compared with a benzodiazepine preparation in patients suffering from sleep disorders according to DSM-IV criteria. Sleep quality, fitness and quality of life were determined by psychometric tests, psychopathologic scales and sleep-questionnaires at the beginning of the therapy, end of therapy (duration 2 weeks) and then 1 week after cessation of therapy. Patients' state of health (4-point scale) and medication tolerability (occurrence of adverse events) were documented. Using the following as parameters "Alphabetischer Durchstreichtest, Feinmotoriktest, Befindlichkeitsskala, Beschwerdeliste, Schlaffragebögen A and B" the differences between beginning and the end of the therapy were analyzed by simultaneous testing of the equality or superiority of the test preparation. The equivalence of both therapies according to sleep quality, fitness and quality of life was proven by a Mann-Whitney-Statistic of 0.50 with a lower boundary of the 95% confidence interval of 0.46. The patients' state of health improved during therapy while showing a deterioration after cessation with both preparations. Withdrawal symptoms, however, were documented with benzodiazepine. Only one adverse drug reaction was reported during this study, namely stomach complaints from both the test and reference medication. This study shows that the investigated hop-valerian preparation in the appropriate dose is a sensible alternative to benzodiazepine for the treatment of nonchronic and non-psychiatric sleep disorders.

[Benzodiazepine withdrawal presenting as pseudo-surgical abdominal pain]. / Sevrage en benzodiazépines révélé par un syndrome douloureux abdominal pseudochirurgical.

A 39-year-old patient was admitted to the emergency department for acute abdominal pain. Physical examination showed a peritoneal syndrome. However, CT-scan, Doppler and blood analysis were unremarkable. As the patient had a history of auto-medication with benzodiazepines at high doses, a withdrawal syndrome was considered. An intravenous administration of 3 mg of midazolam determined the relief of all symptoms in a few minutes.