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.

[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.

[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.

Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment.

In this double-blind, placebo-controlled study of 4 weeks of benzodiazepine treatment followed by 3 weeks of abrupt or gradual drug withdrawal, 16 patients whose benzodiazepine was withdrawn abruptly were worse (p less than .05) than 13 who had received placebo in terms of change in mean anxiety scores from the pretreatment level. The scores of seven patients (44%) whose benzodiazepine was withdrawn abruptly increased 10% or more on both the Hamilton Rating Scale for Anxiety and the Self Rating Symptom Scale. There were no cases of rebound anxiety in 14 patients whose benzodiazepine was withdrawn gradually; fewer cases of rebound anxiety were seen with a benzodiazepine that had a long half-life.

Comparison of tenoxicam and bromazepan in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial.

Fibromyalgia is a painful syndrome of non-articular origin, predominantly involving muscles, and the commonest cause of chronic widespread musculoskeletal pain. The diversity of therapeutic programs for patients with fibromyalgia reflects both the lack of a known pathophysiology for this disorder and the low efficacy of the current therapies. We studied the efficacy of tenoxicam and bromazepan in the treatment of patients with fibromyalgia. One hundred and sixty-four patients from our Rheumatology Outpatient Clinic fulfilling the American College of Rheumatology criteria for the classification of fibromyalgia, with widespread pain at study entry. Each of the 164 patients was randomly assigned to 1 of 4 treatment groups: double placebo (P), tenoxicam (20 mg) + placebo (T), bromazepan (3 mg) + placebo (B)m or tenoxicam (20 mg) + bromazepan 3 mg (TB). Patient global assessment of disease, pain, sleep quality, morning stiffness, and number of tender points were evaluated at baseline and 8 weeks afterwards. At the end of the trial, 17%, 10%, 12%, and 29% of the P, T, B, and TB patients, respectively, had clinical improvement. A statistically significant difference was found only between the T and TB groups. Our data indicate that treatment with tenoxicam + bromazepan can be effective for some patients with fibromyalgia, but the differences with the placebo group were neither clinically nor statistically significant.

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.

Bromazepam in generalized anxiety. Randomized, multi-practice comparisons with both chlorprothixene and placebo.

Bromazepam was compared with placebo and with chlorprothixene in a randomized, double-blind group-comparative multicenter trial in general practice. Two hundred and forty-five patients with generalized anxiety disorder (DSM-III 1980) were treated for 2 weeks with two daily doses of bromazepam, 3 mg or chlorprothixene, 15 mg or placebo. Median reductions in Hamilton Anxiety rating were 12 (bromazepam), 10.3 (chlorprothixene) and 7.3 (placebo). The study revealed significant superiority of bromazepam over placebo (median differences 3.3, 95% confidence limits: 0.3 and 6.1) but not over chlorprothixene (median difference 1.4, 95% confidence limits -0.8 and +3.5). Significantly higher rates of tiredness, sedation and hypersomnia were found on bromazepam and chlorprothixene compared to placebo. Tolerance was rated as "at least good" in 85.6% on bromazepam, in 86% on chlorprothixene and in 87.8% on placebo. Neither previous psychopharmacological treatment nor presence of psychosocial stress were of perceptible influence. Bromazepam and chlorprothixene are both superior to placebo in generalized anxiety states treated in general practice, but spontaneous improvements/placebo effects are substantial.

Bromazepam: acute benefit-risk assessment in general practice.

A study was carried out in general practice to assess the benefit-risk ratio of a single new drug, bromazepam, prior to marketing. Analysis of data supplied by 393 participating doctors on 3101 patients showed that bromazepam, in a dose range of 3 mg to 9 mg daily in divided doses, was effective as an anxiolytic in 79% of the patients and that the acute risk of treatment was predictable and low. It is concluded that the acute benefit-risk ratio is acceptable with respect to the class of drug and indication for which bromazepam is prescribed.

A multi-centre, double-blind parallel trial of bromazepam ('Lexotan') and lorazepam to compare the acute benefit-risk ratio in the treatment of patients with anxiety.

A double-blind, multi-centre study was carried out in general practice to compare the efficacy and tolerance of treatment with bromazepam and lorazepam in 671 patients with anxiety. Patients were treated at random with either bromazepam (3 to 9 mg per day) or lorazepam (1 to 3 mg per day) for periods up to 2 weeks. In the doctors' global assessment of response, significantly more patients improved on bromazepam (84%) compared with lorazepam (77%). Thirty-three percent of the bromazepam patients reported at least one unwanted event compared with 37% in the lorazepam group. The results are discussed in the context of improving the benefit-risk ratio.

Bromazepam-induced dystonia.

Benzodiazepines are drugs with a good tolerance that are widely used for the treatment of anxiety. Extrapyramidal side-effects are unusual. Diazepam is effective for the treatment of drug-induced dystonias, nevertheless there are some reports of Diazepam-induced dystonia. We report a case history of a patient who developed oromandibular dystonia after taking Bromazepam. The possible mechanisms that cause drug-induced dystonia are described.

Fatal complications of neuroleptic drugs. A clinico-pathological study of three cases.

We report three cases of fatal hyperthermia in the course of neuroleptic drug treatment. One patient developed his symptoms within hours after a single drug dose whereas the two others had a prolonged symptomatology which lasted for several days after the administration of different neuroleptic drugs. Biochemical events included diffuse intravascular coagulation, muscle cell necrosis and acute renal failure. Rhabdomyolysis was proved pathologically in two patients but brain lesions were atypical in all three cases. We conclude that the biochemical and pathological abnormalities seen in these patients are those which have been described by some authors in the malignant hyperthermia syndrome after anaesthesia. The symptomatology however can be insidious and the syndrome can develop after withdrawal of the drugs.

Improved control of nausea and emesis with a new bromazepam-containing ondansetron regimen in ovarian cancer patients receiving chemotherapy with carboplatin and cyclophosphamide.

BACKGROUND: Ondansetron was found to be effective as an antiemetic in numerous clinical trials of highly emetogenic combination-chemotherapy regimens that included cisplatin. Its role in milder emetogenic regimes has not been fully defined. METHODS: This study investigated the efficacy of two different antiemetic regimes in thirty-five patients with ovarian cancer receiving 68 cycles of chemotherapy with carboplatin (350 mg/m2) and cyclophosphamide (600 mg/m2). Ondansetron (3 x 8 mg i.v.) was compared to a bromazepam-containing ondansetron regimen. RESULTS: Nausea was absent in 65% of chemotherapy courses in patients receiving the combination of ondansetron and bromazepam and in 38% of chemotherapy courses in patients receiving ondansetron alone. Complete control of emesis was achieved in 93% of the courses in patients receiving the combination and in 81% of the courses using ondansetron alone. CONCLUSIONS: The addition of bromazepam to ondansetron, and the extension of antiemetic prophylaxis to the day before and the day after chemotherapy improves the control of nausea and emesis compared to ondansetron monotherapy in patients with ovarian cancer.

Clinical experience with Ro 5-3350 (bromazepam).

A pilot study using Ro 5-3350 was followed by a double-blind trial comparing Ro 5-3350 and chlordiazepoxide in a total of 25 patients who were either hospital in-patients or previous in-patients attending an out-patients follow-up clinic. The patients all had a long history of obsessive-compulsive or phobic symptoms. The visual analogue scale, the Taylor Manifest Anxiety Scale and clinical ratings were used to measure the response to treatment. In all three rating methods used, those patients who had received Ro 5-3350, chlordiazepoxide and then Ro 5-3350 in that order, consistently favoured Ro 5-3350. When the clinical ratings were examined by diagnostic groups, it was found that the phobic patients all gave favourable responses to Ro 5-3350. Two of the six patients with severe anxiety or agoraphobic states who had been treated with Ro 5-3350 over periods ranging from three to five years received the medication during the whole term of pregnancy and they were delivered of full-term normal babies. The results suggest that Ro 5-3350 (bromazepam) is a potent anxiolytic most likely to be effective in the relief of visceral manifestations of anxiety. The incidence of side-effects was low and there were no toxic effects reported.

[Bromazepam in the treatment of somatized psychogenic disorders (author's transl)]. / Bromazepam in der Behandlung psychogener Störungen mit Somatisierungstendenz.

The clinical effects are reported of the benzodiazepine derivative, bromazepam (Lexotanil) in the treatment of psychosomatic disorders in the course of neurotic, psychovegetative, and masked depressive syndromes. The drug was administered orally in 301 patients (178 males, and 123 females). Target symptoms were anxiety, tension, and varied organic dysfunction of psychogenic origin. The optimum daily dosage was three times 3 mg; the duration of treatment ranged from 1 week to 34 months. The effect of treatment was considered excellent in 51.5%, good in 42.5%, moderate in 2%, and absent in 4%. The most responsive target symptoms were psychogenic disorders of the cardiovascular system and of the gastrointestinal tract, as well as anxiety, while no true antidepressive effect was observed. Drug tolerance is excellent. Slight fatigue, vertigo or a mild reduction in psychomotor activity were complained of by about 10% of the patients and usually occurred with daily doses of 18 mg or more, whereas no other side effects were observed. There was no obvious tendency to drug dependence even after after long-term treatment of up to 34 months. Bromazepam appears to be a superior compound to other anxiolytic and psychovegetatively active minor tranquillisers on account of its mild hypnotic action. Its anxiolytic effect causes additional indirect sleep induction in the above-mentioned conditions.