Blood concentrations of clobazam and norclobazam in a lethal case involving clobazam, meprobamate and clorazepate.

Clobazam is a benzodiazepine with anti-anxiety and anticonvulsant properties marketed in several countries. Norclobazam, a metabolite of clobazam, has similar pharmacological activity but weaker sedative and tranquilizing effect. The two drugs were detected by GC-MS and determined by HPLC-DAD in the samples from a postmortem case. The femoral blood concentrations of clobazam and norclobazam were 0.72 and 36 µg/mL, respectively. The concentration of the active norclobazam was very high. The sum of both clobazam and norclobazam blood concentration (36.72 µg/mL) was clearly toxic, but was not necessarily fatal. Other associated drugs concentrations were within their therapeutic ranges. Interactions due to drug association were discussed.

[Benzodiazepine poisoning in a neonate: clinical and toxicokinetic evaluation following enterodialysis with activated charcoal]. / Intoxication par les benzodiazépines chez un nouveau-né: évaluation clinique et toxicocinétique de l'entérodizlyse par le charbon activé.

CASE REPORT: A pregnant woman who was a regular user of anxiolytics was admitted to the maternity ward at 38 weeks and 4 days amenorrhea after a massive overdose of clorazepate dipotassium, a benzodiazepine. The exact quantity ingested was undetermined. The infant, born at 39 weeks, presented no spontaneous breathing and tracheal intubation was necessary in the delivery room. The neonatal blood concentrations of the clorazepate metabolites were very high at delivery (26 mg/l nordiazepam and 3.5 mg/l oxazepam) and showed little change over the next 5 days (16 mg/l nordiazepam and 2.1 mg/l oxazepam, with an apparent half-life of 168 h for nordiazepam and 160 h for oxazepam). By day 6, the infant was still dependent on ventilator support and enterodialysis was begun with repeated doses of activated charcoal (1 g/kg every 6 h by gastric tube). Treatment was continued for 5 days and a spectacular diminution in the serum concentrations of the two metabolites was noted on day 11: 1.5 mg/l nordiazepam and less than 0.1 mg/l oxazepam. The nordiazepam and oxazepam half-lifes were reduced to 42 h and 30 h respectively. The concomitant clinical improvement authorized the weaning from ventilation on day 12. CONCLUSION: This is the first report of the use of enterodialysis to treat severe benzodiazepine poisoning in a neonate. Depuration of the toxin was accelerated and the duration of intensive care was shortened thanks to this technique.

[Investigations of poisonings with benzodiazepine derivatives mixtures by thin-layer chromatography]. / Apsinuodijimu alprazolamu, brotizolamu ir klorazepato dikalio druskos misiniu tyrimas plonasluoksnes chromatografijos metodu.

The thin-layer chromatography method was proposed for separation and identification of drugs in mixture alprazolam : brotizolam : clorazepate dipotassium. The mixture of these drugs excreted from body fluid (blood) was investigated by the thin-layer chromatography. Most acceptable is this mobile phase : benzene : dioxane : conc. ammonia : methanol : ethanol (60:25:5:10:10). Rf values for drugs: alprazolam 0.81-0.83, brotizolam 0.59-0.62, clorazepate dipotassium 0.67-0.69.

Very long half-life of paroxetine following intoxication in an extensive cytochrome P4502D6 metabolizer.

A very long half-life of paroxetine (195 h instead of the usual value of around 16 h) was measured after an overdose with 2 g paroxetine and 1 g clorazepate in a patient who was an extensive cytochrome P4502D6 metabolizer. The patient recovered well without any clinically significant complications. A consequence of the close monitoring of paroxetine levels in this patient was that it was decided not to reintroduce any other antidepressant despite her suicide attempt, until normal levels of paroxetine had been reached, which took over 1 month.

[The stumbling toddler]. / De zwalkende kleuter.

Four previously healthy children, two boys aged 5 and one boy and one girl aged 4 more or less acutely developed a stumbling gait. The causes varied from benign such as postviral acute cerebellar ataxia and benign paroxysmal vertigo to potentially life-threatening such as intoxication with benzodiazepines and medulloblastoma. Treatment led to complete or partial recovery. (Sub)acute balance disorders in previously healthy children can be due to cerebellar ataxia, vestibular disorders and abnormal proprioception. Ancillary investigations are warranted in case of gradually developing ataxia, accompanying neurological deficits, suspicion of intoxication, recurrent or familial ataxia, no spontaneous remission or even progression. In children with an isolated cerebellar ataxia without these features, ancillary investigations may be avoided, although in such cases careful follow-up remains necessary.

[Mixed benzodiazepine poisoning and reversal with flumazenil (Ro 15-1788)]. / Intoxicación benzodiacepínica mixta y reversión por flumacenil (Ro 15-1788).

A case of 17 year old female with acute benzodiazepines (800 mg of bentazepan and 400 mg de chlordiazepoxide) and tricyclic antidepressants (500 mg of imipramine) self poisoning is reported. Initial examination showed comatous patient (Glasgow coma scale 7, sedation scale 4) and a critical respiratory failure with a suspicious of pulmonary aspiration of gastric contents. Supportive measures were started and flumazenil administered intravenous (0.1 mg/min) until a total dose of 1.2 mg; 15 minutes later neurological state was absolutely normal. We conclude that flumazenil is a selective and useful benzodiazepine antagonist in the treatment of acute benzodiazepine poisoning.

Serum diazepam concentrations in overdose. Their significance.

Total serum benzodiazepine concentrations were correlated with clinical manifestations in 93 cases of diazepam overdose. Diazepam and nordiazepam were also each separately determined in 101 serum specimens from cases of diazepam overdose, including 27 cases from the aforementioned clinical correlation study. In addition, serum nordiazepam concentrations were measured in five cases of chlorazepate overdose. Concentrations of total benzodiazepine ranged from 1 to 22 microgram/ml. All patients survived with supportive therapy only. Each of the 25 patients who had ingested only diazepam was awake or in grade 0 coma, even when drug concentrations were ten-fold greater than the accepted upper limit of the therapeutic range. None of the patients who had ingested only diazepam needed hospitalization; all were discharged from acute medical care after a period of emergency room observation. The ratios of parent drug to N-desmethyl metabolite (nordiazepam) in those overdose specimens analyzed by gas chromatography averaged 3:1. This high ratio may be useful in differentiating acute overdose from high concentrations resulting from chronic therapy. Although determination of diazepam concentrations aid in establishing that an overdose has occurred, when more than grade I or II coma is present, other drugs or an alternative explanation should be sought, regardless of the drug concentration.