Accidental acute clidinium toxicity.

Clidinium bromide (N-methyl-quinuclidinyl-benzylate) is a rarely used antimuscarinic drug that is marketed in combination with chlordiazepoxide as an antispasmodic for use in irritable bowel syndrome. A case is reported of an accidental staggered overdose of clidinium bromide 50 mg in a patient using illicit chlordiazepoxide. The presenting features were mildly dilated pupils and palpitation secondary to sinus tachycardia that persisted for 11 h after the time of first ingestion. Emergency physicians should be aware of the potential for antimuscarinic toxicity in patients using illicit chlordiazepoxide.

A study of the teratogenic and fetotoxic effects of large doses of chlordiazepoxide used for self-poisoning by 35 pregnant women.

The human teratogenic potential of chlordiazepoxide is debated. To study the effects on the fetal development of very large doses of chlordiazepoxide that were used for a suicide attempt during pregnancy, self-poisoned pregnant women were identified from patients in a toxicological inpatient clinic in Budapest, Hungary. Comparisons were made between congenital abnormalities, intrauterine fetal development, and cognitive-behavioral status of the exposed children born to mothers who attempted suicide with chlordiazepoxide alone or in combination with other drugs during pregnancy and their sib controls. Of 1044 women with self-poisoning during pregnancy between 1960 and 1993, 88 (8.4%) used chlordiazepoxide with or without other drugs for suicide attempt; 35 of these women delivered live-born infants. Doses of chlordiazepoxide taken ranged between 20 and 300 mg, with a mean of 117 +/- 86 mg. Of 35 exposed children, six (17.1 %) were affected with congenital abnormalities compared with three (13.6%) of their 22 sibs (OR with 95% CI: 1.3 (0.3-4.4). Of 18 pregnant women who attempted suicide between the 4th and 12th postconceptional week, the period most sensitive to congenital malformation, four delivered live-born children affected with a congenital abnormality (atrial septal defect type II, complex defect of respiratory system, mild pyelectasis because of the stenosis of ureteropelvic junction, congenital inguinal hernia). Two other children had fetal alcohol syndrome and unrecognized multiple congenital abnormality including talipes equinovarus, deformation type, and four minor anomalies. The pregnancy age-specific mean birth weight indicated intrauterine fetal growth retardation, which was confirmed by a dose-response relationship and by the higher rate of low birth-weight newborns. Cognitive status and behavioral scale of exposed children did not indicate neurotoxic effects. Very large doses of chlordiazepoxide used for suicide attempts during pregnancy did not induce a higher rate of congenital abnormalities but were associated with dose-dependent intrauterine growth retardation.

Clinical course, therapy, outcome and analytical data in amitriptyline and combined amitriptyline/chlordiazepoxide overdose.

A total of 103 cases of amitriptyline (AT) overdose (group 1) and 81 cases of overdose with a fixed combination of AT and chlordiazepoxide (CDE) (group 2), treated at our Intensive Care Unit or reported to our Poison Information Center between 1985-1990, were evaluated with respect to clinical course, symptoms and outcome, as well as efficacy of therapy. The mean amount of AT was considerably higher in group 1 compared to group 2 (13 mg kg-1 vs 7.7 mg kg-1). The most frequent symptoms in both groups were impaired consciousness, anticholinergic symptoms, seizures, arrhythmia and hypotension. Respiratory insufficiency necessitated respirator therapy in 63 of the patients. Two patients in group 1 and one patient in group 2 did not survive. Therapy included primary detoxification by gastric lavage and repeated administration of activated charcoal. In four of eight patients with cardiac conduction disturbances, hypertonic sodium bicarbonate led to a significant reduction in QRS duration and AV interval. Physostigmine was effective in eight of 14 patients with pronounced anticholinergic symptoms. No effect was observed in the other six patients. Haemoperfusion, which was performed in five patients, led to rapid improvement of coma after initiation of therapy in four patients. The clinical efficacy of haemoperfusion in AT overdose despite the high volume of distribution of AT deserves further investigation. The rather high average overdose of AT implies that large package sizes of AT were available to the patients. A major step towards prevention of serious AT overdose would be the prescription of package sizes containing a total of less than 500 mg AT.(ABSTRACT TRUNCATED AT 250 WORDS)

[A comparative evaluation of methods for the isolation of khlozepid from human cadaveric liver]. / Sravnitel'naia otsenka metodov izolirovaniia khlozepida iz pecheni trupa cheloveka.

Comparative evaluation of two isolation methods in fatal chlozepid poisoning was performed using expert material. Isolation by neutral acetone from visceral tissues showed that chlozepid and its metabolites are extracted in amounts 6-13 times greater (in terms of chlozepid) than using A. A. Vasil'eva's method. Quantitative determination was performed by photometry according to the reaction of azo dye formation after hydrochloric acid hydrolysis of the extracts.

Toxicity in a case of acute and massive overdose of chlordiazepoxide and its correlation to blood concentration.

In previous studies no correlation between blood concentration and toxicity was found in acute chlordiazepoxide overdose. We describe a case of acute overdosage with 5.2 g chlordiazepoxide, in which toxicity correlated to blood concentration of the second metabolite of chlordiazepoxide, to demoxepam. Therefore, it is recommended to determine not only chlordiazepoxide, but also its active metabolites in cases of overdose. This can easily been achieved using the described method, HPLC with photodiode array detection.

Lack of evidence of teratogenicity of benzodiazepine drugs in Hungary.

In order to investigate possible teratogenic effects of commonly used benzodiazepines (diazepam, chlordiazepoxide, nitrazepam) in Hungary, four approaches were used: 1. A retrospective case-control study of 630 cases with isolated cleft lip +/- cleft palate, 179 cases with isolated cleft palate, 392 cases of multiple congenital anomalies including cleft lip and/or cleft palate, and their matched control cases; 2. The Case-Control Surveillance System of Congenital Anomalies in Hungary, 1980 to 1984, involving 355 cases with isolated cleft palate, 417 cases with multiple congenital anomalies, and 186 cases with Down's syndrome (as positive controls). Benzodiazepines were taken by 14.9% of 11,073 control pregnant women studied; 3. A prospective study of 33 pregnant women attending the Counselling Clinic following ingestion of benzodiazepines during the first trimester of pregnancy; 4. An observational study involving 12 pregnant women who attempted suicide and one with accidental overdosage with benzodiazepines during pregnancy. None of these four approaches gave any indication of an association between facial clefting and in utero exposure to these substances.

Blood concentrations and clinical findings following overdose of chlordiazepoxide alone and chlordiazepoxide plus ethanol.

Blood concentrations and clinical findings in 25 cases of overdose involving chlordiazepoxide (CDZ) alone ("pure") were compared with those in 23 cases of overdose involving ethanol in addition to CDZ ("mixed"). Both groups consisted predominantly of men who were chronic alcoholics. The mean blood CDZ concentrations did not show statistically significant difference between the two groups ("pure," 5 mg/L; "mixed," 6 mg/L). Following "pure" ingestion, patients were usually alert, and the level of consciousness showed no statistically significant correlation with the blood CDZ concentration. In contrast, after "mixed" ingestion patients were usually lethargic, and the level of consciousness correlated significantly with the blood CDZ concentration (P less than 0.05) but not with the blood ethanol concentration. In neither group was coma noted. For both groups the most common physical findings were tachycardia and dysarthria. Nystagmus was much more common following "mixed" ingestion while seizures, hyperreflexia, and hypertension were more frequent after CDZ overdose alone. Most patients were seen only in the emergency room and were discharged. The implications of these findings are discussed.

Effects of physostigmine on benzodiazepine toxicity.

The interactions between physostigmine and chlordiazepoxide, diazepam, flurazepam were experimentally evaluated in rats and mice by the following test: loss of righting reflex (LRR), acute toxicity, cardiovascular toxicity and EEG pattern. Physostigmine did not modify the duration of LRR produced by chlordiazepoxide. Conversely, the recovery after diazepam was significantly longer. The LD50 of diazepam and chlordiazepoxide were not modified by physostigmine administration, but that of flurazepam was significantly decreased. Heart rate and blood pressure did not change significantly with physostigmine pre-treatment. However, the total lethal dose was lowered for chlordiazepoxide and flurazepam. Only the reversal by physostigmine of the EEG pattern due to benzodiazepines, offers experimental support to the claimed usefulness of physostigmine in benzodiazepine intoxication in humans. Furthermore, the potentiation of flurazepam toxicity must be taken into account in the debate concerning the clinical advantages of physostigmine.