Pharmacokinetics of meprobamate in overdose treated with continuous venovenous hemodiafiltration (CVVHDF).

We report a case of massive suicidal overdose of meprobamate leading to cardiovascular collapse, respiratory failure, and severe central nervous system depression. We observed first-order elimination kinetics despite significant overdose, and demonstrated effectiveness of continuous venovenous hemodiafiltration (CVVHDF) for extracorporeal removal of meprobamate in this patient. Total body clearance was calculated to be 87 mL/minute, with 64 mL/minute (74%) due to CVVHDF. CVVHDF was stopped after 36 hours, and the patient made an uneventful recovery.

[Severe meprobamate poisoning: description of 146 cases in a French department]. / Intoxications graves au méprobamate : description d'une série de 146 cas dans le département de la Loire.

Meprobamate poisoning are serious and sometimes fatal. Faced with a potential stop of marketing, we conducted a multicenter retrospective study to assess the severity criteria presented by patients admitted to the ICU for severe meprobamate poisoning, whether with alone form or in combination with aceprometazine. One hundred fourty-six patients have been enrolled between January 2005 and June 2011: 38 had a single meprobamate poisoning, 104 to meprobamate and aceprometazine and 4 to both forms. At admission, 88% of patients exhibited coma (Glasgow ≤ 7) and half of them a systolic blood pressure ≤ 90 mmHg. Mortality rate was 3%. Our results did not find any significant between-group difference, either in regard of clinical or biological severity criteria. These data argue for a cessation of marketing of all meprobamate-based specialities.

Postmortem carisoprodol and meprobamate concentrations in blood and liver: lack of significant redistribution.

Carisoprodol is a therapeutic and occasionally abused centrally acting muscle relaxant. We compare central blood and liver concentrations of carisoprodol and the metabolite meprobamate to concentrations in peripheral blood in 11 medical examiner cases. Specimens were initially screened for alcohol and simple volatiles by gas chromatography (GC)-flame ionization detection headspace analysis, enzyme-linked immunosorbent array for drugs of abuse, and therapeutic drugs by GC-mass spectrometry (MS). Carisoprodol, when detected by the therapeutic drug screen, was confirmed and quantified by a specific GC-MS procedure. The results suggest that when ingested with other medications, carisoprodol may be a contributing factor in death, even when present at therapeutic concentrations. Considering the cases studied, together with previously published therapeutic and fatal concentrations, blood carisoprodol concentrations greater than 15 mg/L and liver concentrations greater than 50 mg/kg may be considered excessive and potentially fatal. Carisoprodol central blood to peripheral blood ratios averaged 1.31 + 0.33 (mean ± standard deviation), and liver to peripheral blood, 2.83 ± 1.51. Meprobamate central blood to peripheral blood ratios averaged 0.92 ± 0.22, and liver to peripheral blood, 1.25 ± 0.69. The low liver to peripheral blood ratio (less than 5), taken together with the low central blood to peripheral blood ratio, is an indicator that both carisoprodol and meprobamate lack the potential to exhibit postmortem redistribution.

Acute pancreatitis in the course of meprobamate poisoning.

CONTEXT: We report a case of massive poisoning with meprobamate leading to acute pancreatitis. CASE REPORT: A 43-year-old patient with a history of schizophrenia and multiple suicide attempts was admitted to the intensive care unit for severe poisoning with meprobamate (voluntary ingestion of 60 g). On admission, the patient was deeply comatose with low blood pressure and hypothermia. Laboratory analysis revealed leukocytosis and high lipase and amylase serum levels. There was no eosinophilia. Abdominal computed tomography showed pancreatitis grade A. The patient was intubated and ventilated, and intravenous dopamine was infused. The patient regained consciousness and was extubated five days later. Improvement in pancreatic tests was noted several days later. The outcome was favorable. DISCUSSION: According to the Naranjo probability scale, meprobamate-induced acute pancreatitis was probable. Acute pancreatitis in meprobamate poisoning is exceptional. The pathogenesis of pancreatitis-induced meprobamate poisoning may be explained by two mechanisms: stimulation of pancreatic secretion secondary to cholinergic activation and pancreatic ductal hypertension. CONCLUSIONS: The signs of severe meprobamate toxicity are numerous including cardiovascular and central nervous symptoms. Acute pancreatitis should also be added as a possible manifestation of meprobamate poisoning.

Interpretation of drug concentrations in an alternative matrix: the case of meprobamate in vitreous humor.

The use of vitreous humor (VH) as an alternative matrix to blood in the field of forensic toxicology has been described for numerous drugs. Interpretation of drug concentrations measured in VH, as in other matrices, requires statistical analysis of a data set obtained on a significant series. In the present study, two diagnostic tests interpreting postmortem VH concentrations of meprobamate in 117 sets of autopsy data are reported. (1) A VH meprobamate concentration threshold of 28 mg/l was statistically equivalent to that of blood meprobamate concentration threshold of 50 mg/l distinguishing overdose from therapeutic use in blood. The intrinsic qualities of the test were good, with sensitivity of 0.95 and absolute specificity of 1. (2) A novel interpretation tool is proposed, allowing blood concentration range to be evaluated, with a known probability, from VH concentration.

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.

A study of teratogenic and fetotoxic effects of large doses of meprobamate used for a suicide attempt by 42 pregnant women.

The human teratogenic effect of meprobamate is debated. Thus, the available data set regarding very large doses of meprobamate used for a suicide attempt during pregnancy was evaluated for effects on fetal development. Pregnant women were identified from self-poisoned subjects of a total population of approximately three million people (Budapest and surrounding region) who were admitted to the Department of Toxicology Internal Medicine, Koranyi Hospital, Budapest. Comparisons were made of congenital abnormalities, intrauterine fetal growth, and cognitive-behavioral status in exposed children born to mothers who attempted suicide with meprobamate alone or in combination with other drugs during pregnancy with their control sibs. Of 1044 women with self-poisoning during pregnancy between 1960 and 1993, 107 (10.3%) used meprobamate, with or without other drugs for a suicide attempt; 42 of these 107 women delivered live-born infants. The dose of meprobamate used for the suicide attempt ranged between 1000 and 26,000 mg, with a mean of 3690 mg. Of 42 exposed children, seven (16.7%) were affected with congenital abnormalities, however, of their 27 sib controls, four had a CA (14.8%) (OR with 95% CI: 1.7, 0.5-4.9) of 14 had a congenital abnormality. Of 14 mothers who attempted suicide during the 4-12th postconceptional week, two delivered live-born babies affected with mild isolated congenital abnormality: undescended testis and congenital dysplasia of the hip. However, the critical period for production of these two defects did not overlap with the time of the mother's suicide attempt. Mean birth weight and pregnancy age, cognitive status, and behavioral scale of the exposed children did not indicate fetotoxic, including neurotoxic, effects of large doses of meprobamate. Very large doses of meprobamate that were used for self-poisoning during pregnancy did not result in teratogenic or fetotoxic, including neurotoxic, effects on fetal development.

Carisoprodol intoxications: a retrospective study of forensic autopsy material from 1992-2003.

Carisoprodol is commonly prescribed as a centrally acting muscle relaxant, but it is also subject to abuse. The literature describing fatal intoxications with the drug is limited to a relatively small number of cases, and there are inconsistencies with regard to which concentration levels that are toxic. We therefore investigated all forensic autopsies at the Norwegian Institute of Public Health during the period 1992-2003 where carisoprodol was detected. The median concentrations of carisoprodol in intoxication with carisoprodol only or with only minor other analytical findings was 36 mg/l (range 8-65 mg/l; n=5). In the rest of the intoxications, the relevance of carisoprodol relative to the other drugs detected was variable (n=93). When the number of intoxications with carisoprodol each year were divided by the number of defined daily doses (DDD) sold, a fatal toxicity index between 5.6 and 6.9 deaths/1 million DDD was obtained. The total number of cases where carisoprodol was detected increased during the period studied, which correlated to sales figures for the drug. We conclude that carisoprodol can be fatal in concentrations below those indicated in some of the previously published literature. There were, however, only a small number of cases where the cause of death can be attributed to use of carisoprodol alone.

Incidence, causes and prognosis of hypotension related to meprobamate poisoning.

OBJECTIVE: Meprobamate self-poisoning has been reported as potentially inducing hypotension. We examined the incidence and causes of hypotension induced by this poisoning and its prognosis. DESIGN AND SETTING: Retrospective observational study conducted in a medical ICU between June 1997 and October 2003. Seventy-four patients admitted for meprobamate poisoning and needing mechanical ventilation were included. Demographic, clinical, and laboratory data were compared between patients with and without hypotension. All echocardiograms recorded in patients with hypotension were reviewed, and left ventricular (LV) and right ventricular (RV) functions were assessed. RESULTS: Twenty-nine (40%) patients exhibited hypotension without any significant difference in age, gender, cardiac history, or meprobamate concentration in blood when compared to patients without hypotension. Base excess was significantly lower in patients with hypotension. Echocardiography demonstrated a hypokinetic state, associating decreased LV ejection fraction (45+/-15%) and cardiac index (2+/-0.7 l min(-1) m(-2)), and increased inferior vena cava diameter. Most patients with hypotension received inotropic drugs by infusion, and were ventilated for significantly longer. CONCLUSIONS: Meprobamate self-poisoning induces hypotension, notably related to cardiac failure, in about 40% of cases. This has important therapeutic consequences, as frequent inotropic drug infusion. The mechanisms of cardiac toxicity remain largely unknown, and no predictive factor could be isolated.

Comparison of patient questionnaires and plasma assays in intentional drug overdoses.

Our aim was to explore the agreement between clinically collected information on purported drug intake and plasma data in intentional drug overdose. We included all subjects with intentional drug overdose above 15 years of age consecutively admitted to the Emergency Department of the University Hospital during 4 months. Information about drugs used and sources of this information was collected and compared to presence of drug in plasma, concerning four drugs with high toxic potential (tricyclic antidepressants, meprobamate, paracetamol and ethanol). Sensitivity, specificity, predictive positive and negative values of all sources of information pooled were assessed for each drug. 413 intentional drug overdoses were included, 66% with more than one drug. According to clinical information, 8% took tricyclic antidepressants, 11% meprobamate, 9% paracetamol and 41% ethanol. Systematic plasma assays confirmed this in 59% of cases for tricyclic antidepressants, 76% for meprobamate and ethanol, and 77% for paracetamol. Plasma concentrations were considered toxic in 28% of cases for tricyclic antidepressants, 65% for meprobamate, 43% for ethanol and never for paracetamol. Tricyclic antidepressants and meprobamate were found unexpectedly in 3%, paracetamol in 7% and ethanol in 6%. Toxic concentrations were found only with meprobamate. The risk of erroneous, clinically collected information was greater by excess (25 to 40% false positives) than by lack (3 to 7% false negatives). Thus, the consequences of erroneous, clinically collected information were probably more excess cost for the institution than medical risk for the patients. However these results found at the population level may not be true at an individual level.

Assessment of erythrocyte cholinesterase activity in victims of smoke inhalation.

BACKGROUND: The nature of the toxic gases that cause death from smoke inhalation is incompletely understood, and the mechanisms leading to incapacitation remain to be determined. Thermal degradation products of various compounds, including phosphorous-based fire retardants, are suspected capable of impairing human cholinesterase activity. The aim of this study was to measure the erythrocyte cholinesterase activity in victims of smoke inhalation. METHODS: We prospectively measured the erythrocyte cholinesterase activity in blood samples obtained at the scene of residential fires from 49 fire victims. We compared the results with those in an unmatched group of 45 persons with acute drug poisoning. RESULTS: The median (25th-75th percentiles) erythrocyte cholinesterase activity in the 49 fire victims, 1968 IU/L (1660-2276), was significantly lower than in the 45 control subjects 2460 IU/mL (1968-2890), (p = 0.0004). There was no significant difference of the red blood cell counts or plasma protein levels between the 2 groups, while the hematocrit was significantly greater in the fire victims than in the drug-poisoned patients. There was a significant correlation between blood cyanide and carbon monoxide concentrations in the fire victims (r = 0.494, p = 0.002). There was no correlation between erythrocyte cholinesterase activity and either blood cyanide (r = 0.11, p = 0.44) or blood carbon monoxide concentrations (r = 0.04, p = 0.78). CONCLUSIONS: We found a significantly lower level of erythrocyte cholinesterase activity in victims of residential fires, when compared with a convenience sample of hospitalized poisoned patients. Despite the limitations of the study, investigations of the toxic gases potentially responsible for impairment of cholinesterase activity and the clinical significance of this lower enzymatic activity merit further investigation.

Meprobamate overdosage: a continuing problem. Sensitive GC-MS quantitation after solid phase extraction in 19 fatal cases.

We describe a simple method for the urinary identification and blood quantitation of meprobamate suitable for any toxicological laboratory. After urinary screening using GC-MS technology, quantitation is performed by GC-MS in the selected-ion monitoring mode. Isolation of the drug is achieved by solid phase extraction on a C-18 cartridge. A specific elution is obtained by three volumes of acetone:triethylamine (99:1 v/v). Lidocaine is used as internal standard. RSDs (%) of the within-day and between-day precision studies are always less than 7.2 on the entire range of calibration. Linearity is inspected using an analysis of variance ANOVA. Homogeneity of the variances is tested using Hartley's test. Weighted linear regression is then computed. Limits of detection and quantification are given by an analysis of the blanks. The present method was applied in our laboratory over a period of 1 year. Meprobamate appeared as a drug which still has a significant frequency (5.5%) and is the most frequently involved in fatal pharmaceutical overdoses (15.3%). Post mortem concentrations ranged from 41 to 397 mg/l (mean = 182) and are compared to those of the literature.

Continuous arteriovenous hemoperfusion in acute poisoning.

We have investigated the efficacy of a pumpless hemoperfusion technique, continuous arteriovenous hemoperfusion (CAVHP) in 3 cases of acute intoxications with meprobamate, theophylline and phenobarbital. Dramatic responses were noted in both hemodynamic unstable and comatous patients. With this technique, a blood flow of 120 cm3/min could be achieved in severe hypotension. Moreover, with the restoration of blood pressure, blood flow increased to 150-400 cm3/min. Our preliminary experience has shown that CAVHP allows an exceptionally high solute elimination. Hemoperfusion clearances of meprobamate, phenobarbital and theophylline were 198 +/- 5.6 cm3/min, 290.25 +/- 25.33 cm3/min and 192.79 +/- 55 cm3/min, respectively. Our present results suggest that CAVHP is a simple, safe, effective and less costly alterative of conventional hemoperfusion.

[State of shock during acute meprobamate poisoning. 6 cases]. / Etat de choc lors de l'intoxication aiguë par le méprobamate. Six observations.

The prognosis of acute meprobamate poisoning is related to shock whose haemodynamic mechanism remains obscure. We report the results of a retrospective study of six patients with meprobamate poisoning associated with shock and explored by a right heart catheterization. The age of the patients, five women and one man, ranged from 36 to 57 years. Five patients had also ingested other psychotropic drugs. A haemodynamic investigation was performed at admission to the ICU and three hours later, under treatment. Vasoplegia was the predominant feature. A myocardial dysfunction was sometimes associated, which can be explained by a moderate hypothermia. According to these results, we suggest that prior to right heart catheterization, the treatment should include inotropic and alphamimetic agents and that vascular filling should be cautious.