Quantification of fatal helium exposure following self-administration.

Helium is nontoxic at standard conditions, plays no biological role, and is found in trace amounts in human blood. Helium can be dangerous if inhaled to excess, since it is a simple tissue hypoxia and so displaces the oxygen needed for normal respiration. This report presents a fatal case of a middle-aged male victim who died from self-administered helium exposure. For the first time, the quantification of the helium levels in gastric and lung air and in blood samples was achieved using gas chromatography-mass spectrometry after airtight sampling. The results of the toxicological investigation showed that death was caused directly by helium exposure. However, based on the pathomorphological changes detected during the forensic autopsy, we suppose that the fatal outcome was the result of the lack of oxygen after inhalation.

Screening for childhood lead poisoning in the industrial region of Fez, Morocco.

The study objectives were to estimate lead poisoning prevalence among children living next to an industrial area, to compare it to that in a control population, and to establish clinical and biological follow-up of the poisoned children. This is a descriptive cross-sectional study including 150 children (exposed and unexposed) performed between January 2012 and April 2013. It was meant to determine blood lead levels (BLLs) in children considered to be an exposed population (EP N 90), living in the industrial area Ain Nokb Fez compared with BLLs of children of other areas belonging to the same city supposed to be unexposed [UP (N = 60)]. A sociodemographic questionnaire was obtained, and a blood lead analysis was performed. Clinical and biological follow-up has been performed of poisoned children. The sample consisted of 90 EP children with an average age of 6.82 ± 3.32 years and male-to-female sex ratio (SR) of 1.5 and 60 UP children with an average age of 6.45 ± 3.29 years and an SR of 1.2. Among the 150 children recruited, the average of BLLs was 58.21 ± 36 µg/L (18-202.3 µg/L). The average of BLLs in EP children (71 ± 40 µg/L) was statistically greater (p < 0.0001) than that registered in UP children (38 ± 13 µg/L). All poisoned children belonged to the EP group at a prevalence of 21.1 %. The clinical and biological examinations of poisoned children showed a few perturbations such as anemia, hypocalcaemia, and deficiencies in magnesium and iron. No renal disease or objective neurological disorders were observed. In the follow-up of the children with BLL ≥100 µg/L (19 cases). BLL monitoring showed a significant decrease in average of blood concentration ranging from 136.75 ± 32.59 to 104.58 ± 32.73 µg/L (p < 0.0001) and in lead poisoning prevalence (p < 0.001), which decreased to 7.8 % from 21.1. Our study showed a high prevalence of lead poisoning (21.1 %) in EP children. The relocation of the industrial site associated with corrective and preventive measures has contributed to a decrease of exposure and lead poisoning prevalence in the aforementioned population.

Feasibility of, and critical paths for mycophenolate mofetil Bayesian dose adjustment: pharmacological re-appraisal of a concentration-controlled versus fixed-dose trial in renal transplant recipients.

The aim of this study was to analyze retrospectively and critically the different steps of the individual dose adjustment procedure employed in the concentration-controlled (CC) versus fixed-dose trial Apomygre, which showed that mycophenolate mofetil (MMF) dose adjustment using a limited sampling strategy significantly reduced the risk of treatment failures and acute rejection in renal transplants at one year posttransplantation. The number of AUCs performed during the study and circumstances of collection, time of blood sampling, Bayesian mycophenolic acid (MPA) area-under-the-curve (AUC) estimation procedures and physicians' compliance with MMF dose recommendations were retrospectively analyzed. 92% of AUCs scheduled over the study were actually performed. Sampling times were very well respected. Bayesian estimation of MPA exposure was done by the pharmacologists locally in accordance with the protocol instructions and the AUC estimates obtained were virtually all confirmed a posteriori. On the other hand, a second AUC estimated by multiple linear regression could only be provided for 84% of the profiles and showed a large overestimation with respect to Bayesian estimates for AUC values between 10 and 55mgh/L. In the CC arm, a very good physicians' compliance was observed (85%) and application of the dose recommendations led to higher values of AUCs (42.1+/-14.6mgh/L versus 36.7+/-16.3mgh/L, p=0.0035) and to more AUCs in the target range (69% versus 56%, p=0.0343) than when dose recommendations were not applied. By analyzing in detail the feasibility criteria of MMF Bayesian dose adjustment, this study highlighted the requirements for successful extrapolation of the Apomygre trial results to routine practice: (i) respect of the PK sampling time-windows; (ii) use of relevant tools for accurate drug exposure estimation and dose adjustment calculation; and (iii) good compliance of the physicians with regard to the recommended doses.

Cumulative pharmacokinetic study of oxaliplatin, administered every three weeks, combined with 5-fluorouracil in colorectal cancer patients.

The cumulative pharmacokinetic pattern of oxaliplatin, a new diamminecyclohexane platinum derivative, was studied in patients with metastatic colorectal cancer. Oxaliplatin was administered by i. v. infusion (130 mg/m2) over 2 h every 3 weeks, and 5-fluorouracil and leucovorin were administered weekly. A very sensitive method, inductively coupled plasma-mass spectrometry, allowed for the determination of total plasma and ultracentrifugable (UC) and RBC platinum levels on day 1, at 0, 2, and 5 h, and on days 8, 15, and 22. Sixteen patients underwent three or more courses, and six of them underwent six or more courses. The platinum concentration curves were quite similar from one course to another, with a high peak value 2 h after administration (day 1, Cmax = 3201 +/- 609 microgram/liter) and a rapid decrease (day 8, 443 +/- 99 microgram/liter). Cmax of both total and UC platinum levels in plasma remained unchanged throughout the treatment. The mean total platinum half-life in plasma was 9 days. We found residual levels of total platinum on day 22 (161 +/- 45 microgram/liter), but we observed no significant accumulation for the four first cycles (P = 0.57). In contrast, platinum accumulated significantly in RBCs after three courses (+91% at day 22 of the third cycle versus day 22 of the first cycle, P = 0.000018), and its half-life there was equivalent to that of RBCs. The patterns of UC and total platinum concentration curves were very similar and correlated significantly (P < 10(-6)) at all sampling times. The mean UC:total platinum ratio was 15% at day 1 and 5% at days 8, 15, and 22 in the 3-week treatment course. Unlike cisplatin, which rapidly accumulates in plasma as both free and bound platinum, oxaliplatin does not accumulate in plasma, but it does accumulate in RBCs, after repeated cycles at the currently recommended dose (130 mg/m2) and schedule of administration (every 3 weeks).

Long-term pharmacokinetic behavior of platinum after cisplatin administration.

PURPOSE: The platinum concentration in plasma was studied in 19 patients treated by 3 or 4 successive courses of chemotherapy including cisplatin for head and neck cancers. METHODS: Cisplatin was given i.v. daily at 25 mg/m2 by 1-h infusions for 4 days every 3 weeks. Total and ultrafiltrable platinum were measured in plasma using an inductively coupled plasma mass spectrometry (ICPMS) technique. RESULTS: A progressive accumulation of total platinum in plasma was observed with consecutive infusions. The mean (+/- SD) total plasma platinum level detected at the end of cisplatin infusion was 1134 +/- 234, 1407 +/- 268, and 1618 +/- 282 micrograms/l at the end of the first, second, and third courses, respectively. The minimal platinum concentration measured before the second and third courses also increased to 221 +/- 59 and 309 +/- 76 micrograms/l, respectively. The steady state was not reached before the third course. However, differences in the evolution of platinum plasma levels were found among the 19 patients. In 14 patients the pharmacokinetics of platinum was characterized by low initial levels, a progressive accumulation, and a long terminal half-life with a very late steady state. In 5 patients, the pharmacokinetic behavior of platinum was different: platinum levels were directly high, without progressive accumulation, the steady state being reached as early as the first course. Significant levels of ultrafiltrable platinum were found throughout the treatment, even during the intervals between courses with this very sensitive analytical method. A close equilibrium between ultrafiltrable and total platinum (ratio, 6%) persisted for as long as 3 weeks after cisplatin administration. DISCUSSION: These results underline the importance of individual differences in platinum metabolism. The relationship between total and ultrafiltrable platinum are discussed.

Determination of monomethylarsonic acid and dimethylarsinic acid in urine by liquid chromatography-tandem mass spectrometry.

A method for the simultaneous measurement of monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in human urine using liquid chromatography-tandem mass spectrometry with electrospray ionization (LC-ES-MS-MS) was developed. The multiple reaction monitoring mode (MRM) was used for quantitation. The protonated molecule ions (m/z 141.0 for MMA and m/z 139.0 for DMA) were selected as precursor ions, and the same fragment ion AsO+ (m/z 91.1) was monitored as the product ion. A two-step liquid-liquid extraction of MMA and DMA from urine provided recoveries of 92-100%. The coefficients of variation were lower than 7% for the within-day precision and lower than 11% for the between-day precision. The limit of quantitation was 25 microg/L as As for the two analytes. The assay was linear over the range of 25-800 microg/L.

Acute metobromuron poisoning with severe associated methemoglobinemia. Identification of four metabolites in plasma and urine by LC-DAD, LC-ESI-MS, and LC-ESI-MS-MS.

A case of self poisoning with metobromuron, a urea derivative used as a herbicide, is reported. Severe methemoglobinemia observed at the admission (80%) disappeared only at day 11, and hemolysis appeared at day 4 and decreased slowly to day 12. Metobromuron was analyzed by liquid chromatography with diode-array detection. Initial plasma concentration and elimination half-life were 4.9 mg/L and 5 h, respectively. Several metabolites were also detected, and four of those were identified by liquid chromatography-electrospray mass spectrometry. Normetobromuron, bromophenylurea, and bromoacetanilide were detected in plasma, but only N-methyl bromophenylurea was detected in urine. Bromoacetanilide probably results from acetylation of the intermediate bromoaniline. Methemoglobinemia could result from metabolization of metobromuron to bromoaniline and bromoacetanilide.

Determination of opiates and cocaine and its metabolites in biological fluids by high-performance liquid chromatography with electrospray tandem mass spectrometry.

A rapid, sensitive, and specific method for the determination of opiates and cocaine and metabolites in urine, plasma, and blood was established. A one-step extraction followed by liquid chromatography-electrospray ionization tandem mass spectrometry operating in multiple reaction monitoring mode was used. Two chromatographic runs were performed, each in less than 6 min. The lower limit for accurate quantitative determination was 5 microg/L for cocaine and metabolites and 10 microg/L for opiates. Linearity was obtained from 10 to 1000 microg/L. Intraday (n = 6) and interday (n = 6) precisions and recoveries (n = 6) were determined at 10 or 25, 100, and 1000 microg/L concentrations. Precisions with a coefficient of variation less than 15% were obtained. Recoveries between 85 and 115% were determined.

Fatal acute poisoning by bentazon.

A case of fatal suicidal bentazon poisoning is presented along with a description of the different analytical methods involved. A 56-year-old farmer was examined by the family doctor 1 h after voluntarily ingesting 500 mL of FIGHTER (bentazon, 480 g/L water). He presented a Glasgow score of 15, polypnea, diarrhea, and vomiting. During transport by ambulance to the hospital, he tossed, sweated, and suddenly presented breathing difficulty followed by heart failure. Tracheal intubation was impossible (H1.5) despite use of different diameter cannulas because of extreme general muscle rigidity. All attempts at resuscitation failed, and the patient died within 2 h postingestion. Blood and urine samples were taken just before death. General basic and neutral drug screening by high-performance liquid chromatography-diode-array detection and gas chromatography-nitrogen-phosphorus detection showed no strychnine or other drugs or toxics except for citalopram (< 0.1 mg/L) and bentazon, but this weak acidic molecule (pKa3.3) was badly extracted in alkaline conditions. Plasma and urine levels, measured after acidic extraction, protein precipitation, or simple dilution, were 1500 and 1000 mg/L, respectively. Bentazon (M.W. 240) was confirmed by its basic mass spectrum (ESI-, m/z 239, 197, 175, 132) or by that of methylated derivative (El+, m/z 254, 212, 175). An hydroxylated metabolite (ESI-, m/z 255, 213, 191, 148; El+, m/z 284, 242, 163) and the N1-glucuronide conjugate of bentazon (ESI-, m/z 415, 239) were also detected in urine. (Quantitation ions are underlined.) This first case of bentazon poisoning with available analytical data revealed the high toxicity of this compound after large dose ingestion with early and heavy symptoms such as muscle rigidity probably related to muscular toxicity. Comparison with another nonfatal case and with toxicological data on animals is discussed.

[Acute cardiac toxicity of 5-fluorouracil: pharmacokinetic correlation]. / Toxicité cardiaque aiguë du 5-fluorouracile: corrélation pharmacocinétique.

High-dose 5-fluorouracil (5-FU) continuous infusion over a 4-day period seems to dramatically increase the frequency of cardiac complications, which were however extremely rare in the past when it was injected in bolus form (1.6%). In order to evaluate their real incidence we looked for a relation between cardiac toxicity and clinical or 5 FU pharmacokinetic parameters. One hundred and thirty-three patients were followed up from January 1989 to March 1990, treated for head and neck, breast and colorectal cancers by high-dose 5-FU infusion (1,000 mg/sqm/d x 4 d) and cis-platinum (20 mg/sqm/d x 4 d). During each treatment course, daily electrocardiogram and 5 FU plasma assays were performed by high performance liquid chromatography, at 8 am and 8 pm. Twenty-eight patients presented 36 ischemic cardiac manifestations which were sometimes severe. Of these, 29 were asymptomatic. Cardiac toxicity frequency was not increased in the group treated for head and neck cancers. Pharmacokinetic analysis showed wide variations in 5-FU plasma levels in the 133 patients under study (from 20 to 1,200 ng/ml). Cardiac manifestations always appeared during the hours following very high 5-FU plasma levels (greater than 450 ng/ml). Cardiotoxicity seems to be linked to 5-FU plasma levels. Cis-platinum probably increases toxicity in this regimen. These findings indicate the advisability of a close follow-up by daily ECG when 5-FU is administered at high doses in continuous infusion and associated with cis-platinum. We are continuing to study 5 FU cardiac toxicity, especially in other regimens containing 5 FU and aim to evaluate the contribution of cardiac isotopic exams.

Efficacy of 4-methylpyrazole in ethylene glycol poisoning: clinical and toxicokinetic aspects.

Potentially fatal ethylene glycol intoxication in an adult with normal renal function was treated with 4-methylpyrazole administered three hours after the incident occurred. The plasma ethylene glycol concentration was 3.5 g l-1 on admission. The metabolic acidosis present on admission resolved within four hours, and the subsequent clinical course was uneventful. The apparent plasma half-life of ethylene glycol was 16 h and the mean renal and plasma clearances of ethylene glycol were 24 and 25 ml min-1, respectively. These results support the hypothesis that complete blockade of hepatic metabolism of ethylene glycol is achieved by 4-methylpyrazole. The only side-effect observed as a result of treatment was a transient slight increase in serum transaminase activity.

Tungsten determination in biological fluids, hair and nails by plasma emission spectrometry in a case of severe acute intoxication in man.

A healthy 19-year-old recruit in a French artillery regiment drank 250 mL of a mixture of beer and wine that had rinsed in a hot 155-mm gun-barrel. Fifteen minutes later, he complained of nausea followed by seizures. He was comatose for 24 h, presenting signs of encephalopathy. A moderate renal failure was noted initially and worsened to an extensive tubular necrosis with anuria on the day after the incident. The first toxicological investigations only showed a 0.31 g/L blood ethanol. Then inductively-coupled plasma (ICP) emission-spectrometry revealed very high concentrations of tungsten in the "beverage" as well as in gastric content, blood and urine (1540 mg/L, 8 mg/L, 5 mg/L, and 101 mg/L, respectively). The nature of the metal was confirmed by ICP coupled to mass spectrometry. A simple and reliable ICP quantitative assay of tungsten in biological fluids, hair and nails was then developed. It showed high blood levels (> 0.005 mg/L) until day 13 in spite of six hemodialyses, and in urine until D33. Tungsten was also incorporated in hair and nails. To the best of our knowledge, such an intoxication has never been reported before though this drinking seems to be traditional in the French Artillery. It has probably been favored by the unusually high volume of beverage absorbed and by the new alloy of the gun, containing tungsten. The clinical evolution was satisfactory over weeks and the patient was declared totally cured after five months.

Identification and quantitation of neutral and basic drugs in blood by gas chromatography and mass spectrometry.

There is an increasing need for the quantitation of drugs that act on the central nervous system in blood of patients suspected of poisoning. A simple method for quantitative determination of neutral and basic drugs is described. The method involves a basic extraction without derivatization. The plasma extracts are injected on a Hewlett-Packard chromatograph using two nitrogen-specific detectors. In most cases, the comparison of relative retention times on the two columns is sufficient for identification of the ingested drugs. But when the method falls, the use of a gas chromatograph/mass spectrometer equipped with a chemical ionization source is necessary.

[Plasma concentrations of ornidazole in newborn infants and infants after iterative administration]. / Concentrations plasmatiques d'ornidazole chez le nouveau-né et chez le nourrisson après administration répétée.

Ornidazole was administered for ten days to twelve hospitalized neonates at the same daily dose of 20 mg/kg either by one or two IV infusions. Minimum steady-state concentrations measured between the 4th and 10th day ranged from 7.8 to 17.3 (mean = 11.8 +/- 3.2 mg/l) for one daily infusion and from 10.9 to 26.6 (mean = 20.5 +/- 6 mg/l) for two infusions. These minimum concentrations were all above the minimum inhibitory concentration for the most clinically significant anaerobic bacteria. So the single daily administration of ornidazole at the dose of 20 mg/kg is sufficient to obtain therapeutic efficiency.

[Pharmacokinetics of low-dose lithium in healthy volunteers]. / Pharmacocinétique du lithium administré à doses faibles chez le volontaire sain.

The pharmacokinetics of lithium in healthy volunteers receiving low doses of lithium as Lithium Oligosol by sublingual route were investigated in two randomized crossover studies (lithium vs placebo) with a two week wash-out period. In the first study, 8 volunteers received a single dose (1.68 mg) of lithium and in the second 8 another volunteers received repetitive doses of lithium (0.56 mg twice a day) during 11 days. The plasma concentration of lithium was determined by an electrothermal atomic absorption spectrometry. The plasma concentrations of lithium measured during the placebo period were about 1 microgram/L, the peak concentration was 99.4 +/- 22.2 micrograms/L in the single dose study and 49.6 +/- 5.4 micrograms/L in the multiple doses study. In this last one, the residual plasma levels of lithium were between 20 and 25 micrograms/L. The pharmacokinetics parameters measured were: T1/2 = 22.6 +/- 3.1 h; Vd/F = 0.70 +/- 0.09 L/kg and Cl/F = 1.53 +/- 0.12 L/h. The plasma concentrations of lithium are strictly dependent on intake from food or drugs.

[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.

[Responsibility of psychotropic drugs in road accidents]. / Responsabilité des neuropsychotropes dans les accidents de la voie publique.

Serum concentrations of psychotropic drugs were measured in 363 drivers injured in road accidents and admitted to the emergency department of Angers regional university hospital. The figures obtained were correlated to the presumed responsibility of each driver in the accident. Benzodiazepines and phenobarbitone were found in the serum of 39 drivers, and responsibility was significantly increased in this group. The role played by these medicines in road accidents has often been alluded to in the literature, but the value of these previous studies was limited by the lack of quantitative assays. Measuring serum concentrations has permitted a more accurate analysis of the relationship between responsibility for road accident and consumption of psychotropic drugs, including barbiturates. This has prompted the authors to organize a regional information campaign intended for the general public and doctors and aimed at drawing attention to the higher risk of accident among road users taking these drugs.

[Ethyl alcohol levels in the expiratory air vs blood alcohol levels. 204 cases in an emergency unit]. / Ethylométrie dans l'air expiré versus ethanolémie. 204 cas dans un service d'accueil et d'urgence.

OBJECTIVES: Twenty to forty percent of all patients admitted to the emergency ward are positive for blood alcohol. Devices which measure alcohol in expired breath have been increasingly used in these units. This study was conducted to compare the results of breath alcohol analyzers with the classical laboratory methods based on enzyme assay and gas phase chromatography. METHODS: All patients with suspected acute ethanol intoxication at admission to the emergency room were included if blood alcohol had been ordered (enzyme assay and gas phase chromatography). RESULTS: There were 204 patients (151 men (74%) and 53 women (26%); mean age 43 +/- 12.7 years, range 14-80). The coefficient of correlation between blood alcohol level determined by gas phase chromatography (GC) and breath alcohol was 0.96 (r2 = 0.92, p < 10(-4)). The coefficient of correlation between breath alcohol and blood alcohol level determined by enzyme assay was 0.96 (r2 = 0.92, p < 10(-4)). Comparing the coefficients of correlation GC/blood (r2 = 0.92) versus GC/enzyme assay (r2 = 0.96) demonstrated a statistically significant difference (p < 10(-3)). CONCLUSION: In our 204 patients, the breath alcohol analyzer gave 3 false positives and 3 false negatives (2.94%). Even though breath alcohol levels are 21.1% lower than the levels given by gas phase chromatography, it is an instantaneous nonaggressive method well correlated with classical blood tests. Nevertheless, this method could not be used in 19.6% of emergency patients due to physical impossibility or refusal, justifying laboratory tests.

[Plasma noradrenaline in hyperthyroidism and hypothyroidism]. / Noradrénaline plasmatique dans l'hyperthyroïdie et l'hypothyroïdie.

Plasma noradrenaline concentrations (NA) were measured in 11 hypothyroid patients, 24 hypothyroid patients and 30 normal subjects after 30 minutes of supine rest and after 5 minutes of standing. Observed noradrenaline levels, after rest as well as after standing, were significantly higher in hypothyroid patients (NA rest = 0.66 +/- 0.35 microgram/l, NA standing = 1.26 +/- 0.70 micrograms/l) and significantly lower in hyperthyroid patients (NA rest = 0.22 +/- 0.13 micrograms/l, NA standing = 0.37 +/- 0.20 microgram/l) than in normal subjects (NA rest = 0.32 +/- 0.13 microgram/l, NA standing = 0.55 +/- 0.20 microgram/l). The increase in noradrenaline with standing, when expressed in percent, was similar for the three groups studied (about 100%). These results suggest that a sympathetic nervous system adaptation occurs in hyperthyroidism and hypothyroidism as a compensatory phenomenon to the direct effect of thyroid hormones on the heart.

[Chemical submission]. / Soumission chimique.

INTRODUCTION: The clinical submission syndrome is well known by the general population, but too frequently ignored by physicians. OBSERVATION: A 23 year-old woman was drugged by a third person wishing to sexually abuse of her. The diagnosis was proved biologically after the judicial enquiry. COMMENTS: The diagnosis of clinical submission is difficult to make because of the frequent delays in emergency consultations and the difficulties in biological assays, since the doses of drugs administered are often very low and infra-therapeutic. Over a period of one year, we evoked the diagnosis four times and it was confirmed only once. It sometimes leads to diagnostic peregrinations. Close cooperation between the physicians and the police is required so that a judicial enquiry can be rapidly set-up.