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Oxetorone is a serotonin antagonist antimigraine drug but literature relating to its toxic properties is poor. The aim of this study is to describe the toxicological profile of oxetorone and to highlight any relationship between clinical and analytical findings.This is a retrospective and observational study of cases exposure to oxetorone, reported to the Angers Poison and Toxicovigilance Centre between January 2002 and May 2016. Severity was assessed using the Poisoning Severity Score (PSS). Cases where data were incomplete, where oxetorone was deemed not accountable, where clinical signs were linked mainly to a co-ingested drug or where the plasma concentration of oxetorone was negative were all excluded.We included 43 cases of exposure, 31 of whom were suicide attempts. The assumed ingested dose (60-3600 mg) was correlated to severity (rSeveral clinical and paraclinical parameters strongly point towards membrane-stabilising properties of the molecule and the risk of a delayed occurrence of symptoms or a secondary worsening.

International audience; Baclofen is often prescribed in high doses to fight cravings experienced by alcohol-dependent patients. Such an increase in the availability of baclofen is concerning. This study aimed to determine the change in number and profile of self-poisoning with baclofen over time, as baclofen has become increasingly popular, in order to describe the severity of self-poisoning with baclofen and to focus on co-existing alcohol use disorders, and psychiatric illnesses determine predictors of severity. This was a retrospective study of self-poisoning with baclofen as reported by the western France Poison Control Center (PCC), which represents a population of more than 12 million people from January 2008 to March 2014. One hundred and eleven cases of self-poisoning with baclofen were reported to the western France PCC (62 males and 49 females; average age 39 +/- 12). Poisoning severities were as follows: 'null' (nine cases), 'minor' (37 cases), 'moderate' (19 cases) and 'high' (46 cases, including four deaths). The most frequently reported symptoms were neurological (45%) and cardiovascular (27%). The severity was significantly associated with psychiatric disorders (OR = 2.9; p = 0.03). Baclofen, prescribed in high doses, may lead to severe poisoning, particularly in patients with psychiatric illnesses. Authorities should put forward a new policy for prescribing the drug as a treatment for alcohol dependence.

Introduction: Sulcotrione is a herbicidal agent belonging to the family of triketones. Sulcotrione herbicides are used for weed control in maize and flax crops. To date, no cases of human poisoning had been reported in the literature linked to different herbicidal agents in the triketone family. We report here on two cases of the voluntary ingestion of this substance in the form of the branded product MikadoTM, which were recorded by the Angers Poison Centre. Case report: Both cases of voluntary ingestion constituted attempted suicide, and involved two men aged 30 and 37 years. Their symptoms linked to sulcotrione were limited to vomiting, despite elevated plasma concentrations of sulcotrione. In one case, hypertyrosinemia has been demonstrated. The outcome was favourable in both patients and at follow up, no ocular disorders were observed. In the second case, hypotension and transient renal failure could be linked to the concomitant ingestion of chlorophenoxy herbicides. Discussion: In animal toxicity studies, sulcotrione inhibit 4-hydro-phenylpyruvate dioxygenase leading to hypertyrosinemia and corneal opacities. In both cases, no ocular disorders were observed despite hypertyrosinemia in one case. These case reports were consistent with the animal toxicology findings concerning triketones, and particularly their relative safety in mammals following acute poisoning. However it seems prudent to monitor plasma tyrosine concentrations and to screen prospectively for corneal deposits if further acute intoxication events occur.

Objectives: The aims of this study were (i) to investigate the population pharmacokinetics of tacrolimus in renal transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and inter-dose area under the blood concentration-time curve (AUC) from 0 to 12 hours (AUC12) in renal transplant patients. Methods: Full pharmacokinetic profiles were obtained from 32 renal transplant patients at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modelling software NONMEM® version VI. Patients’ genotypes were characterized by allelic discrimination for PXR −25385C>T genes. Results: Tacrolimus pharmacokinetics were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase, with low additive and proportional residual errors of 1.6 ng/mL and 9%, respectively. Both the haematocrit and PXR −25385C>T single nucleotide polymorphism (SNP) were identified as significant covariates for apparent oral clearance (CL/F) of tacrolimus, which allowed improvement of prediction accuracy. Specifically, CL/F decreased gradually with the number of mutated alleles for the PXR −25385C>T SNP and was inversely proportional to the haematocrit value. However, clinical criteria of relevance, mainly the decrease in interindividual variability and residual error, led us to retain only the haematocrit in the final model. Maximum a posteriori Bayesian forecasting allowed accurate prediction of the tacrolimus AUC12 using only three sampling times (at 0 hour [predose] and at 1 and 3 hours postdose) in addition to the haematocrit value, with a nonsignificant mean AUC bias of 2% and good precision (relative mean square error = 11%). Conclusion: Population pharmacokinetic analysis of tacrolimus in renal transplant recipients showed a significant influence of the haematocrit on its CL/F and led to the development of a Bayesian estimator compatible with clinical practice and able to accurately predict tacrolimus individual pharmacokinetic parameters and the AUC12.

Background. To describe a profound cardiac dysfunction and a status epilepticus after a massive bupropion overdose. Case report. A 35-year-old man was admitted in coma following the deliberate ingestion of 12 g of bupropion. The course was marked by the rapid onset of severe and prolonged status epilepticus and cardiogenic shock. Plasma bupropion level determined four hours after the estimated time of ingestion was 1.4 mg/L. All clinical features resolved completely in response to symptomatic treatment. Conclusion. Several cases of bupropion overdose, with sinus tachycardia and seizures rapidly corrected by symptomatic treatment, have been reported in the literature. To our knowledge, this case of overdose with bupropion alone, at very high doses, is the first to describe clinical features comprising severe and prolonged status epilepticus and direct cardiotoxicity with the development of cardiogenic shock documented by echocardiogram.

Objectives Over the last decade, use of phenethylamines has become increasingly prevalent. This study aimed to describe typical aspects of phenethylamine poisoning in order to better inform patient care. Methods Phenethylamine poisoning cases reported to the Poison Control Center of Angers, France, from January, 2007 to December, 2013 were examined. Clinical findings were examined in 105 patients, including phenethylamine used, symptoms and final outcome. Patients were predominantly male (80%), with mean age 26 ± 8 years. Results MDMA (38%), amphetamine (18%) and methamphetamine (14%) were the most commonly reported. Synthetic cathinones (10%) and the 2C series (7%) were also found. Substances most commonly associated with phenethylamine poisoning were cannabis (27%), ethanol (20%) and cocaine (9%). The most frequently reported symptoms included anxiety and hallucinations (49%), mydriasis and headache (41%), tachycardia (40%) and hypertension (15%). Complications such as seizures (7%), cardiac arrest (5%), toxic myocarditis (1%) and hemorrhagic stroke (1%) were also observed. Of the cases, the Poison Severity Score was: null or low, 66%, moderate, 21%, severe or fatal, 13%. Of the patients, 77% received hospital care and 12.4% were admitted to an intensive care unit. Analytical confirmations were obtained for all severe cases. While 93% of patients recovered, there were 5 deaths and 2 patients presented with neurological sequelae. Conclusions Phenethylamine poisonings may be severe in young and healthy individuals. Physicians, toxicologists and analysts should be aware of new phenethylamine consumption trends in order to inform management of patient care and to contribute to a more responsive drug policy.

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.

Case Reports: Two patients severely intoxicated with ethylene glycol became anuric and were treated by hemodialysis and the antidote, 4-methylpyrazole. On admission, their plasma ethylene glycol concentrations were 0.42 and 3 g/L respectively and no alcohol was detected. The elimination of 4-methylpyrazole in the dialysate represented 45% of the total body elimination. Clearances of 4-methylpyrazole by hemodialysis were 80 mL/min and 52 mL/min respectively. Results: In such cases, the authors propose infusion of a 4-methylpyrazole loading dose of 10-20 mg/kg before dialysis and intravenous infusion of 1-1.5 mg/kg/h during the 8-12 hours of hemodialysis to compensate the loss in dialysate.

International audience; We report the case of a 39-year-old woman who presented with serotonin syndrome and hypoglycaemia likely due to intoxication with a very high dose of venlafaxine. This case of venlafaxine-associated hypoglycaemia was treated first by glucose perfusion, but despite large doses, hypoglycaemia recurred. Blood glucose normalized after injection of octreotide, eliminating the need for hypertonic glucose. Octreotide has been shown to decrease glucose requirements and the number of hypoglycaemic episodes in patients with sulfonylurea-induced hypoglycaemia but, to our knowledge, its ability to resolve hypoglycaemic episodes due to massive venlafaxine overdose has not yet been described.

Peganum harmala L. is commonly used in traditional medicine in Morocco for its sedative and emmenagogue properties but expose to the risk of overdose and poisoning. The aim of our study was to analyze a series of 200 cases of poisoning collected in poison control and pharmacovigilance center of Morocco in order to describe the epidemiological, clinical, therapeutic features and outcome of patients and indicate the toxicity of this plant used primarily for therapeutic purposes.This retrospective study performed over a period of twenty four years from January 1984 to December 2008.The mean age of patients was 24.4±16.8 years with a female predominance (167 women against 33 men). Therapeutic circumstance was found in 32.5%, followed by suicide (28.5%) and abortion (13.5%). The symptomatology was dominated by neurological, gastrointestinal and cardiovascular signs respectively 34.4%, 31.9 % and 15.8%. The evolution has been specified in 114 cases, 7 deaths have been deplored with a fatality rate of 6.2%.

Treatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with avizafone and atropine using an auto-injector device.The study was conducted in an open, randomized, single-dose, two-way, cross-over design. At each period, each subject received either intramuscular injections of pralidoxime (700 mg), or two injections of the combination: pralidoxime (350 mg), atropine (2 mg), avizafone (20 mg). Pralidoxime concentrations were quantified using a validated LC/MS-MS method. Two approaches were used to analyse these data: (i) a non-compartmental approach; and (ii) a compartmental modelling approach.The injection of pralidoxime combination with atropine and avizafone provided a higher pralidoxime maximal concentration than that obtained after the injection of pralidoxime alone (out of bioequivalence range), while pralidoxime AUC values were equivalent. Pralidoxime concentrations reached their maximal value earlier after the injection of the combination. According to Akaike and to goodness of fit criteria, the best model describing the pharmacokinetics of pralidoxime was a two-compartment with a zero-order absorption model. When avizafone and atropine were injected with pralidoxime, the best model describing pralidoxime pharmacokinetics becomes a two-compartment with a first-order absorption model.The two approaches, non-compartmental and compartmental, showed that the administration of avizafone and atropine with pralidoxime results in a faster absorption into the general circulation and higher maximal concentrations, compared with the administration of pralidoxime alone.

International audience; Suicide by stabbing to the head and/or driving sharp objects into the skull is of extreme rarity. This article reports the case of a 27-year-old man, who committed suicide by multiple knife stabs and cuts to the head, the torso, one shoulder and the forearms. Autopsy showed a perforating wound of the skull and the 10-cm long broken blade of the knife being still embedded in the right temporal lobe of the brain. The deceased had no history of psychiatric illness but was currently treated by mefloquine, a quinine derivative associated with a high rate of psychiatric adverse effects. Toxicological examination confirmed a recent intake of mefloquine together with chloroquine, another antimalarial drug. To our knowledge, this is the first report of a completed suicide with very strong evidence of mefloquine implication. Discussion focuses upon mefloquine-induced psychiatric disorders and highlights the importance of performing toxicological investigations in cases of unusual suicides.

LDM TEP COLL; International audience; BACKGROUND:In the prospective, randomized, multicenter APOMYGRE trial conducted in France, concentration-controlled mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) exposure significantly reduced the treatment failure and acute rejection during the first posttransplantation year compared with fixed-dose MMF. This analysis investigated the cost effectiveness of dose individualization.METHOD:The study included 65 patients per group (intent-to-treat population). Treatment failure (primary efficacy endpoint) was defined as death, graft loss, acute rejection, or MMF discontinuation because of adverse effects. Data on hospitalizations, drugs prescribed, physicians' fees, laboratory expenses, ambulatory visits, and transportation were retrieved. Costs were calculated from the French National Health System perspective.RESULTS:The mean (95% confidence interval) total yearly cost per patient was Euro 47,477 (Euro 43,933; Euro 51,020) in the concentration-controlled group and Euro 46,783 ( Euro 44,152; Euro 49,414) in the fixed-dose group (P=0.7). The observed incremental cost-effectiveness ratio was Euro 3757 per treatment failure (Purchasing Power Parities United States/France: $4129). Hospitalization and drug costs accounted for approximately 50% and 25% of total costs, respectively. The cost for MPA area under the concentration-time curve and dose calculation was Euro 452 per patient, less than 1% of the total cost.CONCLUSION:In the APOMYGRE trial, therapeutic MPA monitoring using a limited sampling strategy reduced the risk of treatment failure and acute rejection in renal allograft recipients during the first 12 months posttransplantation, at neutral cost.

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.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.

A liquid chromatographic procedure with electrospray ionization tandem mass spectrometric detection has been developed and validated for LSD and iso-LSD determination. A one-step liquid-liquid extraction on 1 ml blood or urine was used. The lower limit for quantitative determination was 0.02 microg/l for LSD and iso-LSD. The analytical procedure has been applied in two positive cases (case 1: LSD=0.31 microg/l, iso-LSD=0.27 microg/l in plasma and LSD=1.30 microg/l, iso-LSD=0.82 microg/l in urine; case 2: LSD=0.24 microg/l, iso-LSD=0.6 microg/l in urine). LSD metabolism was investigated using MS-MS neutral loss monitoring for the screening of potential metabolites. The main metabolite was 2-oxo-3-hydroxy-LSD (O-H-LSD) present in urine at the concentrations of 2.5 microg/l and 6.6 microg/l, respectively, for case 1 and 2, and was not present in plasma. Nor-LSD was also found in urine at 0.15 and 0.01 microg/l levels. Nor-iso-LSD, lysergic acid ethylamide (LAE), trioxylated-LSD, lysergic acid ethyl-2-hydroxyethylamide (LEO) and 13 and 14-hydroxy-LSD and their glucuronide conjugates were detected in urine using specific MS-MS transitions.

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.

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.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).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, p10(-4)). The coefficient of correlation between breath alcohol and blood alcohol level determined by enzyme assay was 0.96 (r2 = 0.92, p10(-4)). Comparing the coefficients of correlation GC/blood (r2 = 0.92) versus GC/enzyme assay (r2 = 0.96) demonstrated a statistically significant difference (p10(-3)).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.

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.

A case of sultopride poisoning (ingested dose 16 g) in a 35-year-old, 65 Kg man is described. On admission myoclonus, mydriasis, vomiting and cardio-respiratory arrest were observed. Torsades de pointes were treated with potassium chloride infusion and pace maker stimulation. Plasma sultopride concentration was 25 mg/l and urinary concentration 12 g/l. A prolongation of Q-T interval may announce severe arrhythmias in sultopride poisoning.

A case of acute meprobamate poisoning in a 43 year-old-woman is reported. Twenty five hours after admission in the intensive care unit, deep coma and cerebral electrical silence were observed whereas the meprobamate plasmatic concentration was 250 mg/l. The patient recovery was uneventful. Meprobamate analysis must be performed for unexplained coma with isoelectric EEG.

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.

A method for the plasma noradrenaline (NA) analysis by reversed-phase liquid chromatography with electrochemical detection is described. The plasma sample preparation includes two-steps: ion-exchange and alumina adsorption. The use of a data system and an automatic sampler enables the injection of samples in series. Using this technique, determination of plasma NA concentration in 34 healthy subjects (27.4 +/- 7.2 years) gave the following results: 0.28 +/- 0.10 micrograms/l after 30 min of resting in the supine position and 0.52 +/- 0.17 micrograms/l after 5 min of upright position.

Plasma noradrenaline (NA) and adrenaline (A) concentrations were measured by high liquid pressure chromatography in five untrained subjects and in five well-trained rowers during an exercise test on bicycle ergometer. Blood samples were collected, via a venous catheter, at rest, after standing 5 minutes, at maximal work level and at 5, 10, 20 minutes of post-exercise. Plasma NA and A concentrations at rest and after 5 minutes of standing were similar in the two groups. At maximal work load (340 +/- 38 for rowers and 220 +/- 11 W for untrained subjects), for a same pulse rate (178.0 +/- 7.6 for rowers and 176.6 +/- 4.7 beats/minutes-1 for untrained subjects), NA and A concentrations were higher in athletes (NA: 5.57 +/- 1.32 microgram/l; A: 0.95 +/- 0.31 microgram/l) than in untrained subjects (NA: 2.13 +/- 0.80 microgram/l; A: 0.40 +/- 0,34 microgram/l). During recovery, no significant difference was observed between the two groups.

Plasma thiopentone concentrations after a single intravenous dose were determined by high pressure liquid chromatography in female surgical patients (n = 13), in pregnant women at term (n = 13) and in neonates (n = 13). In pregnant women, the apparent volume of distribution (Vd = 10.02 +/- 3.26 l X kg-1), plasma clearance (Cl = 22.03 +/- 7.55 l X h-1) and elimination half-life (t 1/2 (3) = 21.71 +/- 11.12 h) were significantly greater than in the surgical patients (Vd = 4.22 +/- 1.16 l X kg-1; Cl = 12.49 +/- 3.50 l X h-1; t 1/2 (3) = 13.79 +/- 3.09 h). Elimination half-life in neonates (t 1/2(e) = 17.9 +/- 9.7 h) was not different from half-life in mothers or in the surgical group. At delivery, the simultaneous concentrations were 5.3 +/- 1.3 mg X l-1 in venous blood and 3.8 +/- 1.6 mg X l-1 in cord venous blood. Apgar score was 10 in eleven neonates. For two babies, an Apgar score at 6 was explained by a uterine incision-to-delivery time interval greater than 2 min.

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 1-1 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.

This automated spectrophotometric method for determination of cholinesterase activity in erythrocytes and plasma is based on measurement of the choline produced at 30 degrees C by the hydrolysis of acetyl-, butyryl-, or succinylcholine. Blanks, standards, and samples are prepared by a Gilson robotic unit. Use of flow-injection analysis for detection allows use of smaller volumes of reagent and sample. We applied this method to the study of 91 healthy subjects and members of two families with succinylcholine sensitivity. Results with use of the three different substrates for determination of activity in plasma correlated well (r greater than 0.94). Results for plasma and erythrocytes from healthy subjects are lower in women less than 50 years old than in women greater than 50 years or men. Values for plasma obtained with succinylcholine substrate (range: 31 to 100 U/L) allow detection of very sensitive subjects--AA phenotypes (less than 10 U/L)--but do not distinguish the UA from the UU phenotype.

The clinical submission syndrome is well known by the general population, but too frequently ignored by physicians.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.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.

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.

Thiopental was used in long-term infusion (3-4.5 mg . kg-1 . h-1 during 4-8 days) to protect the brain from injury following trauma. Thiopental plasma concentrations were measured during infusion (48 patients) and after infusion (14 patients) to determine the kinetics of the drug in continuous infusion. All mean values were mean +/- SD. Steady state concentrations (Css) were 31.8 +/- 10.7 mg/l for an infusion rate of 3.05 +/- 0.37 mg . kg-1 . h-1 and 48.9 +/- 14.6 mg/l for a rate of 4.2 +/- 0.3 mg . kg-1 . h-1. Corresponding steady state clearance decreased when Css increased, indicating possible saturation of the metabolic enzymatic system. Michaelis-Menten kinetics were confirmed by postinfusion data that give, for higher Css, a nonlinear decay of log C versus time. First-order kinetics were only obtained with Css below 30 mg/l. The maximum rate of elimination (Vm) was 1.76 +/- 1.15 mg . l-1 . h-1 (n = 11), and the Michaelis constant (Km) was 26.7 +/- 22.9 mg/l (n = 11). Hepatic enzyme saturation was between 35 and 85%. The volume of distribution at steady state was 4.35 +/- 1.83 l/kg (n = 11). Apparent half-lives of elimination were between 18 and 36 h at the end of infusion, and predicted terminal half-lives were 10.15 +/- 5.43 h (n = 11). Phases of burst-suppression were observed on electroencephalographic traces for concentrations greater than 40 mg/l. The authors' results suggest that a continuous infusion at a dose of 4 mg . kg-1 . h-1 induces EEG changes consistent with a near-maximum reduction in cerebral metabolism. Because of the thiopental Michaelis-Menten kinetics at doses above 4 mg . kg-1 . h-1, the authors suggest that thiopental plasma concentrations be measured and/or the drug effect be measured with the EEG to prevent excessive thiopental overdosage, causing a prolonged recovery time.

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 (P10(-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).