Massive suicidal ingestion of caffeine: a case report with investigation of the cardiovascular effect/concentration relationships.

BACKGROUND: Caffeine poisoning may cause life-threatening arrhythmias and hemodynamic failure. We aimed to investigate the toxicokinetics (TK), toxicodynamics (TD) and TK/TD relationships of caffeine in a case of poisoning. CASE REPORT: A 47-year-old male ingested pure anhydrous caffeine powder (70 g) in a suicide attempt. He developed agitation, tachycardia, and two episodes of ventricular fibrillation treated with defibrillation and tracheal intubation. He was successfully managed using intravenous infusions of esmolol and norepinephrine. METHODS: We modelled the time-course of plasma caffeine concentration (TK study using online liquid chromatography-tandem mass spectrometry), the time-course of blood lactate concentration and infusion rates of esmolol and norepinephrine (TD studies) and the TK/TD relationships. RESULTS: Caffeine TK was of first-order peaking at 258 mg/L with an elimination half-life of 46.2 h and clearance of 2.2 L/h. Caffeine-related effects on blood lactate (peak, 10 mmol/L at 1.25 h postingestion) were described by a Bateman-type equation (formation rate, 0.05 mmol/mg.h; elimination rate, 0.9 mmol/mg.h). Esmolol and norepinephrine infusion rates to reverse caffeine-related cardiovascular effects (peaks at 51-h postingestion) fitted well with a sigmoidal Emax model (EC50, 180.0 and 225.9 mg/L, respectively; Hill coefficient, 10.0). CONCLUSION: Massive caffeine ingestion is characterized by prolonged caffeine elimination. TK/TD relationships are helpful to quantify caffeine-related catecholaminergic effects.

Pharmacokinetic study of metopimazine by oral route in children.

Metopimazine (MPZ) is an antiemetic considered as a currently used drug. In France, it has become the leading antiemetic mediator due to its good tolerance, however, its pharmacokinetics has never previously been studied in children. MPZ was administered by oral route to 8 children with a single dose of 0.33 mg/kg during an endocrine exploration using stimuli well known for its adverse emetic effects. We used biological remnants from sera following an hGH test in order to obtain the MPZ pharmacokinetics. Plasmatic concentrations of MPZ and the active acid metabolite AMPZ, were quantified by HPLC-MS/MS during a 270 min test period. MPZ is quickly absorbed with a median C max of 17.2 ng/mL at one hour and its half-life is 2.18 h. The plasmatic concentrations of AMPZ were higher than MPZ with a median C max of 76.3 ng/mL, a T max to 150 min and its concentration was approximately maintained at 50 ng/mL from 1 to 4 h. The plasmatic concentrations in children are similar to those observed in adults. No adverse effects, nausea or vomiting occurred during the trial. Therefore, these results confirm the MPZ dosage that should be used in children under 15 kg administered as 0.33 mg/kg up to 3 times a day.

Current role of ICP-MS in clinical toxicology and forensic toxicology: a metallic profile.

As metal/metalloid exposure is inevitable owing to its omnipresence, it may exert toxicity in humans. Recent advances in metal/metalloid analysis have been made moving from flame atomic absorption spectrometry and electrothermal atomic absorption spectrometry to the multi-elemental inductively coupled plasma (ICP) techniques as ICP atomic emission spectrometry and ICP-MS. ICP-MS has now emerged as a major technique in inorganic analytical chemistry owing to its flexibility, high sensitivity and good reproducibility. This in depth review explores the ICP-MS metallic profile in human toxicology. It is now routinely used and of great importance, in clinical toxicology and forensic toxicology to explore biological matrices, specifically whole blood, plasma, urine, hair, nail, biopsy samples and tissues.

Analysis of eight glycols in serum using LC-ESI-MS-MS.

A liquid chromatography coupled with electrospray tandem mass spectrometry method was developed for the analysis of ethylene glycol, diethylene glycol, triethylene glycol, 1,4-butanediol, 1,2-butanediol, 2,3-butanediol, 1,2-propanediol and 1,3-propanediol, in serum after a Schotten-Baumann derivatization by benzoyl chloride. Usual validation parameters were tested: linearity, repeatability and intermediate precision, limits of detection and quantification, carry over and ion suppression. Limits of detection were between 0.18 and 1.1 mg/L, and limits of quantification were between 0.4 and 2.3 mg/L. Separation of isomers was possible either chromatographically or by selecting specific multiple reaction monitoring transitions. This method could be a useful tool in case of suspected intoxication with antifreeze agents, solvents, dietary supplements or some medical drug compounds.

Metallic profile of whole blood and plasma in a series of 106 healthy volunteers.

In 2003, we simultaneously quantified 27 metals by inductively coupled plasma-mass spectrometry (ICP-MS) in the whole blood, plasma and urine of 100 healthy volunteers. We again determined the metallic profile in whole blood and plasma during 2012. ICP-MS validated multielementary method was performed for metals in whole blood and plasma. Whole blood vanadium and chromium were quantified using ICP-MS collision cell technology. The aims of the study were to compare and assess any changes in this profile, particularly due to the environment. Healthy male/female staff volunteers (n = 106) with no professional exposure to metals, or medication containing lithium, strontium; or food supplements with trace elements and vitamins and with no metal prosthesis were included. Tobacco consumption and the number of dental amalgams were recorded. Our results demonstrated a blood lead level that had drastically decreased, i.e. reduced by half, during this period (12.5 versus 26.3 µg/L, P < 0.0001). Known differences were observed between males and females for copper and zinc; cadmium and lead were higher in smokers. Median plasmatic mercury, a specific test for dental amalgam exposure, did not significantly increase (0.38 versus 0.28 µg/L, P = 0.11). The ICP-MS metallic profile is a very practical concept that is useful for clinical, forensic and environmental toxicology, including industrial hygiene monitoring.

Determination of levels of current drugs in hospital and urban wastewater.

A rapid, sensitive and highly specific HPLC-MS/MS method with direct on-line preparation was applied for the determination of 20 common pharmaceuticals in hospital and urban wastewater. Median drug concentrations were quite similar in the majority of samples, cerca 1 µg L⁻¹ ranging from 0.06 to 2.67 µg L⁻¹ in both water. Pharmaceutical hospital contribution, below 1 %, was negligible, as compared to the huge amount in the municipal plant flow. Due to only partial elimination in the plant, hundreds of kilograms of harmful waste per year are discharged in the River Seine. Therefore, to reduce potential human and environmental exposure, a topic of major concern, an efficient drug treatment procedure should be used at the municipal plant stage in order to reduce urban wastewater pollution. The HPLC-MS/MS method could be a very useful tool to optimize the pharmaceutical wastewater treatment process.

Importance of anthropogenic metals in hospital and urban wastewater: its significance for the environment.

Thirty-four metals were analyzed by ICP-MS. Among these elements, anthropogenic silver, gadolinium and platinum, were representative markers of medical activities in hospital and urban wastewater. On working days, median hospital wastewater concentrations for anthropogenic silver, gadolinium, and platinum were approximately three, 13 and 27 times higher respectively than the Municipal wastewater. A drastic reduction of their emission was observed during non-working days (minus 94 % for gadolinium and 87 % for platinum). A large percentage of these metals are not trapped in the Treatment Plant, i.e. 88 % for gadolinium and 69 % for platinum. More than 4 kg and 350 g for gadolinium and platinum are respectively discharged per year in the River Seine. Therefore, it is imperative to eliminate these elements in the Plant.

Fatal poisoning due to snorting buprenorphine and alcohol consumption.

High dosage buprenorphine (Subutex(®)) has been prescribed as a replacement therapy for major opioid dependencies in France since 1996. However, several studies have underlined its lethal risk, especially when administered intravenously, or when combined with benzodiazepines, alcohol or other central nervous system depressants. We report three fatal buprenorphine-related poisonings after snorting, among outside protocol individuals, observed at the Forensic Medicine Unit of Caen University Hospital. Medico-legal autopsies and complementary examinations were performed. The results are presented and discussed. Lethal poisoning after snorting buprenorphine was considered the most probable cause of death. These observations illustrate the risk of fatal poisoning by buprenorphine per-nasal route, which has rarely been reported in the literature although snorting is particularly prized by individuals outside the substitution therapy. We also observed the combination of buprenorphine and alcohol. By evaluating the pharmacological characteristics of this substance, as well as the data previously published in the literature, we have attempted to explain the pathophysiological mechanisms of this particular mode of poisoning that can easily be fatal.

[Drug-facilitated crime: a public health problem?]. / La soumission chimique: un problème de santé publique?

Drug-facilitated crime (DFC) is well known to the public, yet general practitioners and other physicians are unfamiliar with this issue, largely because toxicology is not part of the medical curriculum. This often leads to diagnostic errors. The frequency of DFC is underestimated, often owing to late examination and analytical problems. On 24 December 2002 the French authorities issued a circular defining DFC as "the administration of a psychoactive drug without the victim's knowledge, as a means of aggression"; and listing places where victims can be managed On 19 July 2005, the French Agency for Health Product Safety (Afssaps) sent a letter to all professionals potentially concerned by this issue, offering guidelines for both medical personnel and laboratory staff conducting toxicological investigations. One difficulty in drug identification is that the doses administered are often low. Toxicology laboratories need sophisticated equipment and expertise to ensure that the perpetrator is prosecuted or, alternatively, to rule out DFC. More information is needed, not only for the public but also for physicians and toxicologists. Benzodiazepines and related compounds are identified in about 75% of DFC cases.

[The metallic profile: a new biological concept]. / Une nouvelle approche biologique: le profil métallique.

Considerable advances have been made in metals and metalloids analysis over the past decade. This analysis is a basic stage in deficiency or toxicity assessment. A recently introduced technique, inductively coupled plasma mass spectrometry (ICP-MS) is progressively replacing atomic absorption. This analysis permits multi-elementary determinations, many ten or so elements, among periodic classification, with an optimal gain in sensitivity in many biological matrices: i.e. whole blood, plasma, urine, hair, nail, and biopsy samples. Moreover, this method allows semi-quantitative determination with an additional thirty supplementary elements, which enables the toxicologist to sufficiently estimate the toxic levels and metal exposure. The authors demonstrate that the ICP-MS could be very useful for a wide range of clinical applications. Furthermore, this procedure offers new exploration possibilities in various fields such as clinical chemistry but also clinical toxicology, forensic toxicology as well as workplace testing or environmental exposure and permits epidemiologic studies. This analytical method in fact also provides a new biologic approach. To our knowledge we are the first to propose the metallic profile.

[Inductively coupled plasma: a promising new tool with application in human toxicology and public health]. / La torche a plasma: un nouvel equipement aux applications prometteuses au service de la toxicologie humaine et de la santé publique.

The authors describe the use of inductively coupled plasma to detect 32 metals and metalloids in blood, urine, hair and nails. They also report the first case of gadolinium overdose documented by blood analysis with this method Metal speciation, a new approach developed in our laboratory, can distinguish between toxic and non toxic metals.

Unexpected high prevalence of herpes simplex virus (HSV) type 2 seropositivity and HSV genital shedding in pregnant women living in an East Paris suburban area.

Both herpes simplex virus type 2 (HSV-2) seroprevalence and the proportion of HSV-1 genital ulcers are increasing in industrialized countries. The consequences of these epidemiological changes, in pregnant women in France, for both the genital shedding of HSV and vertical transmission, have been poorly evaluated. The HSV-1 and HSV-2 seroprevalence and the rate of subclinical genital shedding of herpes close to delivery were evaluated in pregnant women, with no history of genital herpes, living in the East Paris suburban area. HSV-2 antibody prevalence of 26% was significantly associated with country of origin and was higher than that reported in 2002 in French women from the general population (18%). HSV-2 and HSV-1 genital reactivations were observed in 10% of HSV-2 seropositive and in 4% of HSV-1 seropositive and HSV-2 seronegative women, respectively. The high rates of HSV-2 seropositivity and subclinical herpes genital shedding observed in this study should be considered to promote a national survey in pregnant women to propose strategies to prevent the spread of HSV within the population and to the neonate.

Determination of thiocyanate in plasma by ion chromatography and ultraviolet detection.

A specific and sensitive rapid high-performance liquid chromatographic method has been developed for determination of thiocyanate (SCN-) in plasma. This method is based on anion exchange chromatography after a simple ultrafiltration of plasma diluted in water. The detection of SCN- is carried out in ultraviolet (lambda = 210 nm). The proposed method is linear in the range 1-30 mg/L. Intra-assay and interassay accuracy and precision were maintained within the designated limit (< 20%). The total recovery of SCN- varied between 97 and 103.9%. The method described should be useful for clinical medicine. Moreover, this method was applied to the analysis of SCN- plasma in deceased subjects, within the context of fire, and could be of interest in forensic science as a useful additional measurement tool for cyanide determination in blood.

Experimental heatstroke in baboon: analysis of the systemic inflammatory response.

The objective of this study was to analyze the pattern of the inflammatory response to heatstroke in an experimental baboon model with a view to identifying potential target for therapeutic interventions. Blinded analysis of plasma collected from 12 juvenile baboons (Papio hamadryas) in heatstroke was used. Eight anesthetized animals were heat-stressed in an incubator at 44 degrees C to 47 degrees C until rectal temperature was 42.5 degrees C (moderate heatstroke; n = 4) or systolic arterial pressure fell to <90 mmHg (severe heatstroke; n = 4) and were allowed to recover at room temperature. Four sham-heated animals served as a control group. We performed sequential measurement of cytokines. The rectal temperature on completion of heat stress was 42.5 degrees C +/- 0.0 degrees C and 43.3 degrees C +/- 0.1 degrees C in moderate and severe heatstroke, respectively. Heat stress elicited early, simultaneous release of anti-inflammatory cytokines and chemokines (IL-10, IL-1ra, sTNFr I and II, and IL-8). Circulating levels of IL-12p40 were significantly decreased, whereas TNFalpha, IL-1beta, and IL-4 were below the detection limit in all animals. No baboon survived severe heatstroke; there was neurological morbidity without mortality in moderate heatstroke. Nonsurvivors displayed significantly greater activity/alterations in inflammation markers than survivors. Sham-heated animals had no evidence of inflammation activation. These results show that heatstroke activates complex systemic inflammatory and regulatory responses associated with outcome. Further definition of this ambivalent response is needed before identification of target of successful modulation may become possible.