[Recreational use of cannabis: From effects to harm. Epidemiological data]. / L'usage récréatif du cannabis : des effets aux méfaits. Données épidémiologiques.

As the medical use of so-called "therapeutic cannabis" is in the process of being approved in France, the opening to its recreational use is the next logical step, as it has been always the chronology followed in all countries. Indeed, those who have legalized the drug have previously approved its therapeutic use. This "justifying a project phase" stage seems unavoidable. Therefore, it is appropriate to recall the effects and misdeeds of the drug during its recreational use. The general population surveys carried out in France for 25 years by public health France and the French Observatory of Drugs and Drug Addiction, have followed the evolution of psychoactive substances consumption. Particular attention was focused on cannabis use, which, in a context of wide dissemination for a quarter of a century, rose steadily higher among younger generations, but also among older adults. France is the European country with the highest prevalence of cannabis use among young people and adults. Last 25 years, its diffusion has continued to expand, and the experimentation rate multiplied by near 4. Estimated at 12.7% in 1992, it reached 44.8% in 2017. Moreover, 25% of users in the year aged from 18 to 64 years old were at high risk of problematic use or dependence in 2017. This figure is worrying because it is constantly increasing; it affects 3% of 18-64-year-old, just over a million people.

Silver absorption and toxicity evaluation of silver wound dressings in 40 patients with chronic wounds.

BACKGROUND: Silver-containing dressings are considered to be safe even though there have been some reports of complications, including argyria and various organ system dysfunctions. Despite the widespread use of silver dressings, little research has been done regarding the absorption and toxicity of silver. OBJECTIVE: We aimed to study the systemic absorption of silver in patients with chronic inflammatory wounds and to determine associated factors of systemic silver absorption and evaluated its association with silver toxicity. PATIENTS AND METHOD: Prospective, longitudinal, observational, multicentre, open-label pilot study. Patients from the Dermatology Departments of Lorraine (France) with the following inclusion criteria: (i) a chronic wound of more than 6 weeks and (ii) an ulcer needing silver-containing dressing were included. Before and after 28 days of treatment, clinical characteristics of the wound were recorded; hemogram, hepatic and renal functions, albumin sera and serum silver level were measured. RESULTS: Half of the cases displayed raised levels of silver after 1 month of treatment. Predictive factors for systemic silver absorption were wound area, anaemia and malnutrition with anaemia and malnutrition confirmed on multivariate analysis. Wound vascularization may also play a role, as a higher absorption was observed in cases of wound granulation without arterial components. No toxicity was detected. This work has also emphasized the slow elimination of silver from the body. CONCLUSION: Both long-term application and iterative treatments with silver dressings should be discouraged, especially in the elderly, who often suffer from malnutrition and anaemia to avoid potential cumulative toxicity.

[Pharmacokinetics, metabolism, and analytical methods of ethanol]. / Éthanol : pharmacocinétique, métabolisme et méthodes analytiques.

Alcohol is a licit substance whose significant consumption is responsible for a major public health problem. Every year, a large number of deaths are related to its consumption. It is also involved in various accidents, on the road, at work, as well as during acts of violence. Ethanol absorption and its fate are detailed. It is mainly absorbed in the small intestine. It accompanies the movements of the water, so it diffuses in all the tissues uniformly with the exception of bones and fat. The major route of ethanol detoxification is located into the liver. Detoxification is a saturable two-step oxidation. During the first stage ethanol is oxidized into acetaldehyde, under the action of alcohol dehydrogenase. During the second stage acetaldehyde is oxidized into acetate. Genetic factors or some drugs are able to disturb the absorption and the metabolism of ethanol. The analytical methods for the quantification of alcohol in man include analysis in exhaled air and in blood. The screening and quantification of ethanol for road safety are performed in exhaled air. In hospitals, blood ethanol determination is routinely performed by enzymatic method, but the rule for forensic samples is gas chromatography.

Importance of ERK activation in As2O3-induced differentiation and promyelocytic leukemia nuclear bodies formation in neuroblastoma cells.

Neuroblastoma malignant cell growth is dependent on their undifferentiated status. Arsenic trioxide (As2O3) induces neuroblastoma cell differentiation in vitro, but its mechanisms still remains unknown. We used three human neuroblastoma cell lines (SH-SY5Y, IGR-N-91, LAN-1) that differ from their MYCN and p53 status to explore the intracellular events activated by As2O3 and involved in neurite outgrowth, a morphological marker of differentiation. As2O3 (2µM) induced neurite outgrowth in all cell lines, which was dependent on ERK activation but independent on MYCN status. This process was induced either by a sustained (3 days) or a transient (2h) incubation with As2O3, indicating that very early events trigger the induction of differentiation. In parallel, As2O3 induced a rapid assembly of promyelocytic leukemia nuclear bodies (PML-NB) in an ERK-dependent manner. In conclusion, mechanisms leading to neuroblastoma cell differentiation in response to As2O3 appear to involve the ERK pathway activation and PML-NB formation, which are observed in response to other differentiating molecules such as retinoic acid derivates. This open new perspectives based on the use of treatment combinations to potentiate the differentiating effects of each drug alone and reduce their adverse side effects.

[Workplace testing of drugs of abuse and psychotropic drugs]. / Exploration biologique des drogues illicites et des médicaments psychotropes en milieu professionnel.

In France, workplace testing of drugs of abuse and psychotropic drugs is rarely performed; meanwhile it is a major public health problem. Furthermore, France is the European country that has been associated with the highest increase of the use of drugs of abuse, particularly cannabis. So workplace biological screening of drugs of abuse and of psychotropic drugs exposure is of major concern. New analytical techniques have been developed during the last years. The authors will consider analytical screening of drugs of abuse and particularly the comparison of analytical techniques applied to urine and saliva. The advantages and the disadvantages of these two matrices will be considered. Urinary and blood quantification will be reviewed, but also the interest of hair testing to explore chronic exposure. The research of psychotropic drugs in biological fluids is also a part of this paper. New analytical trends are promising and complete analysis of these substances will be soon routinely possible in blood using a single spot test.

Aluminum and vaccines: Current state of knowledge.

French people have never been so wary about vaccines. The use of aluminum salts in vaccine adjuvants to enhance effectiveness is one of the major reasons for this lack of confidence. The direct toxicity of aluminum is often put forward. Direct toxicity of aluminum has long been known-especially with occupational exposure-to be associated with characteristic clinical manifestations and increased blood aluminum level. Intoxication related to the excessive amount of an element in the body, whether be it lead poisoning following exposure to lead or mercury poisoning for instance, is always associated with metal increase in biological media. To date no link has been established between the direct toxicity of aluminum and vaccines. Aluminum levels in biological media of vaccinated subjects are not different from those of unvaccinated subjects. This is consistent with the very small amount of aluminum contained in one dose of vaccine. Indirect toxicity of aluminum was suggested to explain macrophagic myofasciitis in humans in 2011, a disease that could be mediated by an autoimmune/autoinflammatory mechanism. This hypothesis has recently been refuted in a large pharmaco-epidemiological study proving that aluminum-containing adjuvants of vaccines are not responsible for this autoimmune/autoinflammatory syndrome.

Application of inductively coupled plasma mass spectrometry multielement analysis in fingernail and toenail as a biomarker of metal exposure.

The application of inductively coupled plasma mass spectrometry (ICP-MS) to multielement analysis in fingernail and toenail as biological indices for metal exposure is presented. The ICP-MS measurements were performed using a Thermo Elemental X7CCT series. Fingernail specimens were obtained from 130 healthy volunteers, and paired fingernail and toenail samples from 50 additional healthy volunteers of both sexes were collected as well. After warm water and acetone decontamination, 20 mg fingernails and toenails were acid mineralized after a decontamination procedure, and 32-34 elements were simultaneously quantified after acid dilution following water calibration. Li, Be, B, Al, V, Cr, Mn, Co, Ni, Cu, Zn, Ga, Ge, As, Se, Rb, Sr, Mo, Pd, Ag, Cd, Sn, Sb, Te, Ba, La, Gd, W, Pt, Hg, Tl, Pb, Bi, and U could be validated in fingernail and toenail samples. Linearity was excellent, and the correlation coefficients were above 0.999. Quantification limits ranged from 0.04 pg/mg or ng/g (U) to 0.1 ng/mg or microg/g (B). Because of the lack of available certified nail reference material, an adequate quality assessment scheme was ensured by comparison with an interlaboratory nail-testing procedure, and the results showed optimal consistency for elements tested. Results are presented and compared with published multielement data. Six cases of domestic exposure to lead were diagnosed based on fingernail analysis. Application of ICP-MS multielement analysis in fingernail and toenail as a biomarker of metal and nonmetal exposure permits greater noninvasive control of industrial, domestic, or environmental exposure and is very useful for epidemiological studies.

MRI gadolinium-based contrast agents. Radiologists beware!

Gadolinium (Gd) is used in contrast agents as it enhances magnetic resonance imaging (MRI) signals. To reduce Gd toxicity, it is chelated into linear or macrocyclic complexes. Eight Gd-containing contrast agents have been approved by the European Medicines Agency (EMEA) for use in MRI, and six by the US Food and Drug Administration. Stability depends upon its physicochemical properties. When renal function is normal, the Gd is quickly cleared from the body by the kidneys. For patients with chronic kidney disease, the elimination is greatly reduced and Gd may be released from its chelate and deposit in body tissues, leading to nephrogenic systemic fibrosis (NSF). More than 200 cases of NSF have been reported in the world. NSF is characterized by an extensive fibrosis of skin and tissues, a very severe affection with possible lethal outcome. We propose recommendations to avoid the risk of NSF.

[Delta-9-tetrahydrocannabinol pharmacokinetics]. / Pharmacocinétique du delta-9-tétrahydrocannabinol (THC).

Delta-9-tetrahydrocannabinol (Delta-9-THC) is the main psychoactive ingredient of cannabis. Smoking is currently most common use of cannabis. The present review focuses on the pharmacokinetics of THC. The variability of THC in plant material which has significantly increased in recent years leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. This variability of THC content has an important impact on drug pharmacokinetics and pharmacology. After smoking THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level near 160 ng/mL occurs approximately 10 min after inhalation. THC is eliminated quickly from plasma in a multiphasic manner and is widely distributed to tissues, which is responsible for its pharmacologic effects. Body fat then serves as a long-term storage site. This particular pharmacokinetics explains the noncorrelation between THC blood level and clinical effects as is observed for ethanol. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20 and 100% of parent, respectively). The elimination of THC and its many metabolites, mainly THC-COOH, occurs via the feces and urine for several weeks. Thus, to confirm abstinence, urine THC-COOH analysis would be a useful tool. A positive result could be checked by gas chromatography-mass spectrometry THC blood analysis, indicative of a recent cannabis exposure.

[Illicit drugs, medications and traffic accidents]. / Drogues, médicaments et accidentologie.

The European Union (EU) has 25 member-states and 455 million inhabitants. Statistics on traffic accidents in the EU show that more than 45,000 people are killed annually, including 5200 in France. At the same time, nearly two million persons in the EU require medical treatment for traffic-accident-related injuries, including 109,000 in France. In addition, traffic accidents are the major cause of death of those individuals aged 15 to 24 years. One third of the EU inhabitants will be hospitalized during their life due to a traffic accident with a cost over 160 billion euro (2-3% of the Gross Domestic Product). An important contributing factor to crashes is the use of alcohol and/or illicit drugs or medication when driving, as they exert negative effects on cognition and psychomotor functions. For illicit drugs, abuse of cannabis with or without alcohol is a major concern for the EU. In fact, three million Europeans use cannabis daily and 80% of them drive after use. A number of French studies since 1999 have underlined the high prevalence of cannabis found in the blood of injured or killed drivers. From medical or judicial observations, it is clear that cannabis use increases the risk of traffic accidents. Many groups outside Europe have also shown the association between drug abuse and crashes. The number of casualties related to certain medicines, especially benzodiazepines remains at a high level, particularly in the elderly. In many countries the prevalence of medicinal drugs associated with car accidents is higher than with cannabis. Annex III of the European Union Council Directive of July the 29th 1991 in fact states that a driving license should not be issued to or renewed for applicants or drivers who are dependent on psychotropic substances or use them regularly. Recently, France has categorized the medicinal drugs available in the country by using three pictograms: level one yellow, "be careful"; level two orange, "be very careful"; level three red, "don't drive". It is an important campaign that increases awareness among the public and the medical professionals about the potential dangerous effects of medicinal drugs when driving. The EU objective of reducing the number of fatalities to 25,000 by 2010 will require strengthening measures against the use of alcohol, illicit and medicinal drugs by not well-informed drivers. It is not only a really great challenge, but also a significant investment towards improving public health in France as well as in Europe.

Evaluation of the risk of contamination of surgical personnel by vaporization of oxaliplatin during the intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC).

AIMS: To evaluate if oxaliplatin is likely to vaporize under HIPEC conditions and to see if it could be a source of pulmonary contamination for surgeons. METHODS: Three oxaliplatin concentrations (230, 460 and 920 mg oxaliplatin/l), 3 heating temperatures (41, 43 and 45 degrees C) and 3 bubbling durations (30, 60 and 90 min) were tested. Drug vaporization was evaluated by using inductively coupled plasma mass spectrometry (ICP-MS) to analyze platinum concentrations in the trap solutions. RESULTS: At all concentrations of oxaliplatin solutions, heating temperatures and bubbling trap periods, the quantities of vaporized platinum were always insignificantly lower than 1 microg/l. CONCLUSIONS: The experimental risk of pulmonary contamination of hospital staff during HIPEC procedure appears to be negligible. However a monitoring study with an analysis of samples of the operating theatre and urine from surgical personnel should be carried out to confirm these conclusions.

Systemic sclerosis and exposure to heavy metals: A case control study of 100 patients and 300 controls.

OBJECTIVE: This case control study assessed: 1) the relationship of systemic sclerosis (SSc) related to exposure to heavy metals; and 2) the risk of SSc related to occupational exposure in male and female patients. METHODS: From 2005 to 2008, 100 patients with a definite diagnosis of SSc were included in the study; 3 age, gender, and smoking habit matched controls were selected for each patient. All SSc patients and controls underwent detection and quantification of heavy metal traces in hair samples, using multi-element inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: SSc patients exhibited higher median levels of the following metals: antimony (p=0.001), cadmium (p=0.0003), lead (p=0.02), mercury (p=0.02), molybdenum (p=0.04), palladium (p<0.0001) and zinc (p=0.0003). A marked association between SSc and occupational exposure was further found for: 1) antimony (p=0.008) and platinum (p=0.04) in male patients; and 2) antimony (p=0.02), cadmium (p=0.001), lead (p=0.03), mercury (p=0.03), palladium (p=0.0003) and zinc (p=0.0001) in female patients CONCLUSION: The results show the impact of occupational risk factors in the development of SSc for: antimony, cadmium, lead, mercury, molybdenum, palladium and zinc. Thus, occupational exposure should be systematically checked in all SSc patients at diagnosis. Finally, the association between SSc and occupational exposure may be variable according to patients' gender.

[Which biological matrix for cannabis testing?]. / Mise en évidence des cannabinoïdes: quel milieu biologique?

Decisive analytical progress for biological cannabis testing has been achieved over the past ten years. These major contributions allow to accurately identify and quantify in detail the substances present in the body following cannabinoid exposure. Fast and reliable onsite urine testing is used to implement the French law on narcotic drugs and its relationship to motorway safety. A positive test result will indicate a very recent exposure which is detectable up to five days following intake. Then a clinical examination and blood collection are performed by a physician, with a subsequent blood tetrahydrocannabinol (THC) analysis by authorized professionals registered at the judicial court of appeal. A result higher than the cut-off value is associated with a very recent cannabis exposure. Blood, urine, saliva and sweat cannabis determination are assessed according to the most recent pharmacokinetic and analytical data.

Toxicological analysis in agitated patients.

OBJECTIVE: To assess the toxicological etiologies in agitated patients and to evaluate their initial clinical diagnosis in the light of toxicological results analysis. DESIGN: Prospective clinical study. SETTING: Emergency Department (ED) in a 2,650-bed University Hospital. PATIENTS: Fifty-eight consecutively enrolled patients admitted to the ED in agitated states over a 6-month period. MEASUREMENTS AND RESULTS: All patients underwent laboratory tests including blood glucose, ethanol and serum drug screening. Toxicology tests were conducted by fluorescence polarization immunoassay and confirmed by high performance liquid chromatography/diode array detector and gas chromatography-mass spectrometry. The physician's initial diagnosis was evaluated in the light of toxicological analysis results. Serum toxicological analysis revealed that 50/58 patients were under the influence of alcohol and/or a drug. Benzodiazepines (22/58), selective serotonin reuptake inhibitors (5/58) and opiates (4/58) were the most frequently observed. The initial clinical diagnosis was alcohol intoxication in 39 patients, although 1 patient was not under the influence of alcohol and 16 also had benzodiazepine in their sera. Moreover, the diagnosis of serotonin syndrome was overlooked in two patients. CONCLUSION: Most agitated patients were under the influence of alcohol and/or a drug. Benzodiazepine alone or in association with alcohol was surprisingly frequent. A serotonin syndrome may explain the agitation state.

[Biochemical modifications in a case of analbuminemia (author's transl)]. / Modifications biochimiques dans un cas d'analbuminémie

A new case of analbuminemia is described for a six month old child of Algerian origin. The serum albumin concentration was 64 mg/l and its immunochemical action was identical to that of normal albumin. The system reacted by an increase of the synthesis of globulins. For the subject, the alpha1-antitrypsin, ceruloplasmin, haptoglobin, alpha2-macroglobulin, transferrin and immunoglobulins M contents were three times higher than the standard figures. However, it was possible to show that the presence of free bilirubin independent from proteins could be detected at a concentration of 17 mumol/l.

A fatal case of mercuric cyanide poisoning.

A 57-year-old pharmacist was found dead 11 days after his disappearance. At the autopsy, samples of blood, urine, gastric content were obtained. Presence of ethanol, cyanide and mercury were detected in some samples. Cyanide and mercury were identified and quantified using high-performance liquid chromatography with diode array detector (HPLC) in fluorescence mode and ICP with mass selective detector (ICP-MS) respectively. Whole blood concentrations of ethanol was 1.72 g/L. Cyanide and mercury concentrations in whole blood were respectively 0.16 and 3.8 mg/L. Concentrations of cyanide (27 mg/L) and mercury (150 mg/L) in gastric contents prove a massive oral ingestion of mercuric cyanide or mercuric oxycyanide occurred. In this case report, the death was attributed to the combined toxicity of cyanide and mercury.

Identification of ten corticosteroids in human hair by liquid chromatography-ionspray mass spectrometry.

This paper describes a screening procedure based upon high-performance liquid chromatography-ionspray mass spectrometry for the identification of ten corticosteroids in human hair: triamcinolone, prednisolone, prednisone, methylprednisolone, cortisone, cortisol, beta- and dexamethasone, flumethasone and beclomethasone. Hair strands were washed in methylene chloride, pulverized in a ball mill and 50 mg of the powdered hair were incubated in 1 ml Soerensen buffer, pH 7.6 for 16 h at 40 degrees C, in presence of 50 ng cortisol-d3 used as internal standard. Purification of the incubation medium was achieved on SPE C18 Isolute extraction columns. The eluates were evaporated to dryness and resuspended in 30 microliters MeOH before analysis by HPLC-IS-MS in positive and negative modes of detection. The validation parameters were found satisfactory for a corticosteroid screening procedure. The correlation coefficient of the calibration curve ranged from 0.939 to 0.997, showing linearity between 0.1 and 10 ng/mg, excepted for beclomethasone which was between 0.2 and 10 ng/mg. Extraction recovery at 4 ng/mg ranged from 43.2 to 85.7%. Repeatability (CV values) at 4 ng/mg ranged from 6.1 to 17.5%. The limits of detection ranged from 0.03 to 0.17 ng/mg for a signal-to-noise ratio of 2. The detection of prednisone and beclomethasone in three hair specimens obtained from forensic and clinical cases have documented corticosteroids incorporation into human hair.

Fatal overdoses of tramadol: is benzodiazepine a risk factor of lethality?

Tramadol is a centrally acting analgesic agent used in the treatment of mild to moderate pain. It has a low affinity to opioid receptors and inhibits the reuptake of norepinephrin and serotonin producing an analgesic action by blocking nociceptive impulses in the spine. Although 21 drug-combined fatalities including tramadol have been reported, only two fatal overdoses in adults with tramadol alone have been reported to date. We report four additional lethal intoxications, assess the toxicity of tramadol, the detection method and the possible interaction with other central nervous system (CNS) depressants, particularly benzodiazepines. Similarities between tramadol and buprenorphine are discussed, and a possible cytochrome P450-based interaction between tramadol and benzodiazepine is considered. To our knowledge, this relationship has never been reported in the literature.