Alprazolam misuse: Analysis of French Addictovigilance Network data from 2011 to 2020.

OBJECTIVES: Alprazolam, a high-potency and short-acting anxiolytic benzodiazepine, is one of the most misused benzodiazepines in France. In the context of various reports on alprazolam misuse during the COVID-19 pandemic, the objective of this study was to assess alprazolam abuse potential by analyzing French addictovigilance and international data. METHODS: Data collected from 2011 to 2020 using the following epidemiological tools of the French Addictovigilance Network were analyzed: spontaneous reports (SRs), OPPIDUM (addiction care center data), OSIAP (falsified prescriptions), DRAMES (substance-related deaths), and chemical submission surveys. Moreover, the VigiBase™ database was analyzed to evaluate alprazolam abuse liability worldwide. RESULTS: During the study period, 675 SRs concerning alprazolam misuse were recorded (sex ratio: Ì´1; median age: 39 years). The desired effects were intensification of the therapeutic anxiolytic effect, euphoric effect, and management of substance withdrawal. Alprazolam was the third and first benzodiazepine listed in OPPIDUM and OSIAP surveys. Analysis of the SR and OPPIDUM data showed a recent increase in the alprazolam-opioid combination. In DRAMES data, alprazolam was directly linked to 11 deaths (associated with opioids in 10/11). VigiBase™ data analysis highlighted that France was the third country with the most cases of alprazolam misuse. The disproportionality analysis showed that in France, alprazolam was associated with higher risk of misuse and dependence compared with other benzodiazepines: reporting odds ratio=1.43, (95% CI: 1.04-1.95) and=1.97 (95% CI:1.50-2.59), respectively. CONCLUSIONS: This study highlighted an increase in various signals of alprazolam abuse in France, and an increased use of the alprazolam-opioid combination that was also linked to most of the recorded alprazolam-linked deaths. These signals have been reported also in the international literature, and should be thoroughly investigated.

Adverse events of recreational cannabis use during pregnancy reported to the French Addictovigilance Network between 2011 and 2020.

Cannabis is the main illicit psychoactive substance used by pregnant women in France. The aim of the present national survey was to describe adverse events (AEs) of recreational cannabis use during pregnancy reported to the French Addictovigilance Network (FAN). Spontaneous reports (SRs) of AEs related to recreational cannabis use during pregnancy were collected by the FAN between 01/01/2011 and 31/01/2021 (excluding cannabidiol and synthetic cannabinoids). Over the study period, 160 SRs involved cannabis use alone or in association with tobacco (59% of all SRs) which increased. Among the 175 maternal AEs, the most commons were psychiatric AEs experienced by 96 (64.9%) women, in particular cannabis use disorders (n = 89, 60.1%), dependence (n = 54, 36.5%) and abuse (n = 21, 14.2%). Among the 57 fetal AEs, the most common were heart rhythm disorders that affected 25 (16.9%) fetuses and intrauterine growth restriction (IUGR) (n = 20, 13.5%). Among the 140 neonatal AEs, the most common were IUGR experienced by 39 (26.3%) newborns and prematurity (n = 32, 21.6%). Twelve cases of congenital malformations were observed and 4 intrauterine/neonatal deaths. Furthermore, some of these AEs (n = 13) were unexpected. Cannabis use during pregnancy has problematic consequences for both mothers and infants who need close monitoring.

Chronic intraperitoneal injection of polyethylene glycol 200 in mice induces hippocampal neuroinflammation.

In vivo treatment of hydrophobic substances requires the use of organic solvents, which are often toxic. Consequently, polyethylene glycols (PEGs), which are considered as nontoxic, have been widely used for many years in chemistry and biology. We used PEG 200, which was administrated by intraperitoneal (i.p.) injection once a week to mice. After 4 months of injections, at the dose of 1.67 mL/kg, a surprising increase in expression of GFAP (glial fibrillary acidic protein) and IBA1 (ionized calcium binding adaptor molecule 1), glial markers of astrocytes and microglia respectively, was observed in the mice's hippocampus. These results were associated with a dramatic increase in pro-inflammatory cytokine interleukin-1ß (IL-1ß) expression, all together suggesting an inflammatory process. It is important to communicate these results to the scientific community to provide awareness of this potential effect when PEG 200 is used under similar conditions as a vehicle in mice.

Adverse events of recreational cannabis use reported to the French addictovigilance network (2012-2017).

AIMS: To describe the adverse events (AEs) of recreational cannabis use in France between 2012 and 2017. METHODS: AEs related to recreational cannabis use, alone or in combination with alcohol and/or tobacco reported to the French Addictovigilance Network were analysed (excluding cannabidiol and synthetic cannabinoids). RESULTS: Reporting of AEs tripled between 2012 (n = 179, 6.3%, 95% confidence interval [CI] = 5.4-7.2) and 2017 (n = 562, 10.1%, 95% CI = 9.3-10.9), reaching 2217 cases. They concerned mainly men (76.4%) and users aged between 18 and 34 years (18-25: 30.9%; 26-34: 26.3%, range: 12-84 years). Cannabis was mainly inhaled (71.6%) and exposure was most often chronic (64.2%). Many types of AEs were reported: psychiatric (51.2%), neurological (15.6%), cardiac (7.8%) and gastrointestinal (7.7%), including unexpected AEs (n = 34, 1.1%). The most common effect was dependence, ranging from 10.1% (95% CI = 7.9-12.3) to 20.3% (95% CI = 17.3-23.2) over the study period. Cannabinoid hyperemesis syndrome (n = 87, 2.8%) emerged from 2015. Deaths accounted for 0.2% of all AEs (4 men and 3 women aged on average 35 years). A chronic pattern of cannabis use was reported in 4 of them (intracranial hypertension in the context of lung cancer, suicide, cerebral haematoma, neonatal death with concomitant chronic alcohol use), while in the other cases the toxicological analysis identified cannabis use (ruptured aneurysm and unknown aetiology). CONCLUSION: This study showed a multitude of AEs related to recreational cannabis use, including unexpected AEs and deaths. It highlights the problem of dependence and the emergence of cannabinoid hyperemesis syndrome.

Trans ε-Viniferin Decreases Amyloid Deposits With Greater Efficiency Than Resveratrol in an Alzheimer's Mouse Model.

In a previous study, we showed that viniferin decreased amyloid deposits and reduced neuroinflammation in APPswePS1dE9 transgenic mice between 3 and 6 months of age. In the present study, wild type and APPswePS1dE9 transgenic mice were treated from 7 to 11 or from 3 to 12 months by a weekly intraperitoneal injection of either 20 mg/kg viniferin or resveratrol or their vehicle, the polyethylene glycol 200 (PEG 200). The cognitive status of the mice was evaluated by the Morris water maze test. Then, amyloid burden and neuroinflammation were quantified by western-blot, Enzyme-Linked ImmunoSorbent Assay (ELISA), immunofluorescence, and in vivo micro-Positon Emission Tomography (PET) imaging. Viniferin decreased hippocampal amyloid load and deposits with greater efficiency than resveratrol, and both treatments partially prevented the cognitive decline. Furthermore, a significant decrease in brain uptake of the TSPO PET tracer [18F]DPA-714 was observed with viniferin compared to resveratrol. Expression of GFAP, IBA1, and IL-1ß were decreased by viniferin but PEG 200, which was very recently shown to be a neuroinflammatory inducer, masked the neuroprotective power of viniferin.

Natural stilbenes effects in animal models of Alzheimer's disease.

Alzheimer's disease is one of the most frequent neurodegenerative diseases. This pathology is characterized by protein aggregates, mainly constituted by amyloid peptide and tau, leading to neuronal death and cognitive impairments. Drugs currently proposed to treat this pathology do not prevent neurodegenerative processes and are mainly symptomatic therapies. However, stilbenes presenting multiple pharmacological effects could be good potential therapeutic candidates. The aim of this review is to gather the more significant papers among the broad literature on this topic, concerning the beneficial effects of stilbenes (resveratrol derivatives) in animal models of Alzheimer's disease. Indeed, numerous studies focus on cellular models, but an in vivo approach remains of primary importance since in animals (mice or rats, generally), bioavailability and metabolism are taken into account, which is not the case in in vitro studies. Furthermore, examination of memory ability is feasible in animal models, which strengthens the relevance of a compound with a view to future therapy in humans. This paper is addressed to any researcher who needs to study untested natural stilbenes or who wants to experiment the most effective natural stilbenes in largest animals or in humans. This review shows that resveratrol, the reference polyphenol, is largely studied and seems to have interesting properties on amyloid plaques, and cognitive impairment. However, some resveratrol derivatives such as gnetin C, trans-piceid, or astringin have never been tested on animals. Furthermore, pterostilbene is of particular interest, by its improvement of cognitive disorders and its neuroprotective role. It could be relevant to evaluate this molecule in clinical trials.

Severe craving associated with kaolin consumption.

PURPOSE: Kaolin eating is an ancestral and worldwide tradition, particularly in women in order to relieve nauseas and abdominal troubles. Nevertheless, damaging effects such as anemia and intestinal troubles are well documented. However, compulsive disorders associated with kaolin intake are less known. RESULT: We reported in this paper a severe craving observed in a young woman consuming kaolin for several years, associated with a microcytic iron-deficiency non-regenerative anemia. CONCLUSION: This paper allows to draw attention among physicians who are rarely informed of this practice imported from abroad and have consequently a limited role in informing patients of the potential deleterious side effects of geophagia.

[Illogical association nalmefene and opioids: Analysis in the French pharmacovigilance database]. / Association illogique nalméfène et opioïdes : analyse dans la base française de pharmacovigilance.

INTRODUCTION: Nalmefene, an opioid antagonist, causes withdrawal syndromes in patients exposed to an opioid agonist. Despite its contraindication, this illogical drug association persists, especially with opioid substitution drugs (ODS). We measured the benefits of the modification in the summary of product characteristics (SPC) in March 2015 and the package leaflet of Selincro® in September 2016 on this misuse. MATERIAL AND METHOD: We analyzed the observations regarding a use of nalmefene with an opioid between September 2014 and August 2017 in the French pharmacovigilance database and the laboratory. RESULTS: The combination nalmefene and methadone was reported in about half of the cases (46/90). Observations were highest between October 2015 and March 2016 (29/90) and then decreased. Those with self-medication have increased. From October 2016, declarations become rarer. CONCLUSION: The effect of modifications in the SPC and the package leaflet on the use of nalmefene with ODS was real and progressive.

Relevance of electroencephalogram assessment in amyloid and tau pathology in rat.

In order to contribute to a better knowledge on the relationship between amyloid and tau pathology, and electroencephalography (EEG) disturbances, the aim of this study was to evaluate the effects of injection of beta amyloid Abeta(1-42) peptide, tau (a recombinant AAV (Adeno-Associated Virus) containing the human transgene tau with the P301 L mutation on rats and the combination of both, on the power of brain's rhythm (delta, theta, alpha, beta and gamma waves) during the different sleep/wake states of animals by EEG recording. Currently, no preclinical studies explore the effect of the tau pathology on EEG. The experimentations were performed 3 weeks and 3 months post injections. Beta amyloid deposits and hyperphosphorylated Tau are observed by immunohistofluorescence, only in the hippocampus. Furthermore, using a radial arm water maze, the main effect was observed on working memory which was significantly impaired in Abeta-Tau group only 3 months post injections. However, on EEG, as early as the 3rd week, an overall decrease of the EEG bands power was observed in the treated groups, particularly the theta waves during the rapid eye movement (REM) sleep. Beta amyloid was mainly involved in these perturbations. Obviously, EEG seems to be an interesting tool in the early diagnostic of amyloid and tau pathologies, with a good sensitivity and the possibility to perform a follow up during a large period.

Natural polyphenols effects on protein aggregates in Alzheimer's and Parkinson's prion-like diseases.

Alzheimer's and Parkinson's diseases are the most common neurodegenerative diseases. They are characterized by protein aggregates and so can be considered as prion-like disease. The major components of these deposits are amyloid peptide and tau for Alzheimer's disease, α-synuclein and synphilin-1 for Parkinson's disease. Drugs currently proposed to treat these pathologies do not prevent neurodegenerative processes and are mainly symptomatic therapies. Molecules inducing inhibition of aggregation or disaggregation of these proteins could have beneficial effects, especially if they have other beneficial effects for these diseases. Thus, several natural polyphenols, which have antioxidative, anti-inflammatory and neuroprotective properties, have been largely studied, for their effects on protein aggregates found in these diseases, notably in vitro. In this article, we propose to review the significant papers concerning the role of polyphenols on aggregation and disaggregation of amyloid peptide, tau, α-synuclein, synphilin-1, suggesting that these compounds could be useful in the treatments in Alzheimer's and Parkinson's diseases.

Ultrastructural study of liver and lead tissue concentrations in young mallard ducks (Anas platyrhynchos) after ingestion of single lead shot.

Lead (Pb) represents a serious threat to wildlife and ecosystems. The aim of this study was to examine the subcellular effects of dietary Pb pellet ingestion on mallard (Anas platyrhynchos) livers. After ingestion of a single Pb shot (LS4 size class: 0.177 ± 0.03 g) in 41 mallard ducks (22 males and 19 females) versus 10 controls (5 males and 5 females), all 7-week old, a morphologic study was conducted by TEM (transmission electron microscopy) of liver at the subcellular level. The results in treated mallards showed at a magnification of 2500 X that hepatic parenchyma was altered as evidenced by intralysosomal electron-dense deposits, which are compatible with Pb deposits. Further, at a higher magnification (15,000 X) in both genders, deterioration of mitochondria was observed in which the crests and, to a lesser extent, outer membrane were lysed. While the rough endoplasmic reticulum was fragmented, intracytoplasmic electron-dense material compatible with Pb deposits was maximally visible, thereby underscoring the deeply destructive effect of this metal on the subcellular architecture of the liver. In addition, applying an optimized and validated method in a clean room using electrothermal atomic absorption spectrophotometer (ETAAS) with Zeeman background correction, the objective was to improve and refine certain indispensable measurements pertaining to Pb impregnation in tissues other than liver such as kidneys, bones, and feathers of mallards. Data demonstrated show that compared with controls, Pb accumulation increases significantly, not only in the liver (3-fold), but also in the bones and the feathers (14-fold). No significant difference was noted between males and females. Bearing in mind the marked subcellular toxicity attributed to Pb, this study reinforces present-day arguments advocating limitation of game consumption.

Copper brain protein protection against free radical-induced neuronal death: Survival ratio in SH-SY5Y neuroblastoma cell cultures.

In Creutzfeldt Jakob, Alzheimer and Parkinson diseases, copper metalloproteins such as prion, amyloid protein precursor and α-synuclein are able to protect against free radicals by reduction from cupric Cu+2 to cupreous Cu+. In these pathologies, a regional copper (Cu) brain decrease correlated with an iron, zinc or manganese (Mn) increase has previously been observed, leading to local neuronal death and abnormal deposition of these metalloproteins in ß-sheet structures. In this study we demonstrate the protective effect of Cu metalloproteins against deleterious free-radical effects. With neuroblastoma SH-SY5Y cell cultures, we show that bovine brain prion protein in Cu but not Mn form prevents free radical-induced neuronal death. The survival ratio of SH-SY5Y cells has been measured after UV irradiation (free radical production), when the incubating medium is supplemented with bovine brain homogenate in native, Cu or Mn forms. This ratio, about 28% without any addition or with bovine brain protein added in Mn form, increases by as much as 54.73% with addition to the culture medium of native bovine brain protein and by as much as 95.95% if the addition is carried out in cupric form. This protective effect of brain copper protein against free radical-induced neuronal death has been confirmed with Inductively Coupled Plasma Mass Spectrometry Mn and Cu measurement in bovine brain homogenates: respectively lower than detection limit and 9.01µg/g dry weight for native form; lower than detection limit and 825.85µg/g dry weight for Cu-supplemented form and 1.75 and 68.1µg/g dry weight in Mn-supplemented brain homogenate.

Optimisation of Direct Copper Determination in Human Breast Milk Without Digestion by Zeeman Graphite Furnace Atomic Absorption Spectrophotometry with Two Chemical Modifiers.

Milk is an important food in the human diet, and copper (Cu) in human milk is indispensable to children's normal growth and development. It is consequently important that Cu deficiency, occurring in malnourished women or in malabsorption following bariatric surgery, be prevented. The objective of this work is to provide hospital-based paediatricians with a tool enabling rapid measurement of Cu in human breast milk through a technique that biology laboratories can easily apply. Using electrothermal atomic absorption spectrophotometry with Zeeman correction, we have optimized this method with two chemical modifiers and without digestion for analytical procedure. Detection limits and quantification limits for Cu in human milk were found to be 0.077 and 0.26 µmol/L, respectively. Within-run (n = 30) and between-run (n = 15) variations in a pool of human milk samples were 1.50 and 3.62%, respectively. Average recoveries ranged from 98.67 to 100.61%. The reliability of this method was also confirmed by analysing certified reference material (10%). In breast milk samples collected from 100 lactating mothers, Cu mean (±1 SD) was 7.09 ± 1.60 µmol/L. In conclusion, with minimal preparation and quick determination, the method proposed is suitable for measurement of Cu in human breast milk.

Interlaboratory comparison study on lead in blood, in external quality assessment schemes since 1996: a progress report.

In 1992, at the request of the French labor ministry, an External Quality Control for lead in whole blood (F-EQCPbB) came into being. After 15 years (1996-2011), the ministry wished to exploit the database collected with a sufficient number of laboratories. Indeed, the number of participating laboratories had decreased from 73 to 41. However, the key finding pertained to the highly improved performance of the laboratories, which was associated with a spread of the results over the entire range of tested PbB (9 and 700 µg/l). So, it was that in laboratories having participated for >10 years, the good scores rose between 1996 and 2011 from 49% to 93%. To sum up, analysis has shown progressive and highly pronounced diminution of CVs (%) for all the ranges having undergone testing. We have observed increasing use of inductively coupled plasma with mass spectrometry (from 9% in 2005 to 29% in 2011) and decreasing use of electrothermal atomic absorption spectrometry. That said, and provided that they are based on the same degree of expertise in metrology, on all tested concentrations the two analytical techniques yield results that are not statistically different. Thanks to the F-EQCPbB, laboratories have enhanced their proficiency and registered demonstrably improved performance.

[The external quality assessment schemes for lead in blood organized by the French national agency for medicine and health product safety: a synthesis of 15 years of activity]. / L'évaluation externe de la qualité des analyses de plombémie organisée par l'Agence nationale de sécurité du médicament et des produits de santé : bilan de 15 années de contrôle.

In 1992, at the request of the French labor ministry following questions on the ability of medical biology laboratories to satisfactorily measure blood lead level (PbB), a national PbB quality control came into being. Only in 1996 did this external quality control include a number of laboratories sufficient to allow for a significant retrospective evaluation. After fifteen years (1996-2011), The French National Agency for Medicines and Health Products Safety wished to exploit the database collected. The number of participating laboratories went down from 73 to 41. On the other hand, the key finding pertained to the highly improved performance of the laboratories, which was associated with a spread decrease of the results over the entire range of tested PbBs (9 to 700 µg/L). Since 2006, we have observed increasing use of the inductively coupled plasma with mass spectrometry and decreasing use of electrothermal atomic absorption spectrometry. Provided that they rely on identical metrology expertise, the two analytical techniques lead to results on all the tested concentrations that are not statistically different.

If exposure to aluminium in antiperspirants presents health risks, its content should be reduced.

Since aluminium (Al) pervades our environment, the scientific community has for many years raised concerns regarding its safety in humans. Al is present in numerous cosmetics such as antiperspirants, lipsticks and sunscreens. Al chlorohydrate is the active antiperspirant agent in underarm cosmetics and may constitute for Al a key exposure route to the human body and a potential source of damage. An in vitro study has demonstrated that Al from antiperspirant can be absorbed through viable human stripped skin. The potential toxicity of Al has been clearly shown and recent works convincingly argue that Al could be involved in cancerogenic processes. Nowadays, for example, Al is suspected of being involved in breast cancer. Recent work in cells in culture has lent credence to the hypothesis that this metal could accumulate in the mammary gland and selectively interfere with the biological properties of breast epithelial cells, thereby promoting a cascade of alterations reminiscent of the early phases of malignant transformation. In addition, several studies suggest that the presence of Al in human breast could influence metastatic process. As a consequence, given that the toxicity of Al has been widely recognized and that it is not a physiological component in human tissues, reducing the concentration of this metal in antiperspirants is a matter of urgency.