National reflection on organs-on-chip for drug development: New regulatory challenges.

Organs-on-chip (OoC) are innovative and promising in vitro models, particularly in the process of developing new drugs, to improve predictivity of preclinical studies in humans. However, a lack of regulatory consensus on acceptance criteria and standards around these technologies currently hinders their adoption and implementation by end-users. A reflection has been conducted at the National Agency for Medicines and Health products safety (ANSM) in order to address this issue, which has gained momentum at the international level in recent years. If the subject of OoC is of international interest, France is also in the process of structuring an OoC network, in order to best support the emergence of this new technological innovation. Focusing on liver-on-a-chip, the authors drafted a first list of regulatory requirements to help standardize these devices and their use. Technological and biological relevance of liver-on-a-chip was also evaluated, in comparison with current in vitro and in vivo models, based on the available literature. The authors offer an analysis of the current scientific and regulatory situation, highlighting the key regulatory issues for the future.

Perception of pharmacy students toward opioid-related disorders and roles of community pharmacists: A French nationwide cross-sectional study.

Background: Community pharmacists are among the frontline health professionals who manage patients with an opioid-related disorder (ORD). Pharmacists frequently have a negative attitude toward these patients, which could have a negative impact on their management. However, education on ORD may improve the attitude of future healthcare professionals. This cross-sectional study aimed to assess French pharmacy students' perceptions of ORD. Methods: This online survey was performed by emails sent to French pharmacy schools (between January 14, 2019 and May 31, 2019). The primary outcome was the perception (visual analogic scale) of ORD as a disease, the roles of community pharmacies (delivery of opioid agonist therapy-OAT and harm reduction kits), and the efficacy of OAT. The secondary outcomes assessed professional experience, university experience of and education on ORD, and the individual characteristics of students. Results: Among the 1,994 students included, 76.3% perceived ORD as a disease and felt that it was normal for pharmacists to deliver OAT (78.9%) and harm reduction kits (74.6%). However, only 46.9% perceived OAT as being effective. Multivariable analyses showed that females had a more positive perception in recognizing ORD as a disease. The progression through university years increased the positive perception of ORD as a disease and the delivery of OAT and harm reduction kits by pharmacists. Education on substance-related disorders had no impact on any scores. Students who had already delivered OAT had a negative perception of their efficacy. The students who had already performed pharmacy jobs or traineeships had a negative perception of harm reduction kit delivery. Conclusion: Education on substance-related disorders had no impact on students' perceptions. It seemed that the maturity acquired through university years had a stronger impact on the students' perceptions of ORD. Efforts must be made to improve our teaching methods and reinforce the confidence of students in the roles of community pharmacists.

Metallic Profile of Whole Blood and Plasma in a Series of 99 Healthy Children.

In recent years, special emphasis has been put on heavy metals. Children are very sensitive to accumulation of metals. Furthermore, as regards elements, the reference values in children are scarce in the literature as it is difficult to obtain the large quantity of blood necessary to analyze many metals by the conventional atomic absorption spectrometry technique. An inductively coupled plasma mass spectrometry (ICP-MS) procedure that uses a reduced sample of 0.3 mL whole blood or plasma is adapted to multielemental determinations. We applied a previously validated technique for adults that simultaneously quantifies 25 elements by ICP-MS in whole blood and 23 in plasma in a series of 99 healthy children ranging from under 5 years to <18 years, without exposure to metal or drug-containing metals. The aims of the study were to compare metallic concentrations according to the age among children and metallic concentration differences between children and adults. The blood and plasma pediatric metallic profile is a practical useful tool for many purposes in clinical toxicology, forensic toxicology and any cases of metal environmental exposure.

Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment.

Experimental studies investigating the effects of endocrine disruptors frequently identify potential unconventional dose-response relationships called non-monotonic dose-response (NMDR) relationships. Standardized approaches for investigating NMDR relationships in a risk assessment context are missing. The aim of this work was to develop criteria for assessing the strength of NMDR relationships. A literature search was conducted to identify published studies that report NMDR relationships with endocrine disruptors. Fifty-one experimental studies that investigated various effects associated with endocrine disruption elicited by many substances were selected. Scoring criteria were applied by adaptation of an approach previously used for identification of hormesis-type dose-response relationships. Out of the 148 NMDR relationships analyzed, 82 were categorized with this method as having a "moderate" to "high" level of plausibility for various effects. Numerous modes of action described in the literature can explain such phenomena. NMDR can arise from numerous molecular mechanisms such as opposing effects induced by multiple receptors differing by their affinity, receptor desensitization, negative feedback with increasing dose, or dose-dependent metabolism modulation. A stepwise decision tree was developed as a tool to standardize the analysis of NMDR relationships observed in the literature with the final aim to use these results in a Risk Assessment purpose. This decision tree was finally applied to studies focused on the effects of bisphenol A.

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.

Ecological risk assessment of the presence of pharmaceutical residues in a French national water survey.

In this study, we focused on the list of 33 chemicals that was established through a French national prioritisation strategy. Assessing the potential risks to the environment was a step-wise procedure: (i) we determined the Predicted Environmental Concentration (PEC) of all molecules measured in the national survey based on the highest recommended dose used, (ii) we used the Measured Environmental Concentration (MEC) and the Predicted No-Effect Concentration (PNEC) to establish the Risk Quotient (RQ) based on either a PEC/PNEC (estimated risk) or MEC/PNEC (real risk) ratio. The risk assessment was performed using a binary ecological classification suggesting that appreciable risk is likely (RQ⩾1). Of the 15 molecules quantified in the survey, 12 had a PEC higher than the action limit value of 0.01µg/L. According to the EU Guideline, environmental risk was estimated as likely for the following five compounds: acetaminophen (RQ=1.6), ibuprofen (RQ=600), diclofenac (RQ=15), oxazepam (RQ=2.1) and carbamazepine (RQ=3.2). Only ibuprofen was identified as posing real environmental risk based on its MEC (RQ=1.9).

[Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis]. / Les grands traits de la pharmacocinétique du delta-9-tétrahydrocannabinol (THC); les nouveaux cannabinoïdes de synthèse; le cannabis et la sécurité routière.

Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11-OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself.

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.

Assessment of the health risks related to the presence of drug residues in water for human consumption: application to carbamazepine.

Pharmaceutical residues have been detected at low (usually ng/L) concentrations in drinking water sources. The detection of drugs in water intended for human consumption (WIHC) has raised questions of safety. In the absence of regulatory or other official guidance, water utilities are faced with a problem of which pharmaceutical residues should be monitored and the toxicological limits that should be required. In this essay, we define an approach for the assessment of health risks related to chemicals found in drinking water. We use the examples of carbamazepine and its main metabolite 10,11-epoxycarbamazepine to demonstrate our approach, which involves application of the following algorithm: (1) when there is human or animal toxicity data, a toxicity reference value (TRV) can be calculated; (2) when this is not applicable, an attempt should be made to derive the TRV using known information about the minimum therapeutic dose (MTD); and (3) when no applicable data is available, at all, a threshold of toxicological concern (TTC) should be estimated. In the case of carbamazepine, where relevant toxicological data exists, we derived a TRV, based on the known minimum therapeutic dose (MTD). For carbamazepine's metabolite 10,11-epoxycarbamazepine, there is no toxicological data, so we applied the TTC approach. Using this approach, and combining our estimates with what is known about these chemicals' margin of exposure (MOE), suggests that there is likely to be no appreciable risk to human health exposure to carbamazepine or its major metabolite, even given the inevitable uncertainties in exposure scenarios.

Impact of drugs on the environment: state of play, risks, evaluation, communication.

The aim of this Round Table was to perform an initial assessment of the state of play of the impact of drugs on the environment. Demographic growth throughout the world and drug consumption which is constantly on the increase result in an ever increasing presence of medicinal substances in the various compartments (air, water, soil) with potential repercussions on the environment and on health. For the first time, the Giens pharmacology workshop have scheduled this topic outside the conventional sphere of action of Giens. A very high level of interest in this topic came forward both from the members of the round table and the listeners and it is certain that the round table opens the door to new initiatives for a subject about which there is still little knowledge. The following issues were therefore successively addressed: the fragmentation of the knowledge about the subject and its deficiencies concerning the impact on health, both of the wastes as a whole and that of specific drugs, the performances of the water treatment methods, the sources of pollution, the environmental impact, the lines of regulatory development, the impact on the environment and health and the training programmes to be set up among all protagonists, both professional and in the general public.

[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.

The toxic effects of toluene on the optokinetic nystagmus in pigmented rats.

The effects of 375 mgm(-3) (100 ppm) toluene in air inhalation were evaluated on pigmented rats during either repeated exposures over five consecutive days 3h a day or during a single 4-h exposure. At the end of the inhalation period, the animals were returned to fresh air to evaluate their ability to recover optokinetic performance. The optokinetic responses were analyzed using a magnetic search coil technique previously described. After repeated toluene exposure, the eye position at rest of all the rats was unsteady. In response to visual stimulation, the eye velocity was slower and more irregular than in the control state. At the end of the stimulation, the environment of the animals became stationary, but the eye did not immediately return to a fixed stable position. A similar effect was observed after a single exposure. An increase of the optokinetic deficit was observed after single or repeated 375 mgm(-3) toluene exposures. No recovery was observed even after a single exposure. In view of the fact that toluene is a widely used solvent, these results show that inhalation of low concentrations, even for short single exposures, must be taken into account, because gaze destabilization could cause vertigo symptoms.

[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.

Ethical observations on the choice of parenteral solvents. Choice of parenteral solvent....

The parenteral administration of insoluble drugs leads to the use of biologically active solvents inducing effects associated with ethical cause of concern including pain and pharmacological interactions. Selected vehicles currently used were ethically and scientifically reviewed. Our investigations allowed reinforcing the formulation decision tree with an ethical point of view. The last generation of cyclodextrin appears to be the safest solvent. Second choice could be lipidic emulsions, third choice being co-solvents, and finally non-ionic surfactants because of their hypersensitivity reactions. Screening tests including pH, osmolality measurements, cytotoxicity, and hemotoxicity, should allow to check the formulation tolerance before the animals' administration.