Search

Background: Mycophenolate mofetil (MMF) has been used to treat interstitial lung disease (ILD), but mycophenolate (MPA) pharmacokinetics was not reported for this use. This ancillary study of the EVER-ILD protocol aimed at describing the pharmacokinetic variability of MPA using population modelling in ILD., Methods: Concentrations of MPA were measured during an 8-h course for 27 ILD patients treated with 1000 mg MMF b.i.d. Absorption, distribution and elimination of MPA were described using population compartment models with first-order transfer and elimination rate constants, while accounting for both absorption peaks using gamma absorption models., Results: The pharmacokinetics of MPA was best described using a two-compartment model and two gamma absorption models, model performances of this model were still similar to those of a one gamma absorption model. This pharmacokinetics seemed to be notably influenced by body weight, renal function and inflammatory status. The distribubtion value area under the concentration curve between two administrations of MMF was AUC 12  = 52.5 mg.h/L in median (interquartile range: 42.2-58.0 mg.h/L)., Conclusion: This is the first study reporting MPA pharmacokinetics in ILD. This pharmacokinetics appears to be similar to other indications and should be further investigated in future studies., (© 2024 The Author(s). Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Background: Due to its psychoactive effects, ketamine has become a drug used for non-medical purpose., Objectives: To assess the latest trends in ketamine use among people with substance use disorder and to characterize its clinical complications using complementary health data sources of the French Addictovigilance Network., Methods: First, we extracted all reports involving ketamine from 2012 to 2021 from the database of the OPPIDUM program (i.e., a multicentric program conducted in collaboration with hundreds of substance abuse treatment facilities that collects data on drugs used by subjects with substance use disorders). We described the reports globally and the changes from 2012 to 2021. Second, we extracted all cases involving ketamine from July 2020 to December 2022 from the French National Pharmacovigilance Database (BNPV). We identified the cases related to ketamine use among people with substance use disorder and described them., Results: There was a 2.5-fold increase in the number of ketamine users with substance use disorder in the OPPIDUM program, from 35 (0.7%) subjects in 2012 to 89 (1.7%) subjects in 2021. There was an increase in the proportion of subjects who were daily users, had distress upon discontinuation, and presented addiction. There were 238 cases related to ketamine use among people with substance use disorder in the French National Pharmacovigilance Database from July 2020 to December 2022. Among them, 94 (39.5%) cases involved ketamine use disorder, 20 (8.4%) cases involved urinary tract and kidney symptoms, and 13 (5.5%) cases involved hepatobiliary symptoms., Conclusion: The trend observed over 10 years reflects the growth in ketamine use among people with substance use disorder, although it does not allow to estimate the rates of non-medical use of ketamine in the general population. Ketamine-induced uropathy and cholangiopathy are reported in ketamine users with substance use disorder, especially in case of repeated and/or prolonged use of high doses., (© 2024 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Background: The combination dextropropoxyphene/paracetamol (DXP/P) was the most prescribed opioid analgesic until its withdrawal in 2011., Objectives: This study investigated dispensations of analgesics in chronic users of DXP/P during the 18 months following its withdrawal., Methods: A cross-sectional study repeated yearly was conducted by using the French reimbursement database from 2006 to 2015. Chronic DXP/P users were defined as patients who received at least 40 boxes of DXP/P in the year prior to withdrawal. Data on analgesic dispensing were analyzed at DXP/P withdrawal (T0) and then every 6 months for 18 months., Results: A total of 63 671 subjects had a DXP/P reimbursement in the year prior to its discontinuation, of whom 7.1% were identified as chronic users (mean age: 71.5 years, women: 68.7%). Among the patients taking DXP/P alone at T0 (74.6%), one fourth switched to a peripheral analgesic, one fourth to a combination of peripheral analgesic/opioid, one fourth to another opioid, and the others mainly discontinued their treatment (14.1%) or died. During the following 12 months, most of the subjects taking only peripheral analgesics continued this treatment, while half of the subjects with a combination of opioid/peripheral analgesic or taking only an analgesic remained on this type of treatment., Conclusion: Eighteen months after DXP/P withdrawal, more than 10% of patients stopped taking an analgesic. Vigilance is required regarding any change in analgesics by regularly reassessing patients' pain and, in the case of opioid treatments, by monitoring the risk of use disorders., (© 2023 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

A fifth vaccine against Covid-19, NVX-CoV2373 Nuvavoxid® (Novavax), a protein-based adjuvanted vaccine, was recently marketed in Europe. The main clinical trial before marketing concluded to a 'vaccine efficacy' of 89.7% without talking about other validated efficacy parameters. We further analysed the data of this clinical trial using the different validated methods of risk expression: absolute risks (AR), AR reduction (ARR) and number needed to treat (NNT). ARR and NNT values were 1.22% and 82, respectively, for an RR value of 0.10. Description of these parameters allowed defining some interesting characteristics of NVX-CoV2373 efficacy according to age, race, variant and coexisting illness. Finally, we ask that the results of clinical trials be systematically presented, using not only RR but also including AR, ARR and NNT., (© 2022 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Clinical pharmacology is the study of drugs in humans, from first-in-human studies to randomized controlled trials (RCTs) and benefit-risk ratio assessment in large populations. The objective of this review is to present the recent innovations that may revolutionize the development of drugs in the future. On behalf of the French Society of Pharmacology and Therapeutics, we provide recommendations to address those future challenges in clinical pharmacology. Whatever the future will be, robust preliminary data on drug mechanism of action and rigorous study design will remain crucial prior to the start of pharmacological studies in human. At the present time, RCTs remain the gold standard to evaluate the efficacy of human drugs, although alternative designs (pragmatic trials, platform trials, etc.) are emerging. Innovations in healthy volunteers' studies and the contribution of new technologies such as artificial intelligence, machine learning, and internet-based trials have the potential to improve drug development. In the field of precision medicine, new disease phenotypes and endotypes will probably help to identify new pharmacological targets, responders to therapies, and patients at risk for drug adverse events. In such a moving landscape, the development of translational research through academic and private partnership, transparent sharing of clinical trial data and enhanced interactions between drug experts, patients, and the general public are priority areas for action., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Prominent features of esketamine (e.g., similar mechanism of action as ketamine and target population) require to be vigilant regarding its benefits/risks balance and its risks of abuse in real-life settings. The aim of this study was to review all available pharmacological and clinical data to assess the abuse potential of esketamine shortly after its marketing. This multidimensional study is a quantitative and qualitative analysis of complementary data sources, ranging from preauthorization data (i.e., fundamental pharmacology and clinical trials) to real-life settings data (i.e., pharmacovigilance databases and web forums). According to esketamine pharmacology, its psychoactive effects play a role both in its therapeutic effect and its abuse potential. Only one out of the three short-term efficacy trials found a significant difference between esketamine and placebo in treatment-resistant depression. Beside adverse events that may be sought for abuse purpose (e.g., dissociation, sedation, euphoric mood, hallucination, feeling drunk, and derealization), clinical signs related to substance use disorder (e.g., tolerance, withdrawal syndrome, and drug dependence) and misuse (e.g., off-label use) were also identified in pharmacovigilance databases. Analysis of pharmacovigilance narratives and web forums showed that esketamine psychoactive effects are appreciated by some patients, while they are badly experienced by others. Strict compliance with the market authorization, close monitoring of patients by psychiatrists, and surveillance of any signs of misuse, abuse, or dependence must be part of any treatment course., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Following minor changes of excipients of Levothyrox®, the French Pharmacovigilance Database was overwhelmed by patients' spontaneous reports of adverse drug reactions associated with the new formula. After noticing that most of these reports differed from those related to other drugs, we aimed to characterize their features and compared them with spontaneous reports associated with other chronic treatments as comparators. We randomly sampled patient reports associated with either Levothyrox® new formula (n = 200) or comparator drugs (n = 200) from March 2017 till March 2018 from the National Pharmacovigilance Database. We evaluated the number of incriminated drugs and adverse drug reactions per report and verified whether they were "expected" or not according to the Summary of Product Characteristics. Levothyrox®-associated reports included, on average, more adverse drug reactions (8 ± 4) than comparators (2 ± 2, P < 0.01) and mentioned mostly one drug (98.5% of reports), whereas comparators mentioned two at least (P < 0.001). The quantitative distribution of adverse drug reactions per report differed quite significantly, appearing almost Gaussian for Levothyrox® whereas Poisson-like for comparators (P < 0.0001). Age did not differ significantly in the two groups (54.2 vs. 49.7, NS), but female predominated in Levothyrox® group (94.5%) as compared with comparators (60.8%, P < 0.001). A mere third of the Levothyrox®-associated adverse drug reactions were deemed "expected," versus two thirds for comparators (P < 0.001). The pattern of spontaneous reports associated with Levothyrox®, whether fueled by media or influenced by social networks, appears atypical, as compared with that of comparators. Such reports, by their abundance, may impair the automatic detection of relevant concomitant signals., (© 2022 Société Française de Pharmacologie et de Thérapeutique.)

Polypharmacy is a growing concern often described only in older people by cumulating all drugs taken. We aimed to describe chronic polypharmacy in France, regardless of age. A cross-sectional descriptive study was performed using the 1/97th representative sample of the French health insurance nationwide database (EGB). All subjects alive on January 1, 2015, and covered by the French healthcare insurance were included, and their information collected until December 31, 2015, or date of death. Drug exposures were estimated from drug dispensing dates and treatment durations. Chronic uses of drug were defined as drugs used daily for more than 6 months. Chronic polypharmacy corresponded to the exposure to five chronic uses of drug or more. In 2015, information of 584 862 subjects was collected (mean age: 42.2 years). Prevalence of chronic polypharmacy was 5.6% and incidence 1.1%. Prevalence of chronic polypharmacy increased noticeably from 0.2% for subjects aged 18 to 40 years to a maximum of 29.2% for subjects aged 80 to 90 years and then decreased to 23.6% for subjects aged 90 years and more. Lipid-modifying agents were the most frequent drugs involved in chronic polypharmacy (10% of exposure). According to age, the most important differences between the younger and older people were found for cardiovascular drugs (43.5% vs. 45.7% of exposure, respectively) and nervous system drugs (13.7% vs. 11.5% of exposure, respectively). This population-based study showed increasing of chronic polypharmacy and evolution of chronic drug patterns with age., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Diarrhoea is an adverse drug reaction of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril + valsartan. It was also described with olmesartan and more recently with other angiotensin receptor blockers. The study was performed to compare diarrhoea reports in pharmacovigilance databases with sacubitril + valsartan and valsartan. The study used reports of diarrhoea with the ARNI sacubitril + valsartan registered: first in the French PharmacoVigilance Database (FPVD) and second in Vigibase®, the WHO Global Individual Case Safety Report database. After description of the main characteristics, disproportionality analyses were performed. Results are reported as reporting odds ratios (ROR) with 95% confidence interval. We found 29 reports of diarrhoea with sacubitril + valsartan in the FPVD and 686 in Vigibase®. With sacubitril + valsartan, diarrhoea occurred more frequently in males around 70 years with a median delay of 3 days. With valsartan, diarrhoea occurred more frequently in females around 68 years with a median delay of 0.5 days. In the FPVD, a significant association was found with sacubitril + valsartan in comparison with valsartan alone before (ROR = 8.78 [5.19-14.85]) and after (ROR = 11.19 [5.89-21.25]) exclusion of concomitant drugs known to be associated with diarrhoea. A significant association was also found in Vigibase® after adjustment on age, sex, reporter and its location (ROR = 1.31 [1.14-1.50]). Diarrhoea reported with sacubitril + valsartan has marked differences in gender, delay of occurrence and frequency of reporting in comparison with diarrhoea with valsartan. From a pharmacodynamic point of view, these results suggest a specific role of sacubitril in diarrhoea., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Accumulating evidence shows that some antidepressants are abused for their psychostimulant effects, but the extent of antidepressants abuse is unknown in subjects with opioid use disorders (OUD). The objective of this work is to assess the prevalence of antidepressant abuse and its correlates in subjects with OUD. Subjects ≥18 year-old in an opiate maintenance treatment (OMT) program who reported using an antidepressant were selected from the OPPIDUM program from 2011 to 2020. The outcome was antidepressant abuse. Antidepressant abusers were identified as subjects reporting at least one of the following behaviors: "drug abuse," "concomitant use of alcohol," "illegal obtaining," and "dose higher than recommended in the Summary of Product Characteristics." Among the 83 040 observations of subjects ≥18 year-old in an OMT program included in the OPPIDUM program from 2011 to 2020, 2708 (3.3%) subjects reported using an antidepressant in monotherapy. Among them, there were 385 (14.2%) abusers. The proportion of abusers was the highest for amitriptyline (n = 31, 25.0%). In multivariate analysis, antidepressant abuse was positively associated with amitriptyline (OR 2.07, 95% CI [1.16, 3.73]; p = 0.015), unemployment (OR 1.52, 95% CI [1.16, 2.01]; p = 0.003), the use of intravenous route of administration (OR 1.77, 95% CI [1.12, 2.80]; p = 0.014), and the use of benzodiazepines (OR 1.53, 95% CI [1.21, 1.94]; p < 0.001). Clinicians should be aware of the risk of antidepressant abuse when prescribing in subjects with OUD, accounting for their heterogeneous pharmacological properties that may account for their abuse potential., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Owing to a broad spectrum and low cost antimicrobial, cotrimoxazole is largely prescribed. However, its use is associated with various adverse drug reactions (ADRs) that warrant to ensure rational prescribing. This study aimed to describe spontaneous reports of cotrimoxazole ADRs and to evaluate the quality of prescription in patients who had ADRs. Suspected cotrimoxazole-induced ADRs cases reported to the Bordeaux regional pharmacovigilance center (France) during a 5-year period were described. Seriousness was assessed according to international criteria. Quality of prescription was assessed by compliance with the Summary of Product Characteristics (SPC) and relevance of cotrimoxazole indication. Then, an ADR was considered as preventable if the cotrimoxazole indication was not relevant, or potentially preventable if indication was relevant but the prescription was not compliant with the SPC. A total of 96 cases were analyzed: median age was 60.5 years (range: 4-94); 59.4% of patients were male. ADRs were mostly cutaneous disorders (n = 46) and hematological disorders (n = 25). A total of 60 serious ADRs occurred in 55 patients. Prescribers complied with all SPC recommendations in 21.9% of cases. Indication of cotrimoxazole was relevant or highly relevant in 41 cases. In 58% of cases, the occurrence of a cotrimoxazole-induced ADR would have been preventable or potentially preventable. In a context of increasing interest for this antibiotic to treat infections due to resistant bacteria, physicians should be more aware of the potential consequences of inappropriate prescribing cotrimoxazole and reserve its use when there is no alternative and under suitable monitoring., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Diarrhea is an adverse drug reaction (ADR) widely reported with olmesartan, an angiotensin II receptor blocker (ARB). Isolated case reports described this ADR with other ARBs. The present study was performed to investigate if, among the different ARBs, some drugs are more at risk of diarrhea than others. Using VigiBase®, the WHO pharmacovigilance database, we performed a disproportionality analysis (case/noncase study). Cases were reports with the MedDRA PT term « diarrhea » and noncases all other reports registered during the same period in Vigibase® from April 6, 1995 to December 31, 2020. After comparison of ARBs and angiotensin converting enzyme inhibitors (ACEIs), the main analysis was a comparison of the diarrhea reporting risk between each ARB and the seven other ARBs. Results are reported as reporting odds ratio (ROR) adjusted on age, gender, exposure to antihypertensive, and antidiabetic drugs with their 95% confidence interval. Among the 22,429,334 deduplicated reports registered in VigiBase® during the study period, 73,507 involved ARBs, including 2119 diarrhea. The reporting risk of diarrhea was higher with ARBs than with ACEIs (ROR = 2.06 (1.55-2.17)). Diarrhea with ARBs mainly occurred in females with a mean age of 65 years. After exclusion of olmesartan (to minimize a notoriety bias), two ARBs were significantly associated with diarrhea: eprosartan (ROR = 1.93 (1.32-2.72) and telmisartan (ROR = 1.41 (1.23-1.62) but not the six others. The present study found first that diarrhea is more frequently reported with ARBs than with ACEIs and second that the risk of diarrhea differs according to the different ARBs. Diarrhea with ARBs is not a class effect., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Several vaccines are being developed as part of the COVID-19 pandemic. The results of clinical trials for these vaccines were published with efficacy values of more than 90%, using mainly relative risk (RR). In this paper, we decided to reanalyse the data using the different validated methods of risk expression. Using main publications, absolute risks (AR), AR reduction (ARR), number needed to treat (NNT) were calculated for five COVID-19 vaccines (tozinameran Comirnaty®, Moderna, Vaxzevria®, Janssen, and Sputnik V vaccines). AR, ARR, NNT, and RR values varied according to COVID-19 vaccines. The order of the different vaccines was not the same according to the chosen efficacy parameters. This is a further example of the need to express results of clinical trials, using not only RR, but also AR, ARR, and NNT in order to clearly present the clinical interest of drugs., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Several papers have reported that tramadol can induce hypoglycemia. However, in some reports, confounding factors can be found, like coadministration of hypoglycemic drugs. We used the WHO pharmacovigilance database (VigiBase®) to investigate whether tramadol alone could be associated with hypoglycemia. All 2010–2019 ICSRs (Individual Case Safety Reports) with the PT term “hypoglycemia” and tramadol were included. Two disproportionality analyses were performed: 1/after inclusion of all reports, 2/after exclusion of concomitant hypoglycemic drugs. Results are expressed as Reporting Odds Ratios (ROR; 95% CI). Among 10 038 436 ICSRs, 97 639 were included. In comparison with codeine, a significant association was found between tramadol use and reports of hypoglycemia before [ROR = 1.54 (1.43–1.66)] or after [ROR = 1.43 (1.31–1.56)] exclusion of hypoglycemic drugs. Tramadol use is associated with a higher risk of hypoglycemia reports than codeine, the other step 2 analgesic, in the presence as well as in the absence of other hypoglycemic drugs. We concluded that hypoglycemia is an adverse drug reaction of tramadol, which can be observed in diabetic as well as in non-diabetic patients., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Buprenorphine has been used in pain and opioid addiction management for nearly 25 years. Compared to methadone, buprenorphine is thought to exhibit less side effects and respiratory depression in case of accidental or suicidal overdose. The aim was to describe the characteristics of exposures reported to a French Poison Control Center (PCC). We conducted a retrospective study including all buprenorphine exposures for which advice of our PCC was required between 2009 and 2018. After data extraction from the electronic medical files and anonymous transfer to an Access base, a statistical descriptive analysis was performed focusing on adolescents over 10 years old and adults. One hundred and ninety-nine cases were analyzed. The major circumstances of exposure were suicide attempts and overdoses in patients with previously identified substance abuse. Buprenorphine exposures have been reduced by 50% between 2009 and 2018. Coingestions, often with benzodiazepines or antidepressants, were almost systematic and 79% of all the series exhibited at least one symptom. Among the symptomatic cases, neurological effects were the most frequent (83%) and respiratory symptoms occurred in 13%. No deaths were registered. Severity did not exceed PSS1 in 80% of all the cases. Treatment was mainly symptomatic even though naloxone was required in at least 5% of the symptomatic cases. Within 24 h after exposure, 120 patients were discharged from the emergency department. Despite loss to follow-up, our results suggest that buprenorphine is relatively safe., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Background: Some case reports have described parkinsonism with amiodarone. We investigated a putative association between parkinsonism and exposure to amiodarone., Methods: We used the WHO pharmacovigilance database (VigiBase ® ). All adverse drug reactions with 'Parkinson-like events' and amiodarone were included. Four disproportionality analyses were performed: 1/after inclusion of all reports, 2/according to sex, 3/for the twenty last years (2000-2019), and 4/after exclusion of concomitant drugs known to induce parkinsonism (antipsychotic, antivertigo, antiemetic antinauseant drugs, flunarizine). Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC)., Results: No significant association was found in the whole population [ROR = 0.83 (0.65-1.06), IC = -0.7 (IC 025  = -0.65)], in men, in women, for the 2000-2019 years, or after exclusion of drugs inducing parkinsonism., Conclusion: We failed to find any signal of parkinsonism with amiodarone. We suggest that reports of parkinsonism with amiodarone could be mainly explained by other underlying causes., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Doctor shopping enables subjects to receive more than the prescribed dose out of any medical management, which suggests a search for high doses and makes doctor shopping a relevant proxy for misuse and potential abuse. Therefore, this study aimed to identify and characterize profiles of subjects with doctor-shopping behavior for methylphenidate in the entire French population. This study is a cross-sectional study of doctor-shopping behavior for methylphenidate in France, in 2016, using the Système national des données de santé, and accounting for overlapping prescriptions. Subjects who obtained >840 mg by doctor shopping were defined as subjects with heavy doctor-shopping behavior, and subjects who obtained >0 mg and ≤840 mg by doctor shopping were defined as subjects with light doctor-shopping behavior. A total of 63 739 subjects were included, and received 339.6 kg of methylphenidate. Among them, 216 (0.3%) subjects had heavy doctor-shopping behavior, and 313 (0.5%) subjects had light doctor-shopping behavior. Compared with subjects with light doctor-shopping behavior, subjects with heavy doctor-shopping behavior were older (64% of 30- to 49-year-old subjects vs. 77% of ≤17-year-old subjects; P < 0.001), received more concomitant dispensings of antipsychotics (37% vs. 26%; P = 0.008) and opioid maintenance treatments (50% vs. 6%; P < 0.001), and had more prescribers (4 [IQR = 2-5] vs. 2 [IQR = 2-3]; P < 0.001). In the French context where prescription and dispensing of methylphenidate are highly regulated and methylphenidate is much less used than in other countries, these results are a warning signal to avoid trivializing methylphenidate in adults., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

As the number and severity of complications related to cocaine use reported to the French Addictovigilance Network have increased, the French health authorities requested a national epidemiologic study of the data collected by this network from 2010 to 2016. For this purpose, the spontaneous reports (SRs) linked to cocaine notified by health professionals were analyzed as well as the data from the pharmacoepidemiological surveys OPPIDUM (observation of illegal drugs and misuse of psychotropic medications) and DRAMES (deaths related to the abuse of licit and illicit psychoactive substances). In total, 1 265 SRs were analyzed (510% increase from 2010 to 2016). Users were mainly men (952/1 261; 75%), with a median age of 35.0 years [IQ 25-75 : 28-42]. Cocaine was consumed through the intranasal route by 52% of users (416/797), followed by intravenous administration (32%, 253/797) and inhalation (24%, 190/797). The use of cocaine powder and crack cocaine was reported in 70% (475/674) and 23% (154/674) of SRs, respectively. Cocaine was consumed with other psychoactive substances and alcohol in 47% (603/1265) and 60% (387/649) of cases, respectively. The main cocaine-related complications were psychiatric complications (29%), neurologic complications (24%) and cardiovascular complications (23%). Analysis of the OPPIDUM survey data showed that in 2016, 15.9 and 2.4% of the included subjects consumed cocaine or crack cocaine the week preceding the survey, the highest rate for the 2006-2016 period. The DRAMES survey indicated that cocaine-related deaths increased by threefold from 2014 to 2016. These data confirm that cocaine use in France is worrying with an increase in the number of severe complications and deaths., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Data are lacking on the impact of ACEI/ARB exposure on unfavorable outcome in the population of patients hospitalized for COVID-19 with hypertension/cardiovascular disease, particularly in Europe. The ACE-CoV study was designed to assess this question. The study was conducted in the Covid-Clinic-Toul cohort, which contains data about all patients hospitalized at Toulouse University hospital, France with a SARS-CoV-2 infection since March, 2020. We selected the patients with a history of cardiovascular disease (heart failure or coronary disease) and/or arterial hypertension. We conducted a subgroup analysis in patients with arterial hypertension. ACEI/ARB exposures at admission were assessed. The outcome was composite: admission to intensive care unit, need of mechanical ventilation or death during the 14 days after admission to hospital. We used logistic regression models with propensity scores (PS) weighted by overlap weighting (OW) and inverse probability of treatment weighting (IPTW). Between March 2020 and April 20, 2020, the Covid-Clinic-Toul included 263 patients. Among them, 111 were included in the ACE-CoV study population. In OW-PS-adjusted analyses, the association of exposure to ACEIs or ARBs with outcome occurrence was OR: 1.56 (95% CI: 0.73-3.33). It was 0.99 (95% CI: 0.68-1.45) for ACEIs and 1.64 (95% CI: 0.77-3.50) for ARBs. Analyses with weighting by the IPTW-PS method gave similar results. Results were similar when considering the subgroup of patients with arterial hypertension. The ACE-CoV study found no association between exposure to ACEIs or ARBs and unfavorable outcome in hospitalized patients for COVID-19 with a history of cardiovascular disease/arterial hypertension., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Chronic cannabis use can be associated with uncontrollable vomiting and abdominal pain. Diagnostic criteria for cannabinoid hyperemesis syndrome (CHS) were defined in 2012 by Simonetto et al. The objectives of this study were to describe the prevalence of CHS, the patients' epidemiological characteristics, and to show the difficulties encountered in caring for these patients in emergency departments, the extent of health care and an unsuitable follow-up in general practices. A prospective cohort of patients with CHS was recruited among a target population of patients leaving the adult emergency services of the Marseille hospitals Nord and La Timone between October 2017 and July 2018, with abdominal pain syndrome of unidentified etiology. Inclusion criteria for the CHS cohort were chronic cannabis use associated with nausea and vomiting. There were 48 patients included in the CHS cohort who took cannabis daily, in a target population of 2 848 patients (i.e. 1.6%). A hot shower was the most effective symptomatic treatment in 54.2% of cases. Patients suffering from CHS spent significantly more hours in emergency departments (11 vs. 6.5), and, on average, visits were more frequent (4.9 vs. 3). 20.3% of them were hospitalized to continue pain medication. Once out of hospital, follow-up was limited, and weaning off cannabis, the only etiological treatment, was difficult to set up. Informing patients about CHS is essential, and a hot shower could be systematically proposed, thus limiting an unnecessary extent of health care. CHS is genuine, medical staff should be made aware of it in occupational training, and it should be seriously considered in health policies., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Considering their novelty and cost, post-marketing evaluation is highly relevant for new anticancer drugs. Identify and characterize available and potentially useful databases for post-marketing evaluation of these specific drugs is necessary. A review was conducted to identify available and accessible databases to study the post-marketing evaluation of drugs in real-life care setting. Databases identified have been classified into medico-administrative databases, medical record databases, and databases resulting from ad hoc collections. Taking as examples databases available in France, each type was described as well as its strengths and limits for a potential use in the oncology field. Record linkage of medico-administrative databases could cover almost the whole population and is now used to evaluate anticancer drugs (e.g., Système National des Données de Santé). Large medical record databases are still lacking, but efforts are currently made to give access to hospital data warehouses for research purposes. Finally, databases resulting from ad hoc collections are also available for some cancer localizations and allow to obtain highly valuable clinical and biological data. A range of important and valuable databases exist but, individually, none is enough to answer to all questions from health authorities, healthcare professionals, and patients. In order to obtain a complete overview on utilization, associated health outcomes and costs of these drugs, it seems necessary to better interlink available databases., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Vitiligo is a common depigmenting disorder ensuing the loss of epidermal melanocytes. It is a multifactorial disease with immunological, genetic and environmental factors including drug exposure. The purpose of the study was to investigate the drugs and therapeutic subclasses associated with vitiligo occurrence reported in VigiBase ® , the WHO pharmacovigilance database. A case/non-case study was carried out by defining cases as vitiligo reports and non-cases as all other reports. The reporting odds ratio (ROR) was calculated for the 'suspected' drugs and drug classes according to ATC level 4. During the study period, 741 cases of vitiligo were registered. Mean age was 49 ± 20 years. The disproportionality analysis showed an association between vitiligo and pembrolizumab (ROR 116.9, 95% Confidence Interval (CI) 94.8, 144.3), nivolumab (ROR 22.6, 95% CI 15.8, 32.4), ipilimumab (ROR 41.7, 95% CI 25.0, 69.7), imiquimod (ROR 152.8, 95% CI 103.0, 226.7), adalimumab (ROR 3.8, 95% CI 2.5,5.8), infliximab (ROR 2.6, 95% CI 1.65, 4.01), alemtuzumab (ROR 27.8, 95% CI 17.6, 43.9), and ustekinumab (ROR 9.3, 95% CI 5.6, 15.6). Concerning the pharmacological classes ATC level 4, a significant association was found with monoclonal antibodies, interferons, selective immunosuppressants, TNF-alpha inhibitors, interleukin inhibitors, and topical antivirals. This study confirmed the expected associations between vitiligo and immune checkpoint inhibitors and strengthened the emerging signal about the association between vitiligo and imiquimod, TNF-alpha inhibitors and interferons. New signals were shown with selective immunosuppressants including alemtuzumab and interleukin inhibitors., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Psychotropic drugs (PD) are often used close to a cancer diagnosis and may be considered as a way of coping. We aimed to determine the incidence of anxiolytics, hypnotics, antidepressants, and antipsychotics initiation around a diagnosis of chronic myelogenous leukemia (CML). Population-based cohort: Data were extracted from Systeme National des données de Santé (SNDS, the French health insurance database) at the regional level (Midi-Pyrenees area, 2.9 million inhabitants). All newly diagnosed patients treated by a CML tyrosine kinase inhibitor (TKI) between 10/01/2011 and 04/01/2014 were included. Pre-CML (9 months before to 3 months before first TKI prescription-F-TKI) and CML (3 months before to 9 months after F-TKI) phases were defined. The main evaluation criterion was the initiation of PD during CML phase. Determinants associated with this incident PD use were studied through a logistic regression model. We compared pre-CML and CML healthcare consumption. The cohort included 103 patients (mean age of 60.8 years). PD initiation rate was 35.9%, anxiolytics being the most initiated PD (59.5%). Advanced age was associated with PD initiation (adjusted OR = 1.029, 95% CI = 1.001-1.056). The number of consultations during the pre-CML phase and female gender tended to be associated with increased risk of PD initiation in univariate analysis. For PD initiators, healthcare consumption was greater in CML but not in pre-CML phase. PD initiation is a frequent finding around a CML diagnosis. Its risk increases with age. It could be a way to identify a subgroup with higher healthcare consumption., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Self-medication (SM) is a common practice perceived by patients as harmless which can, however, entail health risks. The aim of the study was to identify drug-drug interactions (DDIs) involving SM drugs leading to adverse drug reactions (ADRs) in the National French Pharmacovigilance Database. All ADR reports from 1 January 1985 to 31 July 312018, coded as 'interaction' and 'self-medication', were selected and studied. Patient characteristics, the level and type of interaction, and the therapeutic classes of the drugs were examined. Adverse drug reactions were analysed and classified according to the system organ classes of the Medical Dictionary for Regulatory Activities. One hundred and three reports totalling 158 ADRs (71% severe cases) were included; 153 DDIs (59.5% pharmacodynamic) involving 234 drugs were identified. The latter included 119 SM drugs (51% available on prescription), mainly analgaesics, anti-inflammatory drugs, dietary supplements and antibiotics. Haemostasis disorders and renal failure were the most frequently reported ADRs. The analysis of reference documents raised concerns on the lack of information provided by package leaflets. In conclusion, the present study highlights the risks of medically unapproved re-use of prescription drugs or the consumption of dietary supplements without monitoring possible interactions and ADRs. Patient awareness could be improved by more regular updates of medication package inserts., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Differential shotgun proteomics identifies proteins that discriminate between sets of samples based on differences in abundance. This methodology can be easily applied to study (i) specific microorganisms subjected to a variety of growth or stress conditions or (ii) different microorganisms sampled in the same condition. In microbiology, this comparison is particularly successful because differing microorganism phenotypes are explained by clearly altered abundances of key protein players. The extensive description and quantification of proteins from any given microorganism can be routinely obtained for several conditions within a few days by tandem mass spectrometry. Such protein-centred microbial molecular phenotyping is rich in information. However, well-designed experimental strategies, carefully parameterized analytical pipelines, and sound statistical approaches must be applied if the shotgun proteomic data are to be correctly interpreted. This minireview describes these key items for a quick molecular phenotyping based on label-free quantification shotgun proteomics., (© 2020 The Authors. Environmental Microbiology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

In adults, statins safety profile is well known. However, literature data on their adverse drug reactions (ADRs) remain scarce in children in real-life setting. In order to better characterize ADRs related to 'real-life' use of statins in children, we reviewed statin-related ADRs recorded in the World Health Organization (WHO) global database of individual case safety reports (ICSRs), VigiBase. Methods. Individual case safety reports (ICSRs) in children (2-11 years) and adolescents (12-17 years) associated with statins from January 1, 1987, to July 18, 2017, were extracted from VigiBase. Characteristics of ICSRs, type of ADRs according to MedDRA classification (SOC and PT), and ICSR seriousness were described using SAS 9.4. A total of 311 ICSRs were identified for 8 statins with 712 ADRs. Musculoskeletal disorders (n = 85, 27.3%) were the first registered ADRs followed by general disorders (n = 67, 21.5%; mainly asthenia and pain). More than 1 out of 5 ADRs were 'injury, poisoning and procedural complications' (n = 67), mainly accidental or intentional exposures (n = 44, 14.1%), overdoses (n = 14, 4.5%), or off-label use (n = 11, 3.5%). Overall, 133 (42.8%) reports were 'serious', including 11 deaths. Deaths mainly involved adolescents with intentional overdose and completed suicide with other associated drugs in 75% of reports. Our study identified rare but serious safety issues (rhabdomyolysis, myalgia, and hepatocellular injury). These ADRs can impact quality of life or lead to life-threatening complications in children. Our results should be supplemented with other data sources. Spontaneous statin ADR reports in children to pharmacovigilance networks must be promoted., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Prednisone is an anti-inflammatory drug widely used in internal medicine and rheumatology, but dosing remains empirical. The active metabolite of prednisone is free prednisolone. The aim of this work was to build a population pharmacokinetic (PK) model that can predict free prednisolone concentrations in patients with inflammatory/immunologic conditions.A total of 107 patients from the department of internal medicine of Cochin hospital provided 343 observations. Blood samples drawn for biological analyses were used for drug determination. Total plasma prednisolone concentrations were measured by liquid chromatography-mass spectrometry, and the data were modelled using Monolix. The pharmacokinetics was ascribed a one-compartment open model with three transit compartments standing for the absorption and metabolism process. The model used predicts free concentrations that served to derive total concentrations given published binding constants. Only size parameters influenced the pharmacokinetics. Free prednisolone CL U /F and V U /F, scaled allometrically on lean body weight, were, respectively, 26.7 L/h and 94.3 L for 50 kg LBW. CL U /F interindividual variability was 0.20. The additive and proportional residual variabilities were, respectively, 4.3 µg/L and 0.20. The results point out some dosing issues, that is the possibility of under- or over-dosage in thin or overweight patients respectively., (© 2019 Société Française de Pharmacologie et de Thérapeutique.)

Methadone has been prescribed in France as opioid substitution therapy as a syrup formulation since 1995 and as capsules since 2008. Following two publications showing on a national scale the high risk of methadone poisoning in children and the lack of difference in poisoning severity between both methadone formulations, French health authorities chose to benefit from the experience acquired by the network of French poison centres concerning poisoning by this substitution medication. The aim of this study was to identify and compare the main circumstances of methadone exposure collected by a poison centre on a national scale over a period of 7 years. Retrospective descriptive study of cases of methadone exposure was compiled by the network of French poison centres between 15 October 2010 and 15 October 2017. Analysis of 1415 files revealed two major circumstances: 47% misuse and 41% suicide attempts. Severity scores evaluated according to the PSS were higher for misuse than for suicidal behaviour, despite the supposed ingested dose being statistically higher in the latter. The results also confirmed the lack of significant difference in methadone exposure between both of the formulations (syrup and capsules). This series of methadone exposure on a national scale is one of the largest compiled series in international medical literature. On the one hand, it highlights the severity of methadone poisoning (in suicidal behaviour and even more so in misuse behaviour), and on the other hand, it confirms that the capsule formulation does not seem to represent a higher risk than the syrup formulation., (© 2019 Société Française de Pharmacologie et de Thérapeutique.)

Buprenorphine is a µ-partial agonist and k-antagonist acting on central opioid receptors. Patented for analgesia in 1968, buprenorphine has been used as opioid substitutive therapy since the 1990s, as well as methadone. The aim was to document pediatric poisoning, to discover the severity, and to evaluate the treatment with naloxone. All pediatric poisonings reported to the poison control center Marseille (France)-from January 1, 2009 to December 31, 2018-were included. Analysis put value on gender, age, estimated quantity, symptoms and their delay, place of treatment, medical treatment, utilization of antidotes, severity of intoxications, and patients' outcome. Fifty-four infant poisonings with buprenorphine were recorded, doses varied between 1 and 36 mg, and children showed mainly neurological (somnolence, miosis…) and gastroenteric (vomiting) effects. Pulmonary effects were described for four children. According to the poisoning severity score, 8 intoxications were classified as 'no symptoms or signs', 37 as minor poisonings, 3 as moderate, none as severe or fatal and 6 were unknown. Medical care was required for 46 children, and four of them were treated with naloxone. Buprenorphine poisoning can cause neurological, gastroenteric, and respiratory symptoms. Even licking a tablet leads to intoxication because of maximal tablet's absorption while placing it under the tongue. Hospital admission is necessary even at small doses. Naloxone was efficient in the four described cases. Parents have to be aware of the poisoning risk with buprenorphine. Recently, commercialized instantly dissolving formulations could cause more severe intoxications., (© 2019 Société Française de Pharmacologie et de Thérapeutique.)

The early Frankia-Alnus symbiotic molecular exchanges were analyzed in detail by protein and RNA omics. For this, Frankia cells were placed in the presence of Alnus roots but separated by a dialysis membrane for 64 h. The bacterial cells were then harvested and analyzed by high-throughput proteomics and transcriptomics (RNA-seq). The most upregulated gene clusters were found to be the potassium transporter operon kdp and an ABC transporter operon of uncharacterized function. The most upregulated proteins were found to be acyl dehydrogenases and the potassium transporter Kdp. These suggest a preadaptation to the impending stresses linked to the penetration into isotonic host tissues and a possible rearrangement of the membrane. Another cluster among the 60 most upregulated ones that comprised two cellulases and a cellulose synthase was conserved among the Frankia and other actinobacteria such as Streptomyces. Cellulase activity was detected on CMC all along the length of the root but not away from it. Frankia alni ACN14a was found to be unable to respire or grow on glucose as sole carbon source. The cellulose synthase was found active at the tip of hyphae in response to Alnus root exudates, resulting in a calcofluor stained tip., (© 2019 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Atropinic drugs are known to potentially induce physical and/or mental impairments in the elderly. The aim of this study was to investigate trends of atropinic exposure in patients ≥65 years in France between 2006 and 2015. A repeated cross-sectional study was performed quarterly from January 1, 2006 to December 31, 2015, in the 'Echantillon Généraliste des Bénéficiaires (EGB)', a representative sample of the French population. Exposed patients were identified using the Anticholinergic Durán's list. Outcomes were rate of patients exposed to at least one atropinic drug (atropinic prevalence rate) and atropinic burden per patient (sum of atropinic burden scores). Interrupted time series were used to analyze the impact of market withdrawal of some drugs with atropinic properties during the period of the study. The number of patients ≥65 years registered in the EGB ranged from 75 611 in 2006 to 95 389 in 2015. Atropinic prevalence rate decreased significantly from 45.6% in 2006 to 33.2% in 2015 (-12.4%, slope significance P < 0.05). Subjects aged ≥85 years were the most exposed. Total atropinic burden decreased significantly between 2006 and 2015 (2.2 ± 1.7 in 2006; 2.0 ± 1.5 in 2015; slope significance P < 0.05), especially in patients ≥85 years. Market withdrawals for safety reasons of some atropinic drugs were significantly associated with a decrease in the atropinic prevalence rate (P < 0.05) and atropinic burden per patient (P < 0.05). In conclusion, atropinic drug exposure in the elderly significantly decreased in France between 2006 and 2015. This decrease can be partly explained by regulatory measures against some atropinic drugs., (© 2019 Société Française de Pharmacologie et de Thérapeutique.)

Drug-induced hypertension was described with several pharmacological classes, especially with serotonin reuptake inhibitors (SRIs). However, this link has remained controversial: the French summary of product characteristics specify a risk of hypertension only with paroxetine and sertraline. To identify a possible class effect common to all SRIs, our study investigated the reports of hypertension associated with SRIs in two pharmacovigilance databases. Two different types of investigations were performed: (i) a comparative study in VigiBase ® , which is the World Health Organization (WHO) pharmacovigilance database (PVDB), from where notifications of hypertension with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were extracted. The relationship between the suspected SRIs and the occurrence of hypertension was assessed by calculating reporting odds ratio (ROR) in a case/non-case design; (ii) a descriptive study of hypertension reports associated with SRIs in the French pharmacovigilance database (FPVDB). In VigiBase ® , 14 824 notifications of SRI-induced hypertension (2.5%) were identified (mean age 54.3 years, mainly women 69.1%). Among them, 3 879 (26.2%) were associated to sertraline; 3 118 (21.0%) to fluoxetine; 2 725 (18.4%) to paroxetine; 2 570 (17.3%) to citalopram; 2 295 (15.5%) to escitalopram; and 237 (1.6%) to fluvoxamine. A significant ROR value was found with all six SRIs (ROR range from 1.16 to 1.92). In the FPVDB, 24 reports of hypertension were found with all six SRIs used at standard doses, mainly in women (66.7%) with a mean age of 57.8 years and a median time of onset of 6 days. In 10 cases (42%), patients had a history of hypertension. This study, performed in real conditions of life, shows a significant pharmacovigilance safety signal between the use of SRIs and the development or worsening of hypertension., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Childhood digestive disorders are a common occurrence and are sometimes unexplained. Maternal medication during the development of the foetus' digestive system may contribute to the increase in childhood digestive disorders, especially with drugs acting on the cholinergic system. This study investigated the association between prenatal exposure to drugs with atropinic properties and the use of digestive disorder medications in childhood (0-3 years). Children from POMME (PrescriptiOn Médicaments Mères Enfants), a French database of reimbursed drugs for pregnant women and their children, were included (N = 8 372). Each drug prescribed during antenatal life was assigned an atropinic score (0 = null, 1 = low, 3 = strong). The prenatal atropinic burden was calculated as the sum of atropinic scores of drugs prescribed. More than 30% (N = 2 652) of the children were prenatally exposed to atropinic drugs. They used significantly more digestive disorder medications than unexposed children (RRa = 1.11 [1.06; 1.16]). The strength of the association increased with the prenatal atropinic burden. Our results suggest long-term digestive effects after prenatal exposure to atropinic drugs., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Objectives: Metastatic colorectal cancer (mCRC) is increasingly treated with targeted therapies, but little is known about real-life mCRC treatment in older adults. The aims were to describe the real-life first-line treatment modalities in older adult mCRC patients, to identify factors associated with treatment modalities, and to evaluate survival with regard to treatment modalities., Patients and Methods: A cohort of mCRC patients aged 65 years and older at diagnosis was identified between 2009 and 2013 using French national healthcare insurance system claims data. Treatment modalities were: treatment with one or more anticancer medication vs best supportive care and, among treated patients, treatment with targeted therapy vs conventional chemotherapy alone. Multivariate logistic regression was used to identify factors associated with treatment by anticancer medication and by targeted therapy. Cox proportional hazards models were used to assess the independent effect of treatment modalities on overall survival while adjusting for baseline covariates identified with logistic regression., Results: A total of 503 patients were included with a median age of 78 years (54% were men). Of these, 299 (59%) were treated with anticancer medications. Among treated patients, 131 (44%) received targeted therapy. In multivariate analysis, age 75 years or older, renal failure, malnutrition, and five or more concomitant medications were associated with a lower likelihood of treatment with anticancer medications. Among treated patients, age 75 years or older, history of cancer, lymph node metastases, and a single metastatic site were associated with a lower likelihood of treatment with targeted therapy. Multivariate Cox proportional hazards models found that treatment with any anticancer medication tended to be associated with a lower risk of death; treatment with targeted therapy was not significantly associated., Conclusion: A more appropriate prescription of anticancer medications in the older adult will require the definition of more explicit criteria to avoid undertreatment. The real benefit of targeted therapies vs conventional chemotherapy alone needs to be confirmed in this population. J Am Geriatr Soc 67:913-919, 2019., (© 2019 The American Geriatrics Society.)

Objective: To evaluate the chronicity of polypharmacy among older adults and to identify factors associated with chronic polypharmacy., Design: Longitudinal cohort study using register data., Setting: Nationwide, Sweden., Participants: All 711,432 older adults (aged 65 years and older) living in Sweden with five or more prescription drugs in October 2010 were included and followed up until December 2013. Mean age at baseline was 77 (SD = 7.8) years, 59% were women, and 7% lived in nursing homes., Measurement: Monthly changes in the exposure to polypharmacy. Data regarding prescription drug use were extracted from the Swedish Prescribed Drugs Register., Results: Overall, 82% were continuously exposed to polypharmacy for 6 months or longer, and 74% for 12 months or longer. The proportion of individuals who remained exposed until the end of the study was 55%. Among the 21,361 individuals who had not been exposed to polypharmacy during the 6-month period before baseline (ie, with a new episode of polypharmacy), only 30% remained exposed for 6 months or longer. The proportion of older adults who spent at least 80% of their follow-up time with polypharmacy was substantially higher among prevalent polypharmacy users at baseline than among those with a new polypharmacy episode (80% vs 24%; P < .01). Factors associated with chronic polypharmacy included higher age, female sex, living in an institution, chronic multimorbidity, and multidose dispensing., Conclusion: Polypharmacy is most often chronic, although a substantial share of older adults experience short, recurring episodes of polypharmacy and are thus exposed to its potential harms in a transient rather than persistent manner. J Am Geriatr Soc 67:455-462, 2019., (© 2018 The American Geriatrics Society.)

In contrast to statins, the risk of diabetes with fibrates was not clearly studied. This study investigates a putative signal of diabetes associated with the use of fibrates using the World Health Organization (WHO) global individual case safety reports database, VigiBase ® . We included all reports registered until the 31st December 2017 in VigiBase ® to measure the risk of reporting 'hyperglycemia or new onset of diabetes' (SMQ term) compared with all other reports [as a reporting odds ratio (ROR 95% CI)] for fibrates, statins, and the combination fibrates + statins. The likelihood that diabetes resulted from statin-fibrate interaction was also estimated. According to the interaction additive model, a ROR value for coexposure exceeding the sum of the RORs estimated for each individual class of drug supports a potential drug-drug interaction (DDI). To assess the stability of our results, we performed several sensitivity analyses, according to outcome definition and after exclusion of putative competitive (hyperglycemic) drugs. We included 19 149 patients exposed to fibrates (without statins), 177 323 to statins (without fibrates) and 3 247 to statins plus fibrates. In contrast to statins (ROR = 1.75, 95% CI 1.72-1.78), no association was found for fibrates (ROR = 0.76, 95% CI 0.71-0.82). The ROR value was lower for the combination statins plus fibrates (ROR = 1.46, 95% CI 1.28-1.67). Similar trends were found in sensitivity analyses. This study, performed in the real conditions of use, failed to find a signal of diabetes with fibrates. It strengths the association previously described with statin without any evidence for a statin-fibrate DDI., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Addictovigilance is a health vigilance dedicated to the survey of medicinal or illicit psychoactive substance use disorders (SUDs). France is the only European country to have a vigilance system specifically dedicated to substances with an abuse/addiction potential. The French Addictovigilance system is organized in a network of regional tertiary centres (called Abuse and Dependence Monitoring Centres, CEIP-Addictovigilance) and works in close collaboration with Regional and National health authorities. Because of the essential and unavoidable nature of their practice in the French Healthcare system, general practitioners (GPs) are key actors to identify and track Addictovigilance signals. They have been involved in several of the pharmacoepidemiological surveys implemented by the French Addictovigilance Network (FAN). Now, they increasingly participate in clinical research projects and studies. In this article, interactions between GPs and the FAN are illustrated with two examples: patients on opioid substitution treatment and patients on opioid analgesics. Collaborations between GPs and the FAN could be further potentiated. In particular, more effective communication on psychoactive SUDs including abuse/addiction is necessary to optimize the implementation of preventive measures for patients on psychoactive substances medications, and to improve the attitudes of GPs and more widely health professionals in the management of any psychoactive user suffering from SUDs. In addition, both adapted training and improved collaborative research could contribute to the optimization (safety, quality) of professional practices., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Isolated arthralgia, without hemorrhagic side effect, exists and is considered as a very rare adverse drug reaction according to vitamin K antagonists' (VKAs) summary of product characteristics. Up to now, there are no literature reports of isolated, nonhemorrhagic joint complications in patients receiving VKAs. Hence, the objective of this study was to describe cases of VKA-related nonhemorrhagic joint disorders (fluindione, warfarin, and acenocoumarol) reported in the French Pharmacovigilance Database (FPVD). Sixty-one reports (male : female ratio, 1.18; median [interquartile range (IQR)] age: 60 [49-72]) were found. Fluindione, warfarin, and acenocoumarol were respectively suspected in 42, 12, and 7 cases. Arthralgia was reported in 47 cases (77%), arthritis in nine cases (15%), capsulitis in three cases (5%), and bursitis in two cases (3%). Although the joint symptoms mainly concerned the lower limbs, all types of joints were affected. Arthralgia was associated with myalgia in 14 cases and with tendinitis in three cases. The median (IQR) time interval between VKA introduction and arthralgia onset was 26 (10-98) days (range: 1-6935). VKA was withdrawn in 44 cases, and a decrease in the intensity of joint symptoms was observed in 30 cases. In three cases, reintroduction of the same VKA led to the recurrence of symptoms. In view of the large prescription of this drug class worldwide, patients and clinicians (and especially primary care physicians and geriatricians) should be aware of this possible adverse drug reaction when confronted with joint disorders in patients of all ages taking VKAs., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Objectives: To assess the risk of hospitalization for trauma associated with use of hypoglycemic glucose-lowering drugs (GLDs) in individuals aged 65 and older., Design: Observational, nested, case-control study., Setting: The Echantillon Généraliste de Bénéficiaires claims database, a 1/97 th representative sample of the population covered by French healthcare insurance., Participants: All persons with a first hospitalization for trauma between 2009 and 2015 were considered as potential cases. They were selected if they had been followed for 365 days or longer at index date, were aged 65 and older, and had no diagnosed cancer. Cases (n=10,743) were matched with up to 10 randomly selected controls on age, sex, and length of follow-up (n=106,629)., Measurements: GLD exposure was considered globally and according to use of hypoglycemic GLDs alone, nonhypoglycemic GLDs alone, or both types of GLDs. Risk of hospitalization for trauma was estimated using hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Risk of hospitalization for trauma was significantly higher with use of GLDs (HR=1.15, 95% CI=1.08-1.22). Greater risk was found only in individuals treated with hypoglycemic GLDs alone (HR=1.26, 95% CI=1.15-1.38), particularly insulin (HR=1.49, 95% CI=1.32-1.68) and glinides (HR=1.34, 95% CI=1.12-1.61)., Conclusion: This study highlights the excess risk of serious trauma with the use of insulin and glinides. J Am Geriatr Soc 66:2086-2091, 2018., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

In France, prescription of narcotics must be written on a tamper-resistant prescription form with specific technical particularities. Dosage and daily dose of medicines shall be written out entirely in letters. These prescription forms are also mandatory for buprenorphine, clorazepate, clonazepam, tianeptine, buccal midazolam and zolpidem owing to traffic, abuse or diversion. In 2012, to assess the use of standard and tamper-resistant prescription forms and the acceptability of the generalization of the latter to all medicines, a national opinion survey was performed, with a postal questionnaire, within three randomized samples of 1500 prescribers (physicians, dentists and midwives). Of the 403 participating prescribers (participation rate of 26.8%), 373 were physicians, 14 dentists and 16 midwives. Tamper-resistant prescription forms were used by 76.2% of prescribers, but only by 5.1% in a computerized version, whereas for standard prescription forms, 61% used computer assisted prescription software. The main reason was the inability of the prescription software to print these forms or to respect the mandatory prescription rules for narcotics. Theft and falsification of prescriptions had ever occurred (working life). Most prescribers (62.5%) were against the generalization of tamper-resistant prescription forms. Those in favour were for a generalization to all medicines (65%) and not only to psychotropic agents. Generalization of tamper-resistant prescription forms is not a consensual solution to prevent medicines' diversion. Some prescribers alluded to the possibility of dematerialization and electronic transmission of prescription forms, which could avoid theft, forgery or falsification., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Driving experiments in real conditions are considered as a 'gold standard' to evaluate the effects of drugs on driving performance. Several constraints are difficult to manage in these conditions, so driving simulation appears as the best alternative. A preliminary comparison is crucial before being able to use driving simulation as a valid evaluation method. The aim of this study was to design a driving simulation method for assessing drug effects on driving. We used cannabis (THC) as a positive control and assessed whether THC affects driving performance in simulation conditions and whether these effects are consistent with performance in real driving conditions. A double-blind, placebo-controlled, two successive two-way crossover design was performed using cigarettes containing 20 mg of THC. Healthy occasional users of THC, aged 25-35 years, who had a consistent driving experience were included. The first two sessions were realized in simulation conditions, and the last two sessions were in real driving conditions. Driving performance was estimated through inappropriate line crossings (ILC) and the standard deviation of the vehicle's lateral position. Participants felt significantly drowsier and more tired after THC, whatever the driving condition. Driving stability was significantly impaired after THC, both in simulated and real driving conditions. We also found that ILC were significantly more numerous in driving simulation conditions, as compared to real driving. In conclusion, the driving simulator was proven to be more sensitive for demonstrating THC-induced effects on driving performances. Driving simulation appears to be a good qualitative predictor of driving safety after drug intake., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Children and young people are seen as fundamental to the design and delivery of clinical research as active and reflective participants. In Europe, involvement of children and young people in clinical research is promoted extensively in order to engage young people in research as partners and to give them a voice to raise their own issues or opinions and for their involvement in planning and decision making in addition to learning research skills. Children and young people can be trained in clinical research through participation in young person advisory groups (YPAGs). Members of YPAGs assist other children and young people to learn about clinical research and share their experience and point of view with researchers, thereby possibly influencing all phases of research including the development and prioritization of research questions, design and methods, recruitment plans, and strategies for results dissemination. In the long term, the expansion of YPAGs in Europe will serve as a driving force for refining pediatric clinical research. It will help in a better definition of research projects according to the patients' needs. Furthermore, direct engagement of children and young people in research will be favorable to both researchers and young people., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Pregnancy can be a motivation for decrease in drug abusing but may also represent a period of high vulnerability for relapse. We aimed to assess psychoactive substance use among women with substance use disorders followed in addiction care centers in France. We analyzed data from women aged 15-44 years included in the 'Observation of illegal drugs and misuse of psychotropic medication (OPPIDUM) survey', an annual cross-sectional survey collecting details on psychoactive substances used. Characteristics of women included in 2005-2012 yearly surveys were compared depending on their pregnant or not pregnant status. Factors, including pregnancy, associated with illicit substance use and medication misuse were investigated through logistic regression. The study included 518 pregnant and 6345 nonpregnant women; 85.3% pregnant women were on opioid maintenance therapy (OMT) (vs. 77.1% of nonpregnant). Pregnancy was associated with lower illicit substance use (adjusted OR 0.71 [0.58-0.88]) and with lower medication misuse (0.66 [0.49-0.89]), whereas financial insecurity and living as a couple were associated with increased risk. Raising children was significantly associated with less risk of substance use. Each substance taken separately, the part of women using illicit substance or misusing medication did not differ depending on whether they were pregnant or not, except for heroin (24.5% in pregnant vs. 17.9% nonpregnant; <0.001). This nationwide study provides new insights into psychoactive substance use in a large mixed population of women with drug use disorders. Results outline the challenge of preventing drug use and initiating care strategies with a specific approach on socio-economic environment., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)