Drugs associated with reversible cerebral vasoconstriction syndrome: A pharmacovigilance study in vigiBase®.

BACKGROUND: Data on drug-induced reversible cerebral vasoconstriction syndrome (RCVS) are scarce. We aimed to describe RCVS characteristics with drugs previously identified as associated with RCVS and investigate potential signals related to other drugs. METHODS: VigiBase® was queried for all reports of RCVS until 31 May 2023. A descriptive study was performed on reports concerning drug classes known to precipitate RCVS. To identify new drugs, a disproportionality analysis was conducted. RESULTS: In total, 560 reports were included. RCVS occurred in patients aged between 45-64 years (40%) and 18-44 years (35%), mainly in females (72.5%). Drugs were antidepressants (38.4%), triptans (6.4%), nasal decongestants (3.7%) and immunosupressants (8.7%). In 50 cases, antidepressants were in association with drugs known to precipitate RCVS. The median time to onset was 195 days for antidepressants and much shorter (1-10 days) for triptans, nasal decongestants and immunosuppressants. The outcome was favorable in 87% of cases, and fatal in 4.4%. We found a disproportionality signal with 14 drugs: glucocorticoids, bupropion, varenicline, mycophenolic acid, aripiprazole, trazodone, monoclonal antibodies (erenumab, ustekinumab and tocilizumab), leuprorelin and anastrozole. CONCLUSIONS: The present study confirms the role of vasoconstrictors in the onset of RCVS, particularly when used in combination and found potential signals, which may help clinicians envisage an iatrogenic etiology of RCVS.

Tobacco Images Choice and Its Association with Craving and Dependence in People who Smoke Cigarettes.

INTRODUCTION: Increased salience of drug-related cues over non-drug reinforcers can drive drug use and contribute to tobacco use disorder (TUD). An important scientific and clinical goal is to effectively measure this elevated drug-seeking behavior in TUD. However, most TUD assessments rely on self-reported cravings and cigarette consumption, not providing an objective measure of the impact of drug-cues on biasing behavior towards drugs. The probabilistic image choice (PIC) task investigates the choice of viewing drug-related pictures as compared to other salient pictures (e.g., pleasant and unpleasant). This study aimed to develop and validate the PIC task for TUD and evaluate the associations between behavioral choice and tobacco craving, daily cigarette consumption, quit attempts and motivation to quit, and nicotine dependence (the Fagerström score). METHODS: We recruited 468 smokers and 121 nonsmokers using the Prolific online platform. Participants performed the PIC task twice (at a one-month interval) and completed other measures relevant to TUD. RESULTS: compared to nonsmokers, tobacco smokers selected to view significantly more tobacco images and less pleasant (non-drug reinforcer) images, a profile that remained stable at retest. Individual differences in choice of tobacco as compared to pleasant images on the PIC task were associated with craving but not with the other tobacco dependence measures, suggesting that the task may serve as a behavioral proxy measure of drug "wanting" rather than of cumulative nicotine exposure or physical dependence. CONCLUSIONS: these results suggest that the PIC task can be a valuable tool for objectively assessing craving-associated tobacco seeking in TUD. IMPLICATIONS SECTION: which should provide a brief description about what the study addsMost of the current measures of tobacco use disorder (TUD) rely on self-reports of consumption, dependence and craving and do not take into consideration the role of drug-related cues in driving tobacco seeking. This study shows that the probabilistic image choice (PIC) task provides an objective, reliable proxy measure of tobacco image seeking behavior in people who smoke cigarettes that is linked to craving (desire) for smoking but not to other measures of TUD. Therefore, the PIC task may be a useful complementary tool for the classification, diagnosis, and prognosis of TUD.

Insomnia and parasomnia induced by validated smoking cessation pharmacotherapies and electronic cigarettes: a network meta-analysis.

We aim to assess the relationship between validated smoking cessation pharmacotherapies and electronic cigarettes (e-cigarettes) and insomnia and parasomnia using a systematic review and a network meta-analysis. A systematic search was performed until August 2022 in the following databases: PUBMED, COCHRANE, CLINICALTRIAL. Randomized controlled studies against placebo or validated therapeutic smoking cessation methods and e-cigarettes in adult smokers without unstable or psychiatric comorbidity were included. The primary outcome was the presence of "insomnia" and "parasomnia." A total of 1261 studies were selected. Thirty-seven studies were included in the quantitative analysis (34 for insomnia and 23 for parasomnia). The reported interventions were varenicline (23 studies), nicotine replacement therapy (NRT, 10 studies), bupropion (15 studies). No studies on e-cigarettes were included. Bayesian analyses found that insomnia and parasomnia are more frequent with smoking cessation therapies than placebo except for bupropion. Insomnia was less frequent with nicotine substitutes but more frequent with bupropion than the over pharmacotherapies. Parasomnia are less frequent with bupropion but more frequent with varenicline than the over pharmacotherapies. Validated smoking cessation pharmacotherapies can induce sleep disturbances with different degrees of frequency. Our network meta-analysis shows a more favorable profile of nicotine substitutes for insomnia and bupropion for parasomnia. It seems essential to systematize the assessment of sleep disturbances in the initiation of smoking cessation treatment. This could help professionals to personalize the choice of treatment according to sleep parameters of each patient. Considering co-addictions, broadening the populations studied and standardizing the measurement are additional avenues for future research.

Impact of brain-derived neurotrophic factor Val66Met polymorphism and response to escitalopram or paroxetine in obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder characterized by its heterogeneous nature and by different dimensions of obsessive-compulsive (OC) symptoms. Serotonin reuptake inhibitors (SRIs) are used to treat OCD, but up to 40% to 60% of patients do not show a significant improvement with these medications. In this study, we aimed to test the impact of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the efficacy of antidepressants in OCD overall, and in relation to the different OC dimensions. METHODS: In a 6-month prospective treatment study, 69 Caucasian OCD patients were treated with escitalopram for 24 weeks or with escitalopram for 12 weeks followed by paroxetine for an additional 12-week period. Patients were genotyped and assessed for treatment response. The main clinical outcomes were improvement of the Yale-Brown Obsessive-Compulsive Scale score and in different OC symptom dimension scores. RESULTS: The Val/Val group comprised 43 (62%) patients, the Val/Met and Met/Met group comprised 26 (38%) patients. Forty-two patients were classified as responders at 12 weeks and 38 at 24 weeks; no significant association was found between BDNF Val66Met and SRIs response at 12 and 24 weeks. In analyses of the different OC symptom dimensions, the Met allele was associated with a slightly reduced score in the aggressive/checking dimension at 6 months (P = .048). CONCLUSIONS: Our findings do not support the usefulness of BDNF Val66Met genotyping to predict overall response to treatment with SRIs in OCD; they did however suggest a better outcome at 6 months for the aggressive/checking symptom dimension for patients carrying the Met allele.

Patterns of use and safety of ibrutinib in real-life practice.

AIMS: To provide real-life data on patterns of use and safety of ibrutinib. METHODS: A cohort study including all patients initiating ibrutinib between 21 November 2014 and 21 November 2018, and followed for 1 year was conducted. Patient characteristics, ibrutinib use and adverse drug reactions (ADRs) were collected from medical records. Kaplan-Meier analysis estimated the probability of developing ibrutinib-associated serious ADRs (SADRs) with a 95% confidence interval (CI). A Cox proportional hazards model was used to investigate factors associated with SADR occurrence. RESULTS: In total, 102 patients were included in the study. The median age was 70.3 years (interquartile range 64.7-75.6), the male/female gender ratio was 2.9. Almost half the patients (47.1%) were prescribed ibrutinib for chronic lymphocytic leukaemia (CLL). Forty-three patients (42.1%) permanently discontinued ibrutinib in the first year, mostly for progression (51.2%) or ADRs (32.6%). Forty-eight patients (47.1%) experienced at least one ibrutinib-associated SADR. Haematological, infectious and vascular disorders were the most frequent SADRs. The probability of developing ibrutinib-associated SADR was 35.1% (95% CI 26.3-45.7%) at 3 months, 44.8% (35.2%; 55.8%) at 6 months and 54.3% (44.0%; 65.2%) at 12 months. Age ≥80 years (hazard ratio [HR] 2.03; 95% CI 1.02-4.05) and CLL (HR 1.81; 95% CI 1.01-3.25) were significantly associated with a higher risk of SADR occurrence. CONCLUSION: This study found a high cumulative incidence of ibrutinib-associated SADRs within the first year of treatment. In view of the risk of SADR, patients aged ≥80 years or treated for CLL deserve special attention.

Serious adverse effects occurring after chemotherapy: A general cancer registry-based incidence survey.

AIMS: Pharmaco-epidemiological surveys enable the frequency of serious adverse effects-and also the determining factors of their occurrence and seriousness-to be quantified. Few studies systematically gathering post-chemotherapy adverse effects data have been conducted. The objective was to assess the incidence of post-chemotherapy serious adverse effects on the basis of cancer registry data. METHODS: The population was composed of new invasive cancer cases, with the exception of haematopoietic tumours and cutaneous carcinomas. These cancers were identified in 2012 among patients living at the time of diagnosis in a region covered by a general cancer registry and by a French regional pharmacovigilance centre, and treated with neo-adjuvant and/or adjuvant first-intention chemotherapy, followed or not by radiotherapy. The study was based on a sample of 1000 patients from the registry, followed by the collection of serious adverse effects and the required information to constitute a pharmacovigilance file. RESULTS: Chemotherapy was associated with a particularly high incidence of serious adverse effects, affecting 44.5% (41.4-47.5%) of the patients. The highest incidence rates were observed when patients were exposed to topo-isomerase II inhibitors such as etoposide and bleomycin (69.2%), vinca-alkaloids (66.7%), topo-isomerase I inhibitors (54.5%) and platinum derivatives (52.0%). The clinical context was also linked to incidence, especially in case of metastases (53.3%) and comorbidities (51.3%). Substantial differences were found according to localisation, with a particularly high incidence in bronchial-pulmonary cancers (59.0%). CONCLUSION: The high overall incidence rate of serious adverse effects should motivate a reinforcement of information about drug toxicities and improve knowledge by drawing on patient reporting.

[Drugs and retinal disorders: A case/non-case study in the French pharmacovigilance database]. / Atteintes rétiniennes iatrogènes : étude cas/non cas dans la banque nationale de pharmacovigilance.

Retina is the part of the eye suffering most damage from pharmaceutical molecules. Drug-induced retinopathies have been described but data are scarce and sometimes conflicting especially concerning its potential seriousness. The aim of this study was to investigate potential associations between drugs and retinal disorders using the French Pharmacovigilance data. We used the case/non-case method in the French PharmacoVigilance Database (FPVD) to identify drugs able to induce retinopathies. Cases were reports of retinal disorders in the FPVD between January 2008 and December 2012. Non-cases were all other reports during the same period. To assess the association between retinopathy and drug intake, we calculated the odds-ratio (OR) [with their 95% confidence intervals] for all drugs associated with at least 3 cases of retinopathy. Among the 123 687 adverse drug reactions recorded during the studied period, we identified 164 cases of retinal disorders. Significant associations were found for 11 drugs. The main therapeutic classes were antirhumatismals (hydroxychloroquine, chloroquine and etanercept: 18 cases), anti-infective (ribavirine, PEG-interferon-alfa-2a and cefuroxime: 16 cases) and antineoplastic drugs (imatinib and letrozole: 8 cases. Three other drugs were also found: raloxifene (5 cases), erythropoietin beta (4 cases) and ranibizumab (3 cases). Taking into account the limits of the methodology, our study confirmed the association between retinopathy and some expected drugs such as aminoquinolines, interferons, imatinib or ranibizumab. Other drugs like erythropoietin beta, cefuroxime, letrozole and etanercept were significantly associated with retinal disorders although this was not or poorly described in the literature. Thus, further prospective studies are necessary to confirm such associations.

Drug-induced Depression: a Case/Non Case Study in the French Pharmacovigilance Database.

Depression is a complex disorder with heterogeneous clinical anomalies whose neurobiological understanding still remains unclear. Medications have been implicated as potential causes of depression but for many of them, data are controversial. The present study aims to investigate association bet ween drugs and reports of depression. We used the case/non case method in the French pharmacovigilance database (FPVD) to identify drugs associated with depression. Cases were reports of depression in the FPVD between January 2007 and December 2011. Non cases were all other reports during the same period. Data were expressed as reporting odds ratio (ROR) with their 95% confidence interval. Of the 114,692 reports recorded in the FPVD during the studied period, we identified 474 cases of depression. For the majority of the patients, they were considered as "non serious" (56%) and evolution was favorable (64%). Significant RORs were found for antiepileptics (topiramate, levetiracetam), anti-infective and especially anti-retroviral drugs (efavirenz, emtricitabine, tenofovir, etravirine, raltegravir), interferons and other agents including isotretinoin, methylphenidate, sodium oxybate, varenicline, montelukast, flunarizine, adalimumab, anastrozole. Taking into account the limits of the methodology, the present study described associations with mainly expected drugs belonging to various therapeutic classes but it also found a signal with some anti-retrovirals. On the contrary, we did not find some assumed associations like cardiovascular medications, antimalarial. For most of the drugs, one or more mechanisms were found to explain these depressogenic effects on the basis of animal and human literature. Even if such associations need to be confirmed by further prospective studies, cautions are necessary for many drugs to early detect depressive symptoms.

Tobacco Images Choice and Its Association with Craving and Dependence in Cigarette Smokers.

Introduction: Increased salience of drug-related cues over non-drug reinforcers can drive drug use and contribute to tobacco use disorder (TUD). An important scientific and clinical goal is to effectively measure this elevated drug-seeking behavior in TUD. However, most TUD assessments rely on self-reported cravings and cigarette consumption, not providing an objective measure of the impact of drug-cues on biasing behavior towards drugs. The probabilistic image choice (PIC) task investigates the choice of viewing drug-related pictures as compared to other salient pictures (e.g., pleasant and unpleasant). This study aimed to develop and validate the PIC task for TUD and evaluate the associations between behavioral choice and tobacco craving, daily cigarette consumption, quit attempts and motivation to quit, and nicotine dependence (the Fagerström score). Methods: We recruited 468 smokers and 121 nonsmokers using the Prolific online platform. Participants performed the PIC task twice (at a one-month interval) and completed other measures relevant to TUD. Results: compared to nonsmokers, tobacco smokers selected to view significantly more tobacco images and less pleasant (non-drug reinforcer) images, a profile that remained stable at retest. Individual differences in choice of tobacco as compared to pleasant images on the PIC task were associated with craving but not with the other tobacco dependence measures, suggesting that the task may serve as a behavioral proxy measure of drug "wanting" rather than of cumulative nicotine exposure or physical dependence. Conclusions: these results suggest that the PIC task can be a valuable tool for objectively assessing craving-associated tobacco seeking in TUD.

Smokers with higher positive or negative urgency have lower rates of smoking cessation success 12 months after a quit attempt.

Impulsivity dimensions have been shown to be associated with smoking status and tobacco use disorder severity. However, it is important to determine the specific impulsivity traits associated with smoking relapse. This study aimed at investigating the associations between impulsivity traits and smoking cessation success among adult smokers at 12 months after a quit attempt. Participants were 68 adult smokers enrolled in a 3-month course of simvastatine or placebo associated with behavioral cessation support, with a 9-month follow-up (ADDICSTATINE study). They were classified in 3 groups according to smoking status: abstinent, reduction ≥ 50%baseline or reduction < 50%baseline at 3 and 12 months. Impulsivity traits were assessed using the UPPS-P-scale. At 12 months, abstainers and participants who reduced smoking by 50% or more had significantly lower scores in negative and positive urgency compared to participants who reduced smoking by less than 50% (p = 0.011 and 0.0059). These urgency traits scores at 12 months were significantly and negatively correlated with smoking reduction at 12 months (p = 0.017 and 0.0012). These impulsivity traits were also associated with the smoking cessation success at 3 months. Patients who were abstinent at 3 months had also lower negative and positive urgency (p = 0.017 and 0.0039). Smoking cessation success at 3 and 12 months were not associated with the other impulsivity traits, sensation seeking, lack of premeditation or perseverance. Our findings suggest that positive and negative urgency are associated with smoking cessation success. Proposing better tailored-based-treatment targeting these impulsivity traits in combination with conventional treatment may help improving smoking treatment success.

Preliminary Evidence That the Short Allele of 5-HTTLPR Moderates the Association of Psychiatric Symptom Severity on Suicide Attempt: The Example in Obsessive-Compulsive Disorder.

Background: The severity of symptoms represents an important source of distress in patients with a psychiatric disease. However, the extent to which this endogenous stress factor interacts with genetic vulnerability factors for predicting suicide risks remains unclear. Methods: We evaluated whether the severity of symptoms interacts with a genetic vulnerability factor (the serotonin transporter gene-linked promoter region variation) in predicting the frequency of lifetime suicide attempts in patients with a psychiatric disease. Symptom severity and 5-HTTLPR polymorphism were collected from a sample of 95 patients with obsessive-compulsive disorder (OCD). Lifetime suicide attempt was the primary outcome, and antecedent of multiple suicide attempts was the secondary outcome. Results: The gene-by-symptoms interaction was associated with an excess risk of suicide attempts (OR = 4.39, 95CI[1.44, 13.38], p < 0.009) and of multiple suicide attempts (OR = 4.18, 95CI[1.04, 16.77], p = 0.043). Symptom severity (moderate, severe, or extreme) was associated with an approximately five-fold increase in the odds of a lifetime suicide attempt in patients carrying one or two copies of the short allele of 5-HTTLPR. No such relationship was found for patients carrying the long allele. Conclusion: This study provides preliminary evidence for the gene-by-stress interaction on suicide attempt when stress is operationalized as symptom severity. Progress in suicide research may come from efforts to investigate the gene-by-symptoms interaction hypothesis in a variety of diseases.

Duration of the effectiveness of nicotine electronic cigarettes on smoking cessation and reduction: Systematic review and meta-analysis.

Background: The success of pharmacotherapies for smoking cessation in real-life remains limited, with a significant number of long-term relapses. Despite first promising results, the duration of the effectiveness of electronic cigarettes is still unknown. Our objective was to assess the duration of the effectiveness of electronic cigarettes on smoking cessation and reduction in daily smokers. Methods: The databases EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov and PUBMED were consulted until March 23, 2022. We selected only randomized controlled trials with daily adult smokers. The intervention was the nicotinic electronic cigarette vs. non-nicotine electronic cigarette or other validated pharmacotherapies (varenicline, bupropion and nicotine replacement therapy). The minimum duration of the intervention was 3 months, with a follow-up of at least 6 months. Two independent reviewers used the PRISMA guidelines. The primary endpoint was smoking cessation at the end of the intervention and follow-up periods confirmed by a reduction in expired CO < 10 ppm. The reduction was defined as at least 50% of the initial consumption or by a decrease of daily mean cigarette consumption at the end of the intervention and follow-up periods. Results: Abstinence at the end of the intervention and follow-up periods was significantly higher in the nicotine electronic cigarette group, compared to nicotine replacement therapy (NRT) [respectively: RR: 1.37 (CI 95%: 1.32-2.93) and RR: 1.49 (CI 95%: 1.14-1.95)] and to the non-nicotine electronic cigarette condition [respectively: RR: 1.97 (CI 95%: 1.18-2.68) and RR: 1.66 (CI 95%: 1.01-2.73)]. With regard to smoking reduction, the electronic cigarette with nicotine is significantly more effective than NRT at the end of the intervention and follow-up periods [respectively RR: 1.48 (CI 95%: 1.04-2.10) and RR: 1.47 (CI 95%: 1.18-1.82)] and non-nicotine electronic cigarette in the long term [RR: 1.31 (CI 95%: 1.02-1.68)]. Conclusions: This meta-analysis shows the duration of the effectiveness of the nicotine electronic cigarette vs. non-nicotine electronic cigarette and NRT on smoking cessation and reduction. There are still uncertainties about the risks of its long-term use and its potential role as a gateway into smoking, particularly among young people.

Memory disorders associated with consumption of drugs: updating through a case/noncase study in the French PharmacoVigilance Database.

AIMS: To investigate putative associations of reports of memory disorders and suspected drugs. METHODS: We used the case/noncase method in the French PharmacoVigilance Database (FPVD). Cases were reports of memory loss in the FPVD between January 2000 and December 2009. Noncases were all other reports during the same period. To assess the association between memory impairment and drug intake, we calculated an odds ratio with its 95% confidence interval. RESULTS: Among the 188,284 adverse drug reactions recorded, we identified 519 cases of memory loss. The sex ratio was 0.6 and the median age was 54 years (range 4-93). The maximal number of cases occurred between 40-49 and 50-59 years. Evolution was favourable in 63% of the cases. We found significant odds ratios for benzodiazepines (alprazolam, bromazepam, prazepam, clonazepam etc.), benzodiazepine-like hypnotics (zolpidem and zopiclone), antidepressants (fluoxetine, paroxetine and venlafaxine), analgesics (morphine, nefopam and tramadol), anticonvulsants (topiramate, pregabalin, levetiracetam etc.), antipsychotics (aripiprazole and lithium) and other drugs, such as trihexyphenidyl, ciclosporin and isotretinoin. CONCLUSIONS: Our study confirmed an association between memory disorders and some drugs, such as benzodiazepines and anticonvulsants. However, other drugs, such as benzodiazepine-like hypnotics, newer anticonvulsants, serotonin reuptake inhibitor antidepressants, isotretinoin and ciclosporin were significantly associated with memory disorders, although this was not described or poorly described in the literature. Taking account of the limits of this study in the FPVD (under-reporting, notoriety bias etc.), the case/noncase method allows assessment and detection of associations between exposure to drugs and a specific adverse drug reaction, such as memory disorders, and could thus generate signals and orientate us to further prospective studies to confirm such associations.

Environmental enrichment-inspired pharmacological tools for the treatment of addiction.

Environmental enrichment (EE) has been shown to produce powerful beneficial effects in animal models of addiction. In particular, the ability of EE to promote abstinence and prevent relapse may allow for the identification of brain mechanisms responsible for the recovery from addiction. Indeed, the effects of EE on specific brain mechanisms could be mimicked by old or new molecules, which may become novel medications, called enviromimetics. Here, we review the best known enviromimetics for the treatment of addiction and suggest that, whereas these compounds may be relatively ineffective by themselves, they may be useful complements for existing therapeutic approaches to manage addiction which includes behavioural, environmental and pharmacological interventions.

Effectiveness of drugs acting on adrenergic receptors in the treatment for tobacco or alcohol use disorders: systematic review and meta-analysis.

AIM: To assess the efficacy of drugs directly acting on alpha- and beta-adrenergic receptors in the treatment of patients suffering from tobacco or alcohol use disorder. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, studies were identified through PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials and clinicaltrial.gov. We selected only randomized controlled trials with adult patients with tobacco or alcohol use disorders according to DSM-5 criteria. Interventions included any molecule having a direct pharmacological action on alpha- or beta-adrenergic receptors (agonist or antagonist). Comparators were placebo or other validated pharmacotherapies. The duration of the intervention was a minimum of 1 month, with 3 months of follow-up. Measurements included smoking cessation for tobacco; for alcohol, we selected abstinence, alcohol consumption (drinks per day or week) and heavy drinking days (HDD). Ten studies with tobacco and six with alcohol use disorder were included in the qualitative synthesis and fifteen studies in the quantitative analysis. RESULTS: We found that clonidine, an alpha-2 agonist, significantly increased smoking abstinence [relative risk = 1.39 with a 95% confidence interval (CI) = 1.04, 1.84]. Beta-blockers had no significant effect on smoking abstinence. The alpha-1 antagonists prazosin and doxazosin decreased alcohol consumption [SMD = -0.32 (-0.56, -0.07)] but had no effect on abstinence or HDD. CONCLUSIONS: The noradrenaline system may represent a promising mechanism to target in tobacco and alcohol use disorders.

Drug-induced hearing loss: a case/non-case study in the French pharmacovigilance database.

Hearing loss is defined as a decrease in the ability to perceive sounds which can occur suddenly or gradually and affects one ear or both. It is related to various etiologies, in particular drugs. The identification of all drugs that could be associated with hearing loss is essential for the patients' life quality. The objective of our study was to identify signals of hearing loss involving drugs approved in the last 20 years. The occurrence in association with drugs known for their ototoxicity was also analyzed. We used a case/non-case method in the French Pharmacovigilance Database (FPVD). The cases were reports of hearing loss in the FPVD between January 2007 and August 2017. Non-cases were all reports over the same period. We calculated the reporting odds ratio (ROR) with 95% confidence intervals. Among the 555 reports of hearing loss, significant RORs were found for 68 drugs. The main therapeutic classes implicated were antineoplastic agents (n = 240), systemic anti-infective agents (n = 182), immunosuppressants (n = 42) loop diuretics (n = 26), and salicylate analgesics (n = 26). We found signals of hearing loss with azacitidine, vaccines and nevirapine, immunosuppressants such as leflunomide, and biotherapies such as panitumumab and vandetanib. Prescribers should be informed about the potential associations with all these drugs. The role of the pathology itself and the known ototoxic drugs that can be associated do not allow to conclude definitively. Audiograms for the early detection of hearing loss induced by drugs known to be ototoxic are rarely carried out. Preventive treatments exist and must be considered.

Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: A real-life evaluation in France.

AIMS: Despite fluoropyrimidines (FPs) constituting the main component of the chemotherapy combination protocols in 50% of chemotherapies for solid tumour treatments, incidence data for FP-related toxicity are poorly documented in real life. This study evaluated the number of patients receiving FP-based chemotherapies in France, along with the true incidence of FP-related serious adverse effects (SAEs) before the recent mandatory dihydropyrimidine dehydrogenase (DPD)-screening was introduced by French health authorities, DPD being the rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. METHODS: Exhaustive data on the number of patients treated with FP-based chemotherapy in 2013-2014 were collected in the Centre-Val de Loire region of France. True incidence of SAEs was extracted from a cohort of 513 patients with incident solid tumours receiving first-line FP-based chemotherapy. RESULTS: After extrapolation at national level, we estimated that 76,200 patients are currently treated annually with 5FU (53,100 patients, 62% digestive system-related versus 26% breast cancers versus 12% head and neck cancers) or capecitabine (23,100 patients, 45% digestive system-related versus 37% breast cancers versus 18% non-documented). Earlier (in the first two cycles) the SAE incidence rate was 19.3% (95% confidence interval (CI) 16-23%) including one toxic death (0.2%, 95%CI 0-1%). SAE incidence rate was 32.2% (95%CI 28-36%) over the first 6 months of treatment. Incidence of death, life-threatening prognosis or incapacity/disability was 1.4% (95%CI 0.4-2.4%) and 1.6% (95%CI 0.5-2.6%) during first two cycles and first 6 months, respectively. CONCLUSION: These data highlight the significant public health issue related to FP toxicity, with around 1200 patients developing FP-related life-threatening prognosis or incapacity/disability annually in France, including 150 toxic deaths. It is hoped that DPD-deficiency screening will reduce such iatrogenic events and eradicate toxic deaths.

PKR, the double stranded RNA-dependent protein kinase as a critical target in Alzheimer's disease.

Amyloid beta-peptide (Abeta) deposits and neurofibrillary tangles are key hallmarks in Alzheimer's disease (AD). Abeta stimulates many signal transducers involved in the neuronal death. However, many mechanisms remain to be elucidated because no definitive therapy of AD exists. Some studies have focused on the control of translation which involves eIF2 and eIF4E, main eukaryotic factors of initiation. The availability of these factors depends on the activation of the double-stranded RNA-dependent protein kinase (PKR) and the mammalian target of rapamycin (mTOR), respectively. mTOR positively regulates the translation while PKR results in a protein synthesis shutdown. Many studies demonstrated that the PKR signalling pathway is up-regulated in cellular and animal models of AD and in the brain of AD patients. Interestingly, our results showed that phosphorylated PKR and eIF2alpha levels were significantly increased in lymphocytes of AD patients. These modifications were significantly correlated with cognitive and memory test scores performed in AD patients. On the contrary, the mTOR signalling pathway is down-regulated in cellular and animal models of AD. Recently, we showed that p53, regulated protein in development and DNA damage response 1 and tuberous sclerosis complex 2 could represent molecular links between PKR and mTOR signalling pathways. PKR could be an early biomarker of the neuronal death and a critical target for a therapeutic programme in AD.

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

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