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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., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

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., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

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., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The aim of this study was to assess an automated detection method of serious adverse reactions induced by oral targeted therapy (OTT) in patients with cancer, performed in the French Diagnosis Related Groups (DRG) database. Patients with cancer of the Poitiers hospital who started an OTT between 2014 and 2015 were included. This study focused on adverse drug reaction which required inpatient hospitalization (ADR h ). All diagnoses coded in the DRG database for hospital stays that occurred within 3 months after OTT initiation were collected (potential ADR h ). Filters (exclusion criteria) were automatically applied on potential ADR h to exclude diagnoses that were not adverse drug reactions (false positives). A pharmacovigilance review was carried out to identify ADR h in the medical records (reported ADR h ). The sensitivity and specificity of the detection method were estimated for each filter combinations by comparison between potential and reported ADR h . This study included 129 patients. The medical records review led to identify 19 ADR h (all coded in the DRG database) in 14 patients. To maintain a 100% sensitivity of the method detection, the best specificity obtained was 58.3% (95% IC: [55.2-61.4]).The use of restrictive filters ('drug' in the diagnostic label, specific diagnosis code for adverse cancer drug reaction) resulted in a 97.8% specificity (95% IC: [96.6-98.5]) with a 38.2% sensitivity (95% IC: [23.9-55.0]). Our method has detected the third of ADR h with an excellent specificity. Complementary experimentations in pharmacovigilance centers are necessary to evaluate the interest of this tool in routine in addition to spontaneous reporting., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Progressive multifocal leukoencephalopathy (PML) is an often fatal demyelinating disease of the central nervous system. As effective treatment is unavailable, identification of all drugs that could be associated with PML is essential. The objective of this study was to investigate the putative association of reports of PML and drugs. We used the case/noncase method in the French PharmacoVigilance database (FPVD). Cases were reports of PML in the FPVD between January 2008 and December 2015. Noncases were all other reports during the same period. To assess the association between PML and drug intake, we calculated an adverse drug report odds ratio (ROR) with its 95% confidence interval. We have studied the delay of onset of PML for each drug concerned. Among the 101 cases of PML, 39 drugs were mentioned as suspect. The main therapeutic classes suspected with significant ROR were antineoplastic agents (n = 85), immunosuppressants (n = 67), and corticosteroids. A latent interval from the time of drug initiation to the development of PML is established: the median time to onset was 365 days (123-1095 days). The onset of PML is highly variable and differs among drug classes [from 1 to 96 months (IQR: 39.0-126)]. An association between PML and some immunosuppressant drugs was found as expected, but also with antineoplastic agents and glucocorticoids. An important delay of PML onset after stopping treatment is suspected and should alert prescribers. Prescribers but also patients should be informed about the potential associations with all these drugs. Monitoring could be necessary for many drugs to early detect PML., (© 2016 Société Française de Pharmacologie et de Thérapeutique.)

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., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

Background: Romiplostim and eltrombopag, the two marketed thrombopoietin receptor agonists (TPO-RAs), have distinct binding sites and might have distinct pharmacodynamic mechanisms. The aim of this study was to compare their adverse drug reaction (ADR) patterns., Methods: We selected in the French PharmacoVigilance Database all ADRs associated with TPO-RAs from TPO-RA marketing until the 31st of December 2013. Medical charts were reviewed. We conducted disproportionality analyses comparing romiplostim exposure in the reports of a given ADR pattern (thrombosis, neurological, cutaneous, gastrointestinal or hematological) to romiplostim exposure in all other TPO-RA-related ADR reports. Reporting Odds Ratios (RORs) were adjusted for age and gender. We also compared the number of reports of a given ADR pattern per million daily defined doses (DDDs) dispensed in France during the study period., Results: We described 45 reports (53 ADRs) with romiplostim and 26 reports (37 ADRs) with eltrombopag. There were 19 venous thromboses. At least one other risk factor was present in 83.3% of the cases. Ten (55.6%) patients had been splenectomized previously. There were eight arterial thromboses. Another risk factor was noticed in all cases. There was no signal for an excess risk of thrombosis with romiplostim versus eltrombopag (ROR: 1.45, 95% CI [0.48-4.45]). There was a signal for a higher risk of gastrointestinal ADRs with eltrombopag (ROR: 30.28, 95% CI [3.23-383.86]) and of hematological ADRs with romiplostim (ROR: 14.36, 95% CI [1.73-119.08]). Dispensing data-adjusted comparisons led to similar results., Conclusions: This study suggests different ADR patterns between romiplostim and eltrombopag., (Copyright © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

The increased incidence of dementia on the aging population makes this disease a major public health problem. Among known causes of dementia, drug etiology is under considered. We investigated the relationship between exposure to drug therapy and dementia with a case/non-case study using reports of the French Pharmacovigilance database. Among 263 962 adverse effects recorded between 1985 and 2005, 79 (0.03%) are dementia. Median age is 66 (range 3-91). There was 41 women and 37 men. The therapeutic drug class associated with dementia were anticonvulsants, antiparkinsonians, antidepressants, anxiolytics, hypnotics, antipsychotics and morphinics. An association between reporting of dementia and non neurotropic drugs were also found, i.e. interferon alfa-2B, vancomycin and allopurinol. The term "Dementia" is only mentioned in the summary of the characteristics of valproate, but it may concern other drugs. Drug etiology for dementia is a reality but is not necessarily attributed as a cause in aging population, in particular.

Astrocytes are known to play a key role in buffering extracellular pH variations and, in addition, they are particularly resistant to oxidative stress and subsequent lipid peroxidation. This great resistance may be ascribed to the presence of high concentrations of certain antioxidants, but another explanation may be the presence of a high quantity of plasmalogens, which are a special group of glycerophospholipids characterized by a vinyl ether bond instead of an ester bond in the sn-1 position of the glycerol backbone. Plasmalogens are sensitive to free radical attack and acidity, and numerous works have supported the hypothesis that they may be antioxidant molecules that protect cells from oxidative stress. The aim of this work was to investigate, on astrocytes in lactic acid-induced oxidative stress (pH 5.5), the behavior of phospholipids and, in particular, plasmalogens. Two main techniques, based on the susceptibility of the vinyl ether bond to hydrolysis, were employed in this study to measure plasmalogen levels. In both cases, the sn-1 vinyl ether linkage was cleaved using mercuric chloride, producing a lysophospholipid that was assessed by phosphorus measurement or using HCl treatment, producing a long-chain fatty aldehyde assayed by gas chromatography/mass spectrometry. On astrocytes in culture, only plasmenylethanolamine (PlmEtn) was evidenced, representing 40% of glycerophosphoethanolamine lipids. When astrocytes were incubated with lactic acid, no modification in the amount of PlmEtn was seen. Furthermore, free aldehydes and aldehydes corresponding to the quantity of intact plasmalogens were similar to those observed on controls. In addition, the constancy of two lipid peroxidation markers, thiobarbituric acid reactive substances and polyunsaturated fatty acids, was clear evidence of the resistance of these cells in lactic acid conditions. In conclusion, our results fail to demonstrate a major role of plasmalogens in the resistance of astrocytes in lactic acid-induced oxidative stress.

The use of benzodiazepines is not negligible in pregnant woman and self-medication is considerable. To investigate the effects on the fetus of benzodiazepines used during pregnancy, we reviewed animal and clinical studies completed with observations of CRPV (Centres Régionaux de Pharmacovigilance). Pooled results indicate that the risk of malformations associated with first-trimester exposure to benzodiazepines remains small. However, in a fetus exposed essentially to long-acting benzodiazepines on a long-term basis, neonatal hypotonicity, failure to feed and/or withdrawal syndrom could be observed.

The cleavage of the specific vinyl ether linkage at the sn-1 position of plasmalogens leads to the formation of two products: the 1-lyso-2-acyl glycerophospholipid and a long-chain fatty aldehyde. Plasmalogens are measured by quantifying one of these two products. In this paper, we describe a rapid and sensitive procedure for measuring plasmalogens via quantification of long-chain fatty aldehydes. After lipid extraction, the sn-1 vinyl ether bond of plasmalogens is cleaved by acidic hydrolysis. The produced aldehydes are then derivatized with (pentafluorobenzyl)hydroxylamine hydrochloride and analyzed by gas chromatography/mass spectrometry in selected-ion mode. Plasmalogens are then indirectly quantified by subtracting the free aldehydes obtained without prior HCl treatment from the total aldehydes obtained after acidic hydrolysis. This method is applied to three rat brain areas selected for this study. Two of these are affected in neurodegenerative diseases (cerebral cortex and hippocampus) and one is rich in white matter (cerebellum). In comparison to other procedures, the advantages of this method are not only its usefulness in plasmalogen quantification but also the identification of aldehydic breakdown products.

The purpose of this study was to compare the nephrotoxicity of gentamicin and vancomycin alone and in combination. Thirty-two male Sprague-Dawley rats were randomized into 4 groups of 8 animals. Each group received 200mg/kg gentamicin (G) i.m., or 300 mg/kg vancomycin (V) i.v., or an association of 200 mg/kg gentamicin + 300 mg/kg vancomycin (i.m. and i.v., respectively), or 0.9% NaCl solution i.m. and i.v. (controls). To determine AAP, GGT, and NAG enzyme excretions, urine samples were taken over 24-h periods before and after the start of the experiment. A single renal cortical sample was obtained at necropsy for quantitation of antibiotic levels. No significant modifications of urinary excretions of creatinine and enzymuria were noted during the 24-h period before each drug administration or in controls. AAP, GGT, and NAG excretions were significantly increased after G and G + V injections (p < 0.001), whereas only AAP and GGT were statistically higher in rats receiving V (p < 0.05). NAG elimination (mean +/- SD) was higher in G + V (16.0 +/- 0.2 IU/mmol creatinine/24 h; p < 0.001) than g (8.8 +/- 0.6) or V (1.7 +/- 0.2). Surprisingly, mean vancomycin cortical levels decreased in the combination (827 +/- 131 vs. 1964 +/- 23 micrograms/g for V alone; p < 0.001), whereas gentamicin concentration was unchanged (826 +/- 66 vs. 839 +/- 28 micrograms/g for G alone). Determination of enzymuria allowed the nephrotoxicity of the antibiotics to be graded in the following order: vancomycin + gentamicin > gentamicin > vancomycin.

5-fluoro-uracil (5-FU) cardiotoxicity has been often reported during chemotherapy. We collect four atypical cases of cardiac side effects in patients treated by 5-FU for head and neck tumors. We review the literature about the subject, and we propose criteria to detect patients with a high risk level, and to prevent this adverse effect incidence.