Parasomnias and sleep-related movement disorders induced by drugs in the adult population: a review about iatrogenic medication effects.

Parasomnias and sleep-related movement disorders (SRMD) are major causes of sleep disorders and may be drug induced. The objective of this study was to conduct a systematic review of the literature to examine the association between drug use and the occurrence of parasomnias and SRMD. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews, we searched PubMed databases between January 2020 and June 2023. The searches retrieved 937 records, of which 174 publications were selected for full-text screening and 73 drugs were identified. The most common drug-induced parasomnias were nightmares and rapid eye movement (REM) sleep behaviour disorders and sleepwalking. In terms of drug-induced SRMD, restless legs syndrome, periodic limb movement disorders (PLMD), and sleep-related bruxism were most frequent. Medications that inhibit noradrenergic, serotonergic, or orexin transmission could induce REM sleep (e.g., nightmares). Regarding sleepwalking, dysregulation of serotoninergic neurone activity is implicated. Antipsychotics are mentioned, as well as medications involved in the gamma-aminobutyric acid (GABA) pathway. A mechanism of desensitisation-autoregulation of GABA receptors on serotoninergic neurones is a hypothesis. SRMD and PLMD could involve medications disrupting the dopamine pathway (e.g., antipsychotics or opioids). Opioids would act on mu receptors and increase dopamine release. The role of adenosine and iron is also hypothesised. Regarding bruxism, the hypotheses raised involve dysregulation of mesocortical pathway or a downregulation of nigrostriatal pathway, related to medications involving dopamine or serotonin. Parasomnias are rarely identified in drug product labels, likely due to the recent classification of their diagnoses. An analysis of pharmacovigilance data could be valuable to supplement existing literature data.

Prospective assessment of the frequency of and risk factors for bleeding events in patients treated with cefazolin.

PURPOSE: Major bleedings have been described with cefazolin. The objective was to determine the frequency of bleeding events in cefazolin-treated patients and to identify risk factors for these complications. METHODS: Monocenter prospective observational study of all consecutive cefazolin-treated patients. Patients benefited from a daily clinical assessment of bleedings and a twice-a-week blood sampling including hemostasis. Bleedings were classified according to the International Society on Thrombosis and Hemostasis classification: major, clinically relevant non-major bleedings (CRNMB) and minor bleedings. RESULTS: From September 2019 to July 2020, 120 patients were included, with a mean age of 59.4 (± 20.7) years; 70% of them (84/120) were men. At least 1 CRNMB or major bleeding were observed in 10% of the patients (12/120). Compared to patients with no or minor bleeding, patients with CRNMB or major bleeding were, upon start of cefazolin, more frequently hospitalized in an intensive care unit (7/12, 58.3%, vs. 12/108, 11.1%, P < 0.001, respectively) and receiving vitamin K antagonists (4/12, 33.3%, vs. 8/108, 7.4%, P = 0.019, respectively). After multivariate analysis, patients receiving vitamin K antagonists the day prior bleeding and/or treated for endocarditis were factors associated with an increased risk of CRNMB or major bleeding (odd ratio 1.36, confidence interval 95%, 1.06-1.76, P = 0.020 and 1.30, 1.06-1.61, P = 0.015, respectively). CONCLUSIONS: Bleeding events associated with cefazolin treatment are frequent. Close clinical monitoring should be performed for patients treated for endocarditis and/or receiving vitamin K antagonists. Hemostasis work-up could be restricted to these patients.

Frequency and factors associated with infusion-related local complications of vancomycin on peripheral venous catheters.

BACKGROUND: Vancomycin is a reference antibiotic against methicillin-resistant staphylococci. Its administration is associated with infusion-related local complications (IRLC). To reduce this risk, it has been proposed to increase vancomycin dilution in the IV bag and to perform continuous infusion using the volumetric pump. The aim of our study was to assess the safety of peripheral infusion of vancomycin with the volumetric pump. OBJECTIVES: To compare the frequency of IRLC between patients receiving vancomycin and those receiving ß-lactam (BL) antibiotics. Our secondary objective was to assess factors associated with the occurrence of IRLC. PATIENTS AND METHODS: We conducted a prospective observational study in a French tertiary hospital. Between February 2021 and November 2021, we included all patients receiving continuous infusions of vancomycin or BL through a peripherally inserted venous catheter (PIVC). The primary endpoint was the occurrence of IRLC on Day 1 (D1). RESULTS: We included 168 patients (56 vancomycin, 112 BL). At D1, 14 patients (25%) presented IRLC in the vancomycin group versus 11 patients (10%) in the BL group (P = 0.01). There was significantly more IRLC in the group receiving vancomycin at an infused concentration above 5 mg/mL than those receiving BL (8/15, 53.3% versus 11/112, 10%, respectively, P < 0.01). However, no significant difference was observed between patients receiving infused vancomycin concentration ≤5 mg/mL and patients receiving BL (P = 0.4). CONCLUSION: Our data support safe administration of vancomycin if infused at a concentration under 5 mg/mL, through the volumetric pump on PIVC.

Atropine-induced toxicity after off-label sublingual administration of eyedrop for sialorrhoea treatment in neurological disabled patients.

Sialorrhea is a troublesome and disabling symptom defined by the unintentional loss of saliva from the mouth, usually associated with swallowing disorders. Today there is no consensus about the management of sialorrhoea, but off-label use of ophthalmic atropine eyedrop administered sublingually may offer benefits, despite limited safety data. We report 2 cases of atropine overdose after sublingual administration illustrating that atropine can expose to severe adverse effects when administered sublingually. The noncompartmental pharmacokinetic study of atropine performed in 1 patient highlighted that systemic absorption of sublingual atropine was effective (Cmax [1 h] = 2.2 ng mL-1 ; approximately) after a single dose of 1 mg.

Atrial fibrillation at mid-term after bioprosthetic aortic valve replacement ­ implications for anti-thrombotic therapy.

BACKGROUND: Little is known about mid-term (3-month) postoperative atrial fibrillation (MT-POAF) in patients treated with bioprosthetic aortic valve replacement (BAVR). The aim of this study was to describe the natural history, identify the predictors and investigate the potential consequences in terms of anti-thrombotic therapy. METHODS AND RESULTS: During a longitudinal, prospective study, 219 patients were treated with BAVR early (7 days) and at mid-term postoperatively (30 and 90 days). POAF was monitored and risk factors were identified on logistic regression analysis. History of previous AF (OR, 3.08; 95% CI: 1.35-6.98), early POAF (OR, 5.93; 95% CI: 2.96-11.8), and BMI (per 5 kg/m(2): OR, 1.46; 95% CI: 1.03-2.09), were independent predictors for MT-POAF whereas sex, age and Euroscore were not. Results were identical when restricted to the 176 patients free from preoperative AF. In this subgroup, 36 patients (20.4%) had MT-POAF; 33 out of 174 (18.7%) would have required anticoagulation (CHA2DS2VASc score ≥ 1). Conversely, patients with BMI <27.7 and sinus rhythm at early follow-up had a very low risk of MT-POAF (OR, 0.16; 95% CI: 0.06-0.42). CONCLUSIONS: There was a higher than expected occurrence of MT-POAF in patients treated with BAVR, particularly in overweight patients with early POAF. This raises the question of implementing an anti-thrombotic therapy in these patients at higher risk of delayed atrial arrhythmia.

Articular manifestations related to anti-interleukin-5 therapies in severe asthma: a case series.

Articular manifestations should be screened before and during anti-IL-5/5R biologic treatment in severe asthma. Rigorous multidisciplinary team discussion should be carried out to assess the risk-benefit balance of withholding effective treatment. https://bit.ly/3vfPn4k.

Estimating the excess of inappropriate prescriptions of anti-dopaminergic anti-emetics during acute gastroenteritis epidemics in France.

PURPOSE: Anti-dopaminergic anti-emetics (ADA) use for the treatment of nausea associated with gastroenteritis (GE) can be considered inappropriate, as their effects are not supported by evidence of clinical efficacy and can potentially induce serious adverse events. OBJECTIVE: This study quantifies the suboptimal consumption of ADA attributable to seasonal GE epidemics in France and its cost. METHODS: GE epidemiological data were collected and transmitted by the general practitioners (GPs) of Sentinelles network. Epidemic periods were identified by periodic regression. Drug sales data were obtained from pharmacies, and costs data were obtained from the French National Social Security. The ADA use and costs incurred by seasonal GE epidemics were calculated. RESULTS: During the epidemic periods considered in this study, the median age of patients seen by GPs for GE was 24 years old. During each epidemic, a sale increase by 14% for domperidone, by 15% for metoclopramide and 30% for metopimazine was observed. The average cost attributable to seasonal GE epidemic was 5,030,000 Euros, of which 2,160,000 Euros were incurred by the French National Social Security. CONCLUSION: Linking epidemiological databases helped to identify and quantify inappropriate ADA prescriptions. GE treatment guidelines should be disseminated more widely.

Pulmonary toxicity of mTOR inhibitors. Comparisons of two populations: Solid organ recipients and cancer patients.

INTRODUCTION: Mammalian target of rapamycin (mTOR) inhibitors-associated pneumonitis (mTOR-IP) has long been described in solid organ recipients (T) patients but more recently in cancer (K) patients. Its overall characteristics have never been compared between these 2 populations. The aim of this study was to compare them in terms of presentation, severity and outcome in T and in K patients. MATERIAL AND METHODS: We carried out a retrospective study in a single French tertiary center. Four databases were used to ensure the exhaustive collection of all mTOR-IP cases between 2001 and 2020. All clinical, biological, radiological, pathological and outcome data were reviewed. RESULTS: Thirty-nine patients with mTOR-IP were diagnosed during this period, 24T and 15K patients. The average dosage of everolimus and sirolimus was 2,65mg (±1,78) and 2,75mg (±0,96) in T patients, respectively, versus 8,75mg (±2,26) for everolimus in K patients. The overall prevalence of mTOR-IP was 6.4% with a median time of occurrence of 7 months [IQR 3-35 months]. mTOR-IP were significantly more frequent (P<0.001) and occurred earlier (P<0.001) in cancer patients. No clinical, functional, radiological, pathological nor outcome differences were otherwise observed between the 2 groups. Average everolimus blood levels at the time of mTOR-IP diagnosis were in the range of recommended therapeutic values. CONCLUSION: Our study shows that mTOR-IP is comparable in terms of presentation in T and in K patients but that it occurs significantly earlier after drug introduction in the latter. This raises questions as to the potential role of the higher doses used in K patients as well as that of co-treatments in the pathogeny of the disease.

Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients.

PURPOSE: Voriconazole is widely used to treat invasive aspergillosis after lung transplantation. In cystic fibrosis patients, the interindividual variability in drug disposition complicates the optimal voriconazole dosing and increases the risk of toxicity. The objective of this retrospective study was to evaluate the influence of CYP2C19 genotype on voriconazole response in lung transplant patients with cystic fibrosis. METHODS: We retrospectively studied 24 Caucasian cystic fibrosis lung transplant recipients who received voriconazole. We analyzed the influence of CYP2C19 genotype (*2 and *17 alleles) on voriconazole exposure and maintenance dose and side effects. RESULTS: Heterozygous carriers of the CYP2C19*2-deficient allele required lower maintenance doses (440 ± 107 mg/day) compared with wild-type and CYP2C19*17-allele carriers (633 ± 197 mg/day and 600 ± 193 mg/day, respectively, P<0.05). The time to achieve the therapeutic range and the proportion of out-of-range concentrations were significantly higher in the CYP2C19*2 group (31.3% vs. 12.1% and 9.8% of above-range levels in the CYP2C19*1 and CYP2C19*17 groups, respectively) or CYP2C19*17 group (37.9% vs. 15.6% and 13% of below-range levels in the CYP2C19*1 and CYP2C19*2 groups, respectively) (P<0.01). No relationship was found between voriconazole toxicity and CYP2C19 status. CONCLUSIONS: In this frail population, voriconazole exposure is strongly influenced by CYP2C19 genotype, and determining the genotype before voriconazole initiation may help determine the initial dosing regimen that will promptly achieve therapeutic plasma levels without producing out-of-range levels.

Classification of the Severity of Adverse Drugs Reactions.

This poster presents a non-exhaustive study of machine learning classification algorithms on pharmacovigilance data. In this study, we have taken into account the patient's clinical data such as medical history, medications taken and their indications for prescriptions, and the observed side effects. From these elements we determine whether the patient case is considered serious or not. We show the performances of the different algorithms by their precision, recall and accuracy as well as their learning curves.

Evaluating Twitter as a complementary data source for pharmacovigilance.

BACKGROUND: Social media are currently considered as a potential complementary source of knowledge for drug safety surveillance. Our primary objective was to estimate the frequency of adverse drug reactions (ADRs) experienced by Twitter users. Our secondary objective was to determine whether tweets constitute a valuable and informative source of data for pharmacovigilance purposes, despite limitations on character number per tweet. RESEARCH DESIGN AND METHODS: We selected a list of 33 drugs subject to careful monitoring due to safety concern in France and Europe, and extracted tweets using the streaming API from 30 September 2014 to 5 April 2015. Two pharmacovigilance centers classified these tweets manually as potential ADR case reports. RESULTS: Among 10,534 tweets, 848 (8.05%) implied or mentioned an ADR without meeting the four FDA criteria required for reporting an ADR, and 289 (2.74%) tweets were classified as 'case reports.' Among them 20 (7.27%) tweets mentioned an unexpected ADR and 33 (11.42%) tweets mentioned a serious ADR. CONCLUSIONS: With the use of dedicated tools, Twitter could become a complementary source of information for pharmacovigilance, despite a major limitation regarding causality assessment of ADRs in individual tweets, which may improve with the new limitation to 280 characters per tweet.