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.

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.

Adverse drugs reactions (ADR) suspected through phone triage and assessed by medically staffed ambulances: A pilot study.

BACKGROUND: Prompt and definitive diagnosis of adverse drug reactions (ADRs) is a challenge for health care providers. There is a global burden of ADRs worldwide associated with a negative impact on the patient's health, in parallel with increasing costs for the community. This study aims to determine the annual incidence of ADRs in the cohort of patients requiring immediate intervention of the French prehospital emergency medical service (PEMS). The definitive diagnosis of ADR was provided by the follow-up of the entire course of hospitalization from PEMS presentation to final discharge in each suspected case. METHODS: A retrospective study examining the incidence of ADR at the Paris PEMS was performed in 2015. RESULTS: From January the 1st to December the 31st, 2015, 485 cases of suspected ADR were selected. Twenty-eight patients could not be identified at the hospital and were considered as lost to follow-up. For the 457 cases with the final diagnosis and outcome available, 359 had a definitive and new diagnosis of ADR, 9 were related to substance of abuse and alcohol, 14 were duplicates and 75 were excluded by drug causality was ruled out. Long-term follow-up was performed for 359 cases. Among them, 22 patients (6.1%) died of an ADR. Twenty-five severe ADRs were notified for children ages 2 to 16 with a cluster of 9 cases (36%) resulting from an accidental outbreak of poisonings with alimemazine in a classroom. No fatality was reported among children suffering from an ADR. CONCLUSION: The collaboration between PEMS and in hospital Pharmacovigilance Centre is feasible from the PEMS report to the long-term follow-up. The definition of a clinical pattern for some drugs is needed to allow the medical team to anticipate the clinical outcome of the involved patient and therefore adapting the patient's support as soon as possible.

Amoxicillin-induced crystal nephropathy: A nationwide French pharmacovigilance databases study.

AIMS: Amoxicillin (AMX)-induced crystal nephropathy (AICN) is a rarely reported adverse drug reaction (ADR) but its increase has been recently reported in the Paris area. Our aim was to investigate the incidence, characteristics and outcome of AICN in France. METHODS: Retrospective analysis of all AICN cases reported to the French National Pharmacovigilance Database and the Marketing Authorization Holders Pharmacovigilance Database. AICN notification rate was compared to intravenous AMX and AMX-clavulanate sales. RESULTS: In total, 101 AICN cases were included. Intravenous AMX/AMX-clavulanate was prescribed as surgical prophylaxis (32 surgical patients) or to treat infection (69 medical patients). AKI KDIGO stage 3 was observed in 70 patients and 24/70 patients required renal replacement therapy and/or intensive care unit admission. The annual notification rate of AICN was increased by a factor of 13 since 2010 (6 [0;7] and 77 [24;111] cases per 100 000 patient-years of exposure, before and after 2010 respectively; P < .001). In surgical patients, the increase in AICN has been reported since 2010 and was mainly related to inadequate AMX administration. In medical patients, the increase in AICN was observed since 2014. After 2014, medical patients were older (67 [42;77] vs 74 years [64;84] respectively; P < .05) and were treated more frequently for endocarditis (0/20 vs 15/49 respectively; P < .01). A contributing factor was observed or suspected in 62 patients. CONCLUSION: AICN is a severe ADR that dramatically increased in France since 2010. Assessment of AICN contributing factors and AMX drug monitoring in patients receiving high dose of AMX could reduce the risk of AICN.

Dramatic Increase of Amoxicillin-Induced Crystal Nephropathy Found in a Cohort Study of French Pharmacovigilance Centers.

An increase in amoxicillin-induced crystal nephropathy (AICN) incidence has been recently suggested. The aims of this study were to investigate the trend of AICN incidence through Paris' regional centers of pharmacovigilance (Paris RCPVs) and better describe this rare adverse drug reaction. Forty-five AICN cases were identified between 1985 and 2016. All cases, except one, were reported since 2010. Amoxicillin (AMX) was administered intravenously (65 [interquartile range {IQR}, 43 to 110] mg/kg of body weight/day) in all patients, either for treating infection (n = 15) or as surgical prophylaxis (n = 30). Delay between AMX administration and AICN onset was 1 (IQR, 1 to 3) day; 30, 4, and 11 patients developed KDIGO stage 1, 2, and 3 acute kidney injury, respectively. Delay between AICN onset and kidney function recovery was 4 (IQR, 2 to 6) days. Precipitating factors were identified in only one-third of cases. Twelve patients required intensive care unit admission, and 8 needed renal replacement therapy. Neither chronic kidney disease nor death was observed. We confirmed the recent and dramatic increase of AICN in the Paris RCPVs since 2010. The absence of precipitating factors in the majority of cases and the onset of AICN in apparent routine indications, such as surgical prophylaxis, are alarming and justify a high vigilance from all AMX prescribers.

[Cutaneous pigmentation related to intravenous iron extravasation: Analysis from the French pharmacovigilance database]. / Pigmentation cutanée liée à l'extravasation de fer injectable. Analyse de la base française de pharmacovigilance de 2000 à 2016.

INTRODUCTION: Intravenous iron infusion may be complicated by extravasation and lead to cutaneous pigmentation. METHODS: We queried the French pharmacovigilance database to assess the spontaneously reported cases over the 2000-2016 period. RESULTS: Fifty-one cases of cutaneous pigmentation related to intravenous iron extravasation were retrieved, none was associated to necrosis. Most of patients were women aged 20 to 49 years old. The pigmentation was mostly a brown coloration, persisting over one month in 19 cases (37.2%) and over 6 months in 9 cases (17.6%). The management of extravasation and pigmentation was heterogeneous and was rarely followed by a decrease of the coloration. CONCLUSION: Cutaneous pigmentation after intravenous iron extravasation can persist over time and create an aesthetic prejudice, particularly in young women. Standardized extravasation and iron-induced pigmentation management procedures appear necessary.

Phenome-wide association studies on a quantitative trait: application to TPMT enzyme activity and thiopurine therapy in pharmacogenomics.

Phenome-Wide Association Studies (PheWAS) investigate whether genetic polymorphisms associated with a phenotype are also associated with other diagnoses. In this study, we have developed new methods to perform a PheWAS based on ICD-10 codes and biological test results, and to use a quantitative trait as the selection criterion. We tested our approach on thiopurine S-methyltransferase (TPMT) activity in patients treated by thiopurine drugs. We developed 2 aggregation methods for the ICD-10 codes: an ICD-10 hierarchy and a mapping to existing ICD-9-CM based PheWAS codes. Eleven biological test results were also analyzed using discretization algorithms. We applied these methods in patients having a TPMT activity assessment from the clinical data warehouse of a French academic hospital between January 2000 and July 2013. Data after initiation of thiopurine treatment were analyzed and patient groups were compared according to their TPMT activity level. A total of 442 patient records were analyzed representing 10,252 ICD-10 codes and 72,711 biological test results. The results from the ICD-9-CM based PheWAS codes and ICD-10 hierarchy codes were concordant. Cross-validation with the biological test results allowed us to validate the ICD phenotypes. Iron-deficiency anemia and diabetes mellitus were associated with a very high TPMT activity (p = 0.0004 and p = 0.0015, respectively). We describe here an original method to perform PheWAS on a quantitative trait using both ICD-10 diagnosis codes and biological test results to identify associated phenotypes. In the field of pharmacogenomics, PheWAS allow for the identification of new subgroups of patients who require personalized clinical and therapeutic management.

DPP4 inhibitor-induced polyarthritis: a report of three cases.

Dipeptidyl peptidase-4 (DPP4) inhibitors are a novel therapy widespread used in type 2 diabetes mellitus. We describe 3 cases of polyarthritis which delay of appearance strongly suggests a link with DPP4 inhibitors. Three patients presented with bilateral, symmetrical, seronegative polyarthritis after introduction of DPP4 inhibitors (sitagliptine (n = 2) and vildagliptine (n = 1)). Two patients also developed xerostomia and xerostomia, and laboratory test results showed normal values of CRP and erythrocyte sedimentation rate. Joints X-rays were normal. One patient was diagnosed with primary Sjögren's syndrome and treated with hydroxychloroquine, methotrexate and prednisone, with a poor efficacy. When sitagliptine was stopped, all symptoms disappeared, leading to methotrexate and prednisone discontinuation within a month. There were no immunological abnormalities in the 2 other patients, but a chronic viral hepatitis B was found in one patient. Eventually, discontinuation of DPP4 inhibitors led to resolution of symptoms in 1 and 3 weeks for both patients. DPP4 inhibitors seemed to trigger bilateral, non-erosive, seronegative polyarthritis in our 3 patients. DPP4, also known as CD26, is expressed on many cells including lymphocytes and fibroblasts, and its inhibition may lead to immunomodulating effect as suggested by clinical and in vitro studies.

Vestibular disorders following BNT162b2 mRNA COVID-19 vaccination: A retrospective case series.

BACKGROUND: There are few publications regarding manifestations of vestibular disorders (VDs) following BNT162b2 mRNA COVID-19 vaccination. PURPOSE: We describe cases of VD potentially related to BNT162b2 vaccination and calculate its reporting rate, in order to enlarge knowledge about this adverse effect. METHODS: A retrospective analysis of cases of VD following BNT162b2 vaccination reported to the pharmacovigilance centre of Georges-Pompidou European Hospital (France), in 2021 was performed. In order to identify these cases from the pharmacovigilance database containing all our registered cases, we used the Standardised MedDRA Query (SMQ) 'vestibular disorders'. Then we analysed cases with vestibular symptoms, based on the association of typical manifestations. The reporting rate was calculated based on the number of VD cases and the number of vaccinated patients. RESULTS: Among 6608 cases reported to our centre related to COVID-19 vaccines during 2021, 34 VDs associated with BNT162b2 administration were included. They were mainly reported in females (79%), 62% occurred after the first dose and 32% were serious. Symptoms had completely resolved in 13 cases (38%). Vertigo was the most common symptom followed by balance disorders. Three patients received second dose without reappearance of VD. The final diagnosis was reported in 10 patients (six cases of vestibular neuritis, two cases of central VD, two cases of benign paroxysmal positional vertigo). The regional reporting rate was 26 [95% CI: 17-34] cases of VD per 1 million persons vaccinated. CONCLUSION: Although the relationship between vaccination and VD cannot be established, clinicians should be aware of this rare adverse effect.

Intraoperative argatroban vessel irrigation during microsurgical anastomosis in heparin-induced thrombocytopenia patients: About two cases.

Patients with heparin-induced thrombocytopenia or confirmed allergies to heparin have a contraindication to heparin therapy, which poses a problem for intraoperative free flap irrigation in reconstruction. The use of argatroban as an alternative to heparin allowed us to perform a free flap for leg salvage and a deep inferior epigastric perforator flap for breast reconstruction without microvascular complication, with a 0.01 mg/mL solution. We reported two cases of using an alternative treatment to heparin in an emergency and planned surgeries for vessel irrigation during microsurgical anastomosis reconstruction without microvascular complications, suggesting the reliability and effectiveness of its use in case of contraindication to heparin.

Heparin-induced thrombocytopenia in newborns: experience at a pediatric hospital and a literature review.

Background: Heparin-induced thrombocytopenia (HIT) is a rare, difficult-to-diagnose, and potentially serious adverse drug reaction with thrombotic complications. Even though the immune system is still immature during the neonatal period, HIT has been described in newborns with reporting rates ranging from 0% to 2.3%. Therefore, it is important to clarify the risk of HIT in newborns because it can affect the management and monitoring of heparin treatment. Objectives: The objectives of the present study were to review the literature and determine the incidence of HIT after cardiac surgery in newborns in our pediatric hospital. Methods: We searched the literature from 1992 to 2021 for reports of HIT in newborns. Four raters then analyzed all the literature reports on HIT and classified them as "likely," "uncertain," or "unlikely." We also determined the incidence of HIT among newborns having undergone cardiac surgery in our pediatric hospital. Results: Eleven population-based studies and 12 case reports on suspected HIT in 17 newborns were reviewed. One study reported HIT in 14 out of 930 (1.5%) heparin-treated newborns, but the other studies (n = 467 newborns) did not mention HIT at all. None of the cases described in the literature was classified as "likely" by the raters. In our center, none of the 2997 newborns that had undergone cardiac surgery in the previous 16 years was diagnosed with HIT. Conclusion: We conclude that the incidence of HIT in newborns has been overestimated in the literature.

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.

Direct Oral Anticoagulants as Successful Treatment of Heparin-Induced Thrombocytopenia: A Parisian Retrospective Case Series.

Background: Heparin-induced thrombocytopenia (HIT) is a prothrombotic life-threatening disorder caused by an adverse reaction to heparin exposure. In this context, it is imperative to stop heparin immediately and to replace it by a non-heparin anticoagulant therapy. Despite their advantages, the use of direct oral anticoagulants (DOACs) is only emerging for HIT treatment, and their use remains rare. Objective: To improve our knowledge on the emerging role of DOACs as treatment of HIT and give an overview of our local practices in this context. Patients/Methods: This is a multi-centric retrospective case series of HIT patients referred to our Parisian pharmacovigilance network and treated with DOACs. Results: We report the cases of seven patients from four healthcare centers, diagnosed with HIT (4T score ≥ 4, positive anti-PF4/heparin immunoassay and positive serotonin-release assay) and treated with DOACs. After a few days on substitutive parenteral treatment (n = 6) or directly at HIT diagnosis (n = 1), these patients were treated with either rivaroxaban (n = 6) or apixaban (n = 1) during acute HIT phase. Mean time to platelet count recovery after heparin discontinuation was 3.3 days (range 3-5). No patient experienced major or clinically relevant non-major bleeding or thrombosis that could be related to DOAC treatment during follow-up. Conclusions: Our cases studies are consistent with recent guidelines credit to the potential and safe use of DOAC during acute HIT in clinically stable patients.

Toxicological Analysis Unveiling the Low Rate of Self-Reporting of Addictive/Recreative Substances in Acute Severe Drug Overdose Cases.

OBJECTIVE: Toxicological analysis (TA) is advised when assessing the prognosis and the treatment of drug overdose patients. Apart from this use, the value of TA has remained unclear. This study aimed at defining the value of TA regarding the toxicological diagnosis in severe overdose cases that involved addictive or recreational drugs (ARDs) that were used either alone or in combination with medicinal drugs. METHODS: The patients who were enrolled in the study had been admitted to our intensive care unit for the treatment of poisoning. TA was performed using advanced technologies such as mass spectrometry of blood/urine on admission. An occurrence indicated the supposed ingestion of a defined substance. Patients were included in a group depending on the combination of the occurrences of supposed ingested drugs (SID) and the results of the 1) TA: SID+, TA+; 2) SID+, not searched by TA; 3) SID-, TA+. RESULTS: There were 224 occurrences of 90 substances in 70 patients. ARDs were present in 30 patients (43%). ARD accounted for 24 occurrences in the SID+, TA+ group, 10 occurrences in the SID+, not searched group and 196 occurrences in the SID-, TA+ group. In the SID+, TA+ group, 9 occurrences (69%) of ethanol were confirmed by TA. Ingestion of ethanol was invalidated in 4 occurrences (31%). In the patients who denied ethanol ingestion, TA confirmed the non-ingestion of ethanol using 30 blood measures (81%). Ethanol was involved in 57% of the patients, being the lone substance in only 1 case. CONCLUSION: In drug overdose instances that result in organ failure(s) and involve ARDs, self-reporting is of limited value in assessing the patients' exposure to ARD. Multiple consumptions expose patients to unexpected drug interactions.

Moderate-to-severe eosinophilia induced by treatment with immune checkpoint inhibitors: 37 cases from a national reference center for hypereosinophilic syndromes and the French pharmacovigilance database.

A better understanding of immune-related adverse events is essential for the early detection and appropriate management of these phenomena. We conducted an observational study of cases recorded at the French reference center for hypereosinophilic syndromes and in the French national pharmacovigilance database. Thirty-seven reports of eosinophilia induced by treatment with immune checkpoint inhibitors (ICIs) were included. The median [range] time to the absolute eosinophil count (AEC) peak was 15 [4─139] weeks. The median AEC was 2.7 [0.8─90.9] G/L. Eosinophil-related manifestations were reported in 21 of the 37 cases (57%). If administered, corticosteroids were always effective (n = 10 out of 10). Partial or complete remission of eosinophilia was obtained in some patients not treated with corticosteroids, after discontinuation (n = 12) or with continuation (n = 4) of the ICI. The AEC should be monitored in ICI-treated patients. If required by oncologic indications, continuation of ICI may be an option in asymptomatic hypereosinophilic patients, and in corticosteroid responders.