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Objective: To estimate the incidence of hospitalization with a diagnosis of herpes zoster (HZ) and post-herpetic neuralgia (PHN) in France between 2013 and 2020, overall and stratified by age-group and immune status., Methods: Retrospective observational, database study, using the French hospital discharge database, which includes private and public data for all day-care and inpatient stays. Adults aged ≥18 years, hospitalized between January 1, 2013, and December 31, 2020, with a diagnosis of HZ or PHN, were included., Results: Overall, 62 077 adults had a first hospitalization with a diagnosis of HZ or PHN during the observation period. HZ and/or PHN incidence ranged between 14.6 and 16.3 hospitalizations/100 000 persons and was highest in people aged ≥80 years (97.6 hospitalizations/100 000 persons). The immunocompromised (IC) population accounted for 22% of the overall study population. IC patients had longer lengths of stay for HZ per episode compared with non-IC patients (15.5 ± 19.4 days vs 12.2 ± 13.5 days) and higher in-patient mortality (8% vs 4%). Average annual hospitalization costs per patient were higher in the IC vs non-IC population (€8018 vs €5603)., Conclusions: Older age increases hospitalization rates up to 6-fold and IC status increases in-patient mortality up to two-fold., Clinical Trial Registration: The study was conducted by HEVA and data were provided by ATIH according to French regulatory and data protection procedures., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF., Methods: Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long-term HF-related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias., Results: Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67-3.52), dasatinib (aHR = 2.22, 95% CI 1.42-3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69-2.64), crizotinib (aHR = 1.71, 95% CI 1.07-2.72), everolimus (aHR = 1.45, 95% CI 1.26-1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01-1.86). Sensitivity analyses were consistent with our primary analysis., Conclusions: The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: Recent reports have raised concerns about a potential risk of osteonecrosis associated with testosterone treatment (TT). The aim of this pharmacovigilance study was to assess the risk of reporting osteonecrosis associated with the use of TT compared with use of any other medication., Methods: We performed a disproportionality analysis to investigate the risk of reporting osteonecrosis with TT using the WHO database VigiBase ® . We estimated the reporting odds ratio (ROR) and 95% confidence interval (CI) of reporting osteonecrosis with use of TT vs all other drugs, and the adjusted ROR with use of TT vs use of drugs for benign prostatic hyperplasia (BPH)., Results: Among men at least 18 years of age between January 1, 2000, and December 31, 2019, we identified 3479 reports of osteonecrosis, 84 of which were associated with TT use, out of a total of 4,667,754 adverse event reports. Reports of osteonecrosis in TT users occurred with both transdermal and injectable forms, and the mean age at report was 55.4 years. TT use was associated with a greater risk of reporting osteonecrosis compared to all other drugs (ROR, 5.13; 95% CI, 4.13-6.37) and compared with use of drugs for BPH (ROR, 3.00; 95% CI, 2.08-4.30). Half of the osteonecrosis reports associated with TT indicated concomitant use of corticosteroids., Conclusion: TT was associated with a greater risk of reports of osteonecrosis compared to use of any other drug and use of drugs for BPH. This signal should be confirmed in complementary studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Metopimazine is an anti-emetic drug used to treat nausea and vomiting of pregnancy. However, no animal or clinical data are available regarding its safety in pregnant women. The aim of this study was, therefore, to assess the risk of birth defects and pregnancy loss associated with the use of metopimazine during pregnancy in a population-based cohort study., Methods: The study focused on the EFEMERIS database including the prescription and dispensation of drugs for pregnant women in Haute-Garonne, France, between July 2004 and December 2017. This was an observational, retrospective, comparative study. Pregnancy loss and major birth defects were compared between women exposed to metopimazine during pregnancy and those with no exposure using multivariate logistic regression and Cox proportional risk models., Results: Among 135,574 pregnant women, 11,402 (8.2%) were exposed to metopimazine during pregnancy, mostly in the first trimester (more than 70% of women). No association was found between major birth defects and exposure to metopimazine in the first trimester of pregnancy (OR a =[95% CI]=1.06 [0.92-1.23]). Pregnancy loss was negatively associated with metopimazine use during pregnancy (HR a [95% CI]=0.80 [0.72-0.88]), taking into account major potential confounders. Comparable rates were recorded between women exposed to metopimazine and those unexposed to the drug in terms of prematurity (6.7% vs. 6.4%), low birth weight (6.2% vs. 6.2%) and small for gestational age (1.2% vs. 1.4%)., Conclusion: This study illustrates the wide use of metopimazine during pregnancy in France although no studies on efficacy or safety in pregnant women are available. The results of this study do not indicate any teratogenic effect or an increased risk of pregnancy loss of metopimazine., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The Sphingosine kinase-1/Sphingosine 1-Phosphate (SphK1/S1P) signaling pathway is overexpressed in various cancers, and is instrumental for the adaptation to hypoxia in a number of solid tumor models, but no data are available in osteosarcoma. Here we report that SphK1 and the S1P 1 receptor are involved in HIF-1α accumulation in hypoxic osteosarcoma cells. FTY720 (Fingolimod), which targets SphK1 and S1P 1, prevented HIF-1α accumulation, and also inhibited cell proliferation in both normoxia and hypoxia unlike conventional chemotherapy. In human biopsies, a significant increase of SphK1 activity was observed in cancer compared with normal bones. In all sets of TMA samples (130 cases of osteosarcoma), immunohistochemical analysis showed the hypoxic marker GLUT-1, SphK1 and S1P 1 were expressed in tumors. SphK1 correlated with the GLUT-1 suggesting that SphK1 is overexpressed and correlates with intratumoral hypoxia. No correlation was found between GLUT-1 or SphK1 and response to chemotherapy, but a statistical difference was found with increased S1P 1 expression in patients with poor response in long bone osteosarcomas. Importantly, multivariate analyses showed that GLUT-1 was associated with an increased risk of death in flat bone, whereas SphK1 and S1P 1 were associated with an increased risk of death in long bones.

Background: In France, few data are available on the prescription patterns of antiemetic medications in pregnant women., Objectives: The purpose of this study was to describe antiemetic medication prescriptions and trends over time. Can we observe significant changes in pregnant woman prescriptions in recent years?, Methods: We conducted a drug utilization study among pregnant women using data from the EFEMERIS database, including 135 574 pregnant women who had a pregnancy outcome between 2004 and 2017 in Haute-Garonne (France)., Results: During the study period, 40 028 women (29.5%) received at least one antiemetic prescription during pregnancy. Metoclopramide (56.6%), domperidone (34.9%), and metopimazine (28.5%) were the most commonly prescribed antiemetics, whatever the trimester of pregnancy. Prescriptions of ondansetron only concerned 53 women (0.1%). The prevalence of women who received at least one prescription for an antiemetic decreased from 32.5% in 2010 to 21.6% in 2017. This decline mainly concerned domperidone prescriptions (from 13.1% in 2010 to 1.2% in 2017). Metoclopramide prescriptions also decreased slightly (18.3% in 2010 and 14.0% in 2017). Metopimazine prescriptions increased lowly (8.0% in 2010 and 9.0% in 2017)., Conclusion: This study showed a decrease of antiemetic prescriptions between 2010 and 2017, linked to the sharp decrease in domperidone use from 2011, probably related to warnings about the risk of cardiovascular adverse effects following exposure to domperidone. We could not observe real switches to other antiemetic medications. No switches to ondansetron could be noted either, with only rare exposure during pregnancy, contrary to other countries, like the United States., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Introduction: Domperidone is widely used during pregnancy, although the risks associated with pregnant women have not been adequately evaluated., Objective: The objective of this study was to compare the rate of pregnancy outcomes and congenital anomalies between pregnant women exposed and unexposed to domperidone during pregnancy., Methods: We conducted a retrospective cohort study comparing pregnant women exposed and unexposed to domperidone during pregnancy. We used the EFEMERIS database containing the prescriptions and dispensing of drugs to pregnant women in Haute-Garonne, who had a pregnancy outcome between July 2004 and December 2017. We compared pregnant women who were exposed to domperidone at least once during pregnancy to unexposed pregnant women. Logistic regression and Cox proportional risk models were applied., Results: Overall, 13,964 pregnancies (10.3% of pregnancies) were given domperidone. A reduction in the number of pregnant women exposed to domperidone (2004: 17.1% to 2017: 1.2%) was noted. More than 75% of pregnancies were exposed to domperidone in the first trimester of pregnancy. The rate of natural pregnancy termination in pregnant women exposed to domperidone was lower than that in unexposed pregnant women (adjusted hazard ratio = 0.78 [0.71-0.87]). The malformation rate in fetuses/newborns exposed in utero (first trimester) to domperidone is comparable to that of unexposed fetuses/newborns (adjusted odd ratio = 0.89 [0.77-1.03])., Conclusions: This is the first comparative study to enrol a large number of pregnant women exposed to domperidone. Data regarding the malformation rate following exposure to domperidone during the first trimester of pregnancy are reassuring. Women exposed to domperidone during pregnancy have a decreased risk for natural pregnancy termination, probably owing to an indication bias.

After initially hypothesizing a positive relationship between use of renin-angiotensin-aldosterone system inhibitors and risk of coronavirus disease 2019 (COVID-19), more recent evidence suggests negative associations. We examined whether COVID-19 risk differs according to antihypertensive drug class in patients treated by ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers (ARBs) compared with calcium channel blockers (CCBs). Three exclusive cohorts of prevalent ACE inhibitors, ARB and CCB users, aged 18 to 80 years, from the French National Health Insurance databases were followed from February 15, 2020 to June 7, 2020. We excluded patients with a history of diabetes, known cardiovascular disease, chronic renal failure, or chronic respiratory disease during the previous 5 years, to only consider patients treated for uncomplicated hypertension and to limit indication bias. The primary end point was time to hospitalization for COVID-19. The secondary end point was time to intubation/death during a hospital stay for COVID-19. In a population of almost 2 million hypertensive patients (ACE inhibitors: 566 023; ARB: 958 227; CCB: 358 306) followed for 16 weeks, 2338 were hospitalized and 526 died or were intubated for COVID-19. ACE inhibitors and ARBs were associated with a lower risk of COVID-19 hospitalization compared with CCBs (hazard ratio, 0.74 [95% CI, 0.65-0.83] and 0.84 [0.76-0.93], respectively) and a lower risk of intubation/death. Risks were slightly lower for ACE inhibitor users than for ARB users. This large observational study may suggest a lower COVID-19 risk in hypertensive patients treated over a long period with ACE inhibitors or ARBs compared with CCBs. These results, if confirmed, tend to contradict previous hypotheses and raise new hypotheses.