Placental transfer and safety in pregnancy of medications under investigation to treat coronavirus disease 2019

International audienceOBJECTIVE: Treatment of coronavirus disease 2019 is mostly symptomatic, but a widerange of medications are under investigation against severe acute respiratory syndrome coronavirus 2. Although pregnant women are excluded from clinical trials, they willinevitably receive therapies whenever they seem effective in nonpregnant patients andeven under compassionate use.METHODS: We conducted a review of the literature on placental transfer and pregnancy safety data of drugs under current investigation for coronavirus disease 2019.RESULTS: Regarding remdesivir, there are no data in pregnant women. Several other candidates already have safety data in pregnant women, because they are repurposed drugs already used for their established indications. Thus, they may be used in pregnancy, although their safety in the context of coronavirus disease 2019 may differ from conventional use. These include HIV protease inhibitors such as lopinavir/ritonavir that have low placental transfer, interferon that does not cross the placental barrier, and hydroxychloroquine or chloroquine that has high placental transfer. There are also pregnancy safety and placental transfer data for colchicine, steroids, oseltamivir, azi-thromycin, and some monoclonal antibodies. However, some drugs are strictly prohibitedin pregnancy because of known teratogenicity (thalidomide) or fetal toxicities (renin-angiotensin system blockers). Other candidates including tocilizumab, other interleukin 6 inhibitors, umifenovir, and favipiravir have insufficient data on pregnancy outcomes.CONCLUSION: In life-threatening cases of coronavirus disease 2019, the potential risks of therapy to the fetus may be more than offset by the benefit of curing the mother. Although preclinical and placental transfer studies are required for a number of potentialanti-severe acute respiratory syndrome coronavirus 2 drugs, several medications can already be used in pregnant women

Titrated baclofen for high-risk alcohol consumption: a randomized placebo-controlled trial in out-patients with 1-year follow-up

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Maternal-Fetal Transfer and Amniotic Fluid Accumulation of Nucleoside Analogue Reverse Transcriptase Inhibitors in Human Immunodeficiency Virus-Infected Pregnant Women

This study was performed to investigate placental transfer of nucleoside analogue reverse transcriptase inhibitors (NRTIs) and their concentrations in amniotic fluid when given to human immunodeficiency virus (HIV)-infected pregnant women. A total of 100 HIV type 1-infected mothers receiving antiretroviral therapy, including one or more NRTIs, for clinical indications at the time of delivery were enrolled. Maternal blood samples and amniotic fluid were obtained during delivery or cesarean section, and paired cord blood samples were obtained by venipuncture immediately after delivery. Drug concentrations were measured by using high-performance liquid chromatography. A significant relationship between concentrations in maternal and cord plasma samples was found for zidovudine, lamivudine, stavudine, and didanosine. The ratio between the concentrations in cord and maternal plasma samples (R) was high for zidovudine (R = 1.22), its glucuronide metabolite (3′-azido-3′-deoxythymidine-β-d-glucuronide) (R = 1.01), stavudine (R = 1.32), lamivudine (R = 0.93), and abacavir (R = 1.03) and was low for didanosine (R = 0.38). The ratio between the concentrations in amniotic fluid and cord plasma samples was high for zidovudine (R = 2.24), its glucuronide metabolite (R = 2.83), stavudine (R = 4.87), and lamivudine (R = 3.99) and was lower for didanosine (R = 1.14). These findings indicate that most NRTIs cross the placenta by simple diffusion and are concentrated in the amniotic fluid, probably through fetal urinary excretion. The efficacy or toxicity of NRTIs may vary according to placental transfer

Drug-induced IgA vasculitis in children and adults: Revisiting drug causality using a dual pharmacovigilance-based approach

International audienceObjectivesIgA vasculitis (IgAV) is an immune complex small-vessel vasculitis. Drug-induced IgAV cases were rarely reported in the literature. Drug causality assessment is challenging as many other etiological factors can be involved. We performed a pharmacovigilance study to identify the main drugs reported to induce IgAV.MethodsWe used the French pharmacovigilance database (FPVD) and the WHO global individual case safety reports database (VigiBase) to retrieve IgAV cases. Cases from the FPVD were reviewed by two investigators using predefined criteria. Disproportionality analyses (case – non-case approach) were conducted in VigiBase to identify drugs significantly associated with IgAV reporting.ResultsOf the 467 IgAV cases retrieved from the FPVD, 115 (47 children and 68 adults) have been assessed as definite or probable, reported with 178 suspected drugs. Overall IgAV cases were mainly male (58%), with a median age of 33.5 (8.0–63.3) years. No death was reported. Besides, we identified 1558 possible IgAV cases in VigiBase. Among them, 40 were associated with a disproportionality in IgAV reporting. Drugs were mainly vaccines, antibiotics and TNF-α blockers, these finding being consistent in both databases. IgAV reporting with TNF-α blockers was significantly associated with their use in inflammatory bowel diseases, psoriasis or ankylosing spondylitis compared to other indications.ConclusionsOur systematic study enables the identification of culprit drugs in drug-induced IgAV. These results strengthen the immune pathophysiology of IgAV and the role of underlying disease. The list of suspected drugs may be useful for physicians to manage patients with IgAV and consider appropriate drug discontinuation

Insulin-Like Growth Factor-I and Insulin-Like Growth Factor Binding Protein-3 in Alzheimer's Disease

International audienceCONTEXT:Few large studies have been conducted to assess the relationship between circulating IGF and late-life cognition.OBJECTIVE: The aim of the study was to assess the relationship between IGF-I and IGF binding protein-3 (IGFBP-3) serum levels and cognitive impairment, including Alzheimer's disease (AD).METHODS: In this multicentric cross-sectional study, 694 elderly subjects (218 men, 476 women; 78.6 ± 6.7 yr old) were included; 481 had memory complaints and were diagnosed, after comprehensive cognitive assessment, with AD (n = 224) or mild cognitive impairment (MCI) (n = 257). The control group was comprised of 213 subjects without memory complaint and with normal cognition (recruited among patients' caregivers). IGF-I and IGFBP-3 serum levels were determined by ELISA.RESULTS: IGF-I and IGFBP-3 serum levels were significantly associated with cognitive status in men (IGF-I, 137 ± 69 ng/ml for AD vs. 178 ± 88 ng/ml for MCI and 172 ± 91 ng/ml for controls, P = 0.01; IGFBP-3, 3675 ± 1542 ng/ml for AD vs. 4143 ± 1828 ng/ml for MCI and 4488 ± 1893 ng/ml for controls, P = 0.04). In women, IGFBP-3 was significantly associated with cognitive status (3781 ± 1351 ng/ml for AD vs. 4190 ± 1408 ng/ml for MCI and 4390 ± 1552 ng/ml for controls; P < 0.001), but no significant differences between groups for IGF-I occurred. After adjustment for confounding variables (age, educational level, body mass index, diabetes, apolipoprotein E ε4 status), logistic regression indicated that IGF-I [odds ratio (95% confidence interval) = 0.48 (0.26-0.88)] and IGFBP-3 [odds ratio (95% confidence interval) = 0.71 (0.52-0.97)] serum levels were independently associated with AD in men, but not in women.CONCLUSIONS: We report a significant association between low IGF-I and IGFBP-3 serum levels and AD in men, but not in women.TRIAL REGISTRATION: ClinicalTrials.gov NCT00647478

Maternal Betamethasone for Prevention of Respiratory Distress Syndrome in Neonates: Population Pharmacokinetic and Pharmacodynamic Approach

International audienceDespite antenatal corticosteroids therapy, respiratory distress syndrome (RDS) is still a leading cause of neonatal morbidity and mortality in premature newborns. To date, the relationship between in utero fetal drug exposure and occurrence of RDS remains poorly evaluated. This study aims to describe the pharmacokinetics of betamethasone in pregnant women and to evaluate the transplacental drug transfer and administration scheme for the prevention of RDS. Pregnant women > 27 weeks' gestation and who received at least a single dose of betamethasone for prevention of RDS were enrolled. Maternal, cord blood, and amniotic fluid betamethasone time-courses were analyzed using the Monolix software. A total of 220 maternal blood, 56 cord blood, and 26 amniotic fluid samples were described by a two-compartment model with two effect compartments linked by rate transfer constants. Apparent clearances and volumes of distribution parameters were allometrically scaled for a 70 kg third trimester pregnant woman. The impact of a twin pregnancy was found to increase maternal clearance by 28%. Using a fetal-to-mother exposure ratio, the median (95% confidence interval (CI)) transplacental transfer of betamethasone was estimated to 35% (95% CI 0.11-0.67). After adjustment for gestational age and twin pregnancy, RDS was found to be associated to the time spent in utero below quantifiable concentrations (i.e., < 1 ng/mL): odds ratio of 1.10 (95% CI 1.01-1.19) per day increase (P < 0.05). Trying to take into account both efficacy and safety, we simulated different dosing schemes in order to maintain a maximum of fetuses above 1 ng/mL without exceeding the total standard dose

Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

International audienceThe majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer.Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922. Funding. Université Paris Descartes, Ministère de la Recherche et de l'Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris

Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers

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