Functional Role of P-Glycoprotein and Binding Protein Effect on the Placental Transfer of Lopinavir/Ritonavir in the Ex Vivo Human Perfusion Model

Aims. To study the influence of P-glycoprotein (P-glycoprotein, ABCB1, MDR1) function on placental transfer of lopinavir with ritonavir at different albumin concentrations. Methods. Cotyledons were perfused with lopinavir, ritonavir, and the internal control antipyrin, at various albumin concentrations (10, 30, 40 g/L). After the control phase of each experiment, the P-glycoprotein inhibitor ciclosporin A was added at middle perfusion (45 minutes). Fetal Transfer Rate (FTR) and Clearance Index (CLI) were compared between the 2 phases. Results. In the control phase, the clearance index of lopinavir decreased from 0.401 ± 0.058 to 0.007 ± 0.027, as albumin concentrations increased from 10 g/L to higher concentrations (30, 40 g/L). When adding ciclosporin A at physiological albumin concentrations, the clearance index of lopinavir increased significantly 10.3 fold (95% of CI difference [−0.156, −0.002], P = .046) and became positive for ritonavir. Conclusions. Even at high albumin concentrations, inhibition of placental P-glycoprotein increased placental transfer of lopinavir, suggesting that this efflux pump actively reduces placental transfer of the drug. This mechanism may play a role in fetal exposure to maternal antiretroviral therapy

Emerging therapeutic options for breast cancer chemotherapy during pregnancy

Rak piersi jest najczęstszym guzem litym obserwowanym u kobiet w ciąży. Antracyklina jest jednym z leków, które można stosować w chemioterapii ciężarnych w drugim i trzecim trymestrze ciąży. Istnieje niestety mało danych dotyczących możliwości stosowania w terapii w tym okresie ciąży nowych i bardzo skutecznych leków, takich jak taksany, winorelbina czy czynniki anty-HER-2. W celu oceny profilu bezpieczeństwa stosowania tych leków u ciężarnych pacjentek przeprowadzono wszechstronny przegląd dokumentacji dostępnej w piśmiennictwie anglojęzycznym na temat użycia taksanów, winorelbiny, trastuzumabu oraz lapatinibu podczas ciąży. Opisano 24 przypadki ciąż, w których nie zaobserwowano efektów toksycznych 3–4 stopnia u matki ani malformacji u płodu. Mimo iż tylko w jednej z tych prac oceniano farmakokinetykę paklitakselu (Taxol) podczas ciąży, liczne przeprowadzone badania przedkliniczne wskazują, że łożyskowa P-glikoproteina może zapobiegać przezłożyskowemu transferowi taksanów i winorelbiny. Stosowanie trastuzumabu w 3 z 6 przypadków wiązało się z występowaniem bezwodzia. W czasie drugiego i trzeciego trymestru ciąży istnieje możliwość stosowania nowych leków charakteryzujących się korzystnym profilem toksyczności, takich jak taksany i winorelbina, natomiast czynniki anty- HER-2 mogą zaburzać prawidłowy rozwój nerek u płodu i nie powinno się ich stosować u kobiet w ciąży.Breast cancer is the commonest solid tumor observed during pregnancy. Anthracycline-based chemotherapy is feasible during the 2nd and 3rd trimesters of pregnancy, but few data are available on recent and highly active drugs taxanes, vinorelbine and anti-HER-2 agents in this setting. We carried out a comprehensive review of reports documenting the use of taxanes, vinorelbine, trastuzumab and lapatinib during pregnancy in the English literature, in order to evaluate their safety profile in pregnant patients. Twenty-four pregnancies are described, in which no grade 3–4 maternal toxicity nor malformation in the offspring was reported. Whereas only one report studied the pharmacokinetics of paclitaxel (Taxol) during pregnancy, several preclinical reports indicate that the placental P-glycoprotein could prevent the transplacental transfer of taxanes and vinorelbine. The use of trastuzumab was associated with the occurrence of anhydramnios in three of six cases. The administration of recent drugs taxanes and vinorelbine seems feasible during the 2nd and 3rd trimesters of pregnancy, with a favorable toxicity profile. In contrast, anti-HER-2 agents may obscure the normal development of the fetal kidney, and should be avoided during pregnancy

A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial)

To assess the efficacy of the interleukin 1 receptor antagonist anakinra in systemic-onset juvenile idiopathic arthritis (SJIA).status: publishe

Bupivacaine versus lidocaine analgesia for neonatal circumcision

BACKGROUND: Analgesia for neonatal circumcision was recently advocated for every male infant, and its use is considered essential by the American Academy of Pediatrics. We compared the post-operative analgesic quality of bupivacaine to that of lidocaine for achieving dorsal penile nerve block (DPNB) when performing neonatal circumcision. METHODS: Data were obtained from 38 neonates following neonatal circumcision. The infants had received DPNB analgesia with either lidocaine or bupivacaine. The outcome variable was the administration by the parents of acetaminophen during the ensuing 24 hours. RESULTS: Seventeen infants received lidocaine and 19 received bupivacaine DPNB. Ten infants in the lidocaine group (59%) were given acetaminophen following circumcision compared to only 3 (16%) in the bupivacaine group (P < 0.01). Regression analysis showed that the only significant variable associated with the need for acetaminophen was the use of lidocaine (R(2 )= 20.6; P = 0.006). CONCLUSION: DPNB with bupivacaine for neonatal circumcision apparently confers better analgesia than lidocaine as judged by the requirement of acetaminophen over the ensuing 24-hour period

Clinical pharmacodynamic factors in docetaxel toxicity

Neutropenia is the main dose-limiting toxicity occurring in docetaxel treatment. The objective of this study was to identify pharmacodynamic (PD) factors responsible for the neutropaenia caused by docetaxel. Data were obtained from 92 patients treated with docetaxel as a monochemotherapy in two different treatment centres. A semiphysiological population pharmacokinetic–pharmacodynamic (PK/PD) model was applied to describe the time course of neutrophils and the neutropaenic effect of docetaxel. The plasma docetaxel concentration was assumed to inhibit the proliferation of neutrophil precursors through a linear model: Drug effect=Slope × Conc. Slope corresponds to the patients' sensitivity to the neutropaenic effect of docetaxel. Covariate analysis was performed by testing the relationship between the patients' characteristics and Slope using the program NONMEM. The neutropaenic effect of docetaxel showed a high interindividual variability. Three significant PD covariates were identified: serum α1-acid glycoprotein levels (AAG), level of chemotherapy pretreatment, and treatment centre. Extensive pretreatment was associated with an increase in Slope values meaning a higher haematotoxicity. An increase in AAG was associated with a decrease of both Slope and docetaxel plasma clearance. Patients treated in one centre had both higher Slope and docetaxel clearance. The centre effect (most likely due to a bias in the PK part of the study between the two centres) reveals the robustness of the PK/PD model. Individual dosing of docetaxel should be based on previous chemotherapy but not on the AAG level since it has a similar influence on PD and PK docetaxel parameters. This methodology should be applied to further investigate elderly patients and to identify more precisely the characteristics of previous chemotherapy that contribute to the cumulative myelotoxicity

Clinical, methodology, and patient/carer expert advice in pediatric drug development by conect4children

Many medicines are used “off-label” in children outside the terms of the license. Feasible pediatric clinical trials are a challenge to design. Conect4children (c4c) is an Innovative Medicines Initiative project to set up a pan-European pediatric clinical trial network aiming to facilitate the development of new medicines for children. To optimize pediatric trial development by promoting innovative trial design, c4c set up a European multidisciplinary advice service, including the voice of young patients and families, tailored to industry and academia. A network of experts was established to provide multidisciplinary advice to trial sponsors. Experts were selected to join clinical and innovative methodology expert groups. A patient and public involvement (PPI) database, to include the expert opinion of patients and parents/carers was formed. A stepwise process was developed: (1) sponsors contact c4c, (2) scoping interview takes place, (3) ad hoc advice group formed, (5) advice meeting held, and (6) advice report provided. Feedback on the process was collected. Twenty-four clinical and innovative methodology expert groups (>400 experts) and a PPI database of 135 registrants were established. As of September 30, 2022, 36 advice requests were received, with 25 requests completed. Clinical and methodology experts and PPI representatives participated in several advice requests. Sponsors appreciated the advice quality and the multidisciplinary experts from different countries, including experts not known before. Experts and PPI participants were generally satisfied with the process. The c4c project has shown successful proof of concept for a service that presents a new framework to plan innovative and feasible pediatric trials

Circulating biomarkers may be unable to detect infection at the early phase of sepsis in ICU patients: the CAPTAIN prospective multicenter cohort study.

PURPOSE: Sepsis and non-septic systemic inflammatory response syndrome (SIRS) are the same syndromes, differing by their cause, sepsis being secondary to microbial infection. Microbiological tests are not enough to detect infection early. While more than 50 biomarkers have been proposed to detect infection, none have been repeatedly validated. AIM: To assess the accuracy of circulating biomarkers to discriminate between sepsis and non-septic SIRS. METHODS: The CAPTAIN study was a prospective observational multicenter cohort of 279 ICU patients with hypo- or hyperthermia and criteria of SIRS, included at the time the attending physician considered antimicrobial therapy. Investigators collected blood at inclusion to measure 29 plasma compounds and ten whole blood RNAs, and-for those patients included within working hours-14 leukocyte surface markers. Patients were classified as having sepsis or non-septic SIRS blindly to the biomarkers results. We used the LASSO method as the technique of multivariate analysis, because of the large number of biomarkers. RESULTS: During the study period, 363 patients with SIRS were screened, 84 having exclusion criteria. Ninety-one patients were classified as having non-septic SIRS and 188 as having sepsis. Eight biomarkers had an area under the receiver operating curve (ROC-AUC) over 0.6 with a 95% confidence interval over 0.5. LASSO regression identified CRP and HLA-DRA mRNA as being repeatedly associated with sepsis, and no model performed better than CRP alone (ROC-AUC 0.76 [0.68-0.84]). CONCLUSIONS: The circulating biomarkers tested were found to discriminate poorly between sepsis and non-septic SIRS, and no combination performed better than CRP alone

Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome

International audienceTo the Editor:The Aicardi–Goutières syndrome is a genetic encephalopathy that is associated with childhood illness and death. The syndrome is hypothesized to be due to misidentification of self-derived nucleic acids as nonself and the subsequent induction of a type I interferon–mediated response that simulates an antiviral reaction.1 Endogenous retroelements, mobile genetic elements that can be transcribed to RNA and then to DNA by reverse transcription, constitute 40% of the human genome and represent a potential source of immunostimulatory nucleic acid in patients with this syndrome.

Burnout among paediatric residents during the COVID-19 outbreak in France

International audienceThe primary objective of the study was to assess the prevalence of burnout among paediatric residents during the coronavirus disease 2019 (COVID-19) outbreak in France. The secondary objective was to identify risk factors associated with burnout in this population. In a nationwide, cross-sectional survey, a questionnaire was e-mailed to all paediatric residents in France in the first week of May 2020. The prevalence of burnout was assessed with the validated French-language version of the Maslach Burnout Inventory - Human Services Survey. The questionnaire also contained items on the residents' sociodemographic characteristics and professional situation. Three hundred and forty paediatric residents completed the questionnaire. The median age was 27 (interquartile range 25-28) and 285 (83.8%, 95% confidence interval (CI) [79.5-87.6]) of the residents were women. The prevalence of burnout was 37.4%, 95%CI [32.2-42.7]. There was no association between burnout and exposure to the consequences of COVID-19, which may be related to the low incidence of severe COVID-19 among children. In contrast, the hours worked per week and the anxiety scores were significantly associated with burnout. Conclusion: The level of burnout among French paediatric residents is a matter of concern for residents, and cannot be ascribed to the COVID-19 outbreak. Preventive actions should be implemented, with a reduction in working hours and support programs to help manage work-related anxiety. What is Known: center dot Burnout is a concern for both residents and the patients they care for. center dot Natural disasters disrupt the health care organizations and increase the burnout rate. What is New: center dot The prevalence of burnout among paediatric residents in France is 37.4%, 95%CI [32.2-42.7]. center dot COVID-19 outbreak is not associated with burnout in this population but anxiety and working hours per week might be modifiable risk factors