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

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

Simultaneous pharmacokinetic modeling of unbound and total darunavir with ritonavir in adolescents: a substudy of the SMILE trial

Darunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a pharmacological booster, such as ritonavir (RTV) or cobicistat. To better understand the pharmacokinetics (PK) of DRV in this younger population and the importance of the RTV boosting effect, a population PK substudy was conducted within SMILE trial, where the maintenance of HIV suppression with once daily integrate inhibitor + darunavir/ritonavir in children and adolescents is evaluated. A joint population PK model that simultaneously used total DRV, unbound DRV, and total RTV concentrations was developed. Competitive and non-competitive models were examined to define RTV's influence on DRV pharmacokinetics. Linear and non-linear equations were tested to assess DRV protein binding. A total of 443 plasma samples from 152 adolescents were included in this analysis. Darunavir PK was best described by a one-compartment model first-order absorption and elimination. The influence of RTV on DRV pharmacokinetics was best characterized by ritonavir area under the curve on DRV clearance using a power function. The association of non-linear and linear equations was used to describe DRV protein binding to alpha-1 glycoprotein and albumin, respectively. In our population, simulations indicate that 86.8% of total and unbound DRV trough concentrations were above 0.55 mg/L [10 times protein binding-adjusted EC50 for wild-type (WT) HIV-1] and 0.0243 mg/L (10 times EC90 for WT HIV-1) targets, respectively. Predictions were also in agreement with observed outcomes from adults receiving 800/100 mg DRV/r once a day. Administration of 800/100 mg of DRV/r once daily provides satisfactory concentrations and exposures for adolescents aged 12 years and older

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.

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Effet comparé du stiripentol sur le métabolisme de la carbamazépine et du saquinavir (étude in vitro et in vivo)

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Ontogenèse de la P-glycoprotéine lymphocytaire chez l'homme

PARIS-BIUP (751062107) / SudocSudocFranceF

Evaluation pharmacologique des thérapeutiques antirétrovirales

Plus de 10 ans après l arrivée des traitements anti-rétroviraux actifs, le traitement de l infection par le VIH reste un problème thérapeutique complexe et nécessite la poursuite des recherches par une évaluation pharmacologique soigneuse. Au cours de 3 essais prospectifs multicentriques nous avons montré : 1) qu une trithérapie 3-classes était moins efficace qu une trithérapie classique chez des patients naïfs ou faiblement pré-traités ; 2) l absence d interaction entre la cétirizine et la névirapine et l inefficacité de la cétirizine dans la prévention des toxidermies à la névirapine ; 3) que l association lamivudine, ritonavir et indinavir pouvait être utilisée comme stratégie d attente chez certains patients en situation de multi-échec. Au cours d une étude pilote nous avons mis en évidence une diffusion très faible du lopinavir au niveau du tractus génital féminin, et des concentrations d indinavir parfois supérieures à celles obtenues au niveau plasmatique suggérant un transport actif à ce niveauMore than 10 years after the onset of active antiretroviral treatments, the treatment of HIV infection remains a complex therapeutic problem that requires a continued research through careful pharmacological evaluation. In numerous national multicentric therapeutic trials we showed: 1) that a 3 classes therapy was less effective than a traditional 2 classes therapy among naive or zidovudine/didanosine pretreated patients; 2) the absence of interaction between cetirizine and nevirapine but no efficacy of cetirizine in preventing cutaneous reactions to nevirapine therapy; 3) that the combination of lamivudine, ritonavir and indinavir can be used as a maintenance therapy in some highly pre-treated HIV-infected patients with resistant virus populations. The results of a pilot study showed a very weak diffusion of lopinavir at the level of female genital tract whereas the concentrations of indinavir in the genital tract were at times higher than those measured in plasma suggesting an active transport at this site.PARIS-BIUP (751062107) / SudocSudocFranceF