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

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.

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

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

Ontogenèse de la P-glycoprotéine lymphocytaire chez l'homme

PARIS-BIUP (751062107) / SudocSudocFranceF

Pharmacocinétique de population de l'abacavir, de la stavudine et du lopinavir chez l'enfant

La pharmacocinétique chez l'enfant de trois molécules antirétrovirales couramment prescrites en pédiatrie, la stavudine, l'abacavir, et le lopinavir, a été étudiée selon une approche de population. La pharmacocinétique de l'abacavir a ainsi été étudiée sur une population de 105 enfants âgés de 1 mois à un an. Le volume de distribution apparent (Vd/F) et la clairance apparente (CL/F) étaient proportionnels au poids corporel. La posologie actuellement recommandée de 8 mg/kg permettait d'atteindre l'aire sous la courbe (AUC) cible de 6 mg.h/L pour laquelle l'efficacité maximale de l'abacavir est obtenue chez l'adulte. La pharmacocinétique de la stavudine a été étudiée sur une population de 272 enfants âgés de 3 jours à 16 ans. V/F et CL/F étaient tous deux reliés à l'âge, et les recommandations posologiques actuelles permettaient d'atteindre l'AUC moyenne décrite chez l'adulte. La pharmacocinétique du lopinavir a été étudiée sur une population de 135 enfants âgés de 3 jours à 18 ans. V/F et CL/F étaient tous deux reliés au poids corporel, la clairance rapportée au poids étant 3 à 4 fois plus élevée chez les nourrissons de moins de 6 mois. Après l'âge de 12 ans CL/F était également augmentée de 40 % chez les garçons par rapport aux filles. En conclusion ces travaux ont confirmé l'intérêt des posologies actuellement recommandées pour l'abacavir et la stavudine. Par contre, les nourrissons de moins de 6 mois et les garçons de plus de 12 ans apparaissent comme des sous-groupes présentant un risque de sous-dosage au lopinavir. Les éventuelles conséquences de ce sous-dosage sur l'efficacité du traitement et la possible nécessité d'augmenter la posologie de lopinavir chez ces enfants devront être évaluées dans de prochaines études.The pharmacokinetics of three antiretroviral drugs in current use in children, abacavir, stavudine, and lopinavir, was investigated by the use of a population approach. Abacavir pharmacokinetics was studied on 105 children ranging in age from 1 month to 16 years. Apparent distribution volume (Vd/F) and clearance (CL/F) were proportional to bodyweight. The current recommended dosage regimen of 8 mg/kg allowed to achieve the target area under the curve (AUC) of 6 mg.h/L corresponding to abacavir maximal efficacy in adults. Stavudine pharmacokinetics was investigated on 272 children ranging in age from 3 days to 16 years. V/F and CL/F were both related to age and the AUC obtained in adults was achieved with the current recommended paediatric dosage regimen. Lopinavir pharmacokinetics was studied on 135 children ranging in age from 3 days to 18 years. V/F and CL/F were both related to bodyweight, and weight-related clearance was 3 to 4 times higher in infants youger than 6 months compared to older children. After the age of 12, CL/F was also 40 % higher in boys compared to girls. These studies supported the current recommended abacavir and Stavudine dosage regimen. But, infants younger than 6 months and boys older than 12 could be underexposed to lopinavir. The possible consequence of these pharmacokinetic discrepancies on lopinavir efficacy, and the possible need for an increase in lopinavir dosage regimen in these children should further investigated.PARIS-BIUP (751062107) / SudocSudocFranceF

Allongement de l'espace QT chez les patients HIV

PARIS-BIUP (751062107) / SudocSudocFranceF