The current paradigm in Plasmodium falciparum malaria pathogenesis states that young, ring-infected erythrocytes (rings) circulate in peripheral blood and that mature stages are sequestered in the vasculature, avoiding clearance by the spleen. Through ex vivo perfusion of human spleens, we examined the interaction of this unique blood-filtering organ with P falciparum-infected erythrocytes. As predicted, mature stages were retained. However, more than 50% of rings were also retained and accumulated upstream from endothelial sinus wall slits of the open, slow red pulp microcirculation. Ten percent of rings were retained at each spleen passage, a rate matching the proportion of blood flowing through the slow circulatory compartment established in parallel using spleen contrast-enhanced ultrasonography in healthy volunteers. Rings displayed a mildly but significantly reduced elongation index, consistent with a retention process, due to their altered mechanical properties. This raises the new paradigm of a heterogeneous ring population, the less deformable subset being retained in the spleen, thereby reducing the parasite biomass that will sequester in vital organs, influencing the risk of severe complications, such as cerebral malaria or severe anemia. Cryptic ring retention uncovers a new role for the spleen in the control of parasite density, opening novel intervention opportunities. (Blood. 2008;112:2520-2528) IntroductionThe pathogenesis of malaria involves multiple parasite and host factors. 1 Spleen filtering and immune functions have a major impact on the course of plasmodial infection in experimental models. 2,3 In malaria-endemic countries, splenectomy predisposes to fever, to more frequent and higher parasitemia (including circulating mature forms), and may reactivate latent plasmodial infections. 4,5 Despite relatively few published data (reviewed by Bach et al 5 ), clinicians include malaria in the list of infectious diseases justifying increased awareness in splenectomized nonimmune patients. 6 Because key features may differ between animal and human plasmodial infection and because detailed exploration of the human spleen is limited by ethical and technical constraints, 7 the fine interactions between Plasmodium falciparum-infected red blood cells (iRBCs) and the human spleen microcirculatory structures have been explored only indirectly 8,9 or postmortem. 10 Therefore, the mechanisms underlying the putative spleen protective or pathogenic effects during human malaria remain essentially speculative.The architecture of the spleen red pulp (RP) permits intimate scrutiny of red blood cells (RBCs), leading to selective retention of abnormal or senescent RBCs within the RP. 11 To reenter the venous system, RBCs leaving the reticular meshwork of the RP must cross the narrow interendothelial slits in walls of the venous sinuses. This process requires RBCs to undergo considerable deformation: if cells are not sufficiently deformable, they are retained upstream from the venous sinus wall. 11 Such RBC-processin...

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates.• Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age. WHAT THIS STUDY ADDS• A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen.• Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age.• A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced.• Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMSTo describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety. METHODSSixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg -1 of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure. RESULTSIbuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h -1 (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3) 1.49 . AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l -1 h (or AUC3D < 900 mg l -1 h) and in 91% when AUC1D > 600 mg l -1 h (or AUC3D > 900 mg l -1 h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated. CONCLUSIONSTo achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg -1 for neonates younger than 70 h, 14, 7, 7 mg kg -1 for neonates between 70 and 108 h and 18, 9, 9 mg kg -1 for neonates between 108 and 180 h.

The aim was to evaluate emtricitabine (FTC) and tenofovir (TFV) neonatal ingestion through breast milk. Median TFV and FTC breast milk doses represented 0.03% and 2%, respectively, of the proposed oral infant doses. Neonatal simulated plasma concentrations were extremely low for TFV but between the half-maximal inhibitory concentration and the adult minimal expected concentration for FTC. The rare children who will acquire HIV despite TDF-FTC therapy will need to be monitored for viral resistance acquisition.For prevention of mother-to-child transmission (PMTCT) of HIV in resource-limited settings, single-dose nevirapine (sd-NVP) has been commonly administered at the start of labor up to now according to previous World Health Organization (WHO) guidelines. However, the use of sdNVP results in resistance mutations in 15 to 70% of women, at 4 to 6 weeks postpartum, compromising the success of subsequent treatments with NVP in mothers and children (1, 7). Adding a single dose of tenofovir disoproxil fumarate (TDF)-emtricitabine (FTC) reduced these resistance mutations by half (2, 10). TDF and FTC placental transfer has already been studied (4, 5), but no data were reported so far on the transfer of these drugs after birth through breast-feeding. Breast-feeding cessation or replacement feeding introduced under routine circumstances is no longer recommended by WHO, as these interventions are often associated with increased mortality and morbidity (13). Thus, it is important to assess to what extent maternal TDF and FTC are transmitted through breast milk to infants. Furthermore, TDF-FTC-based fully suppressive antiretroviral regimens represent now a recommended approach for PMTCT in pregnant, delivering, and breast-feeding women (14).Five Ivorian mothers included in the ANRS 12109 TEmAA (Tenofovir/Emtricitabine in Africa and Asia) study and who chose to exclusively breast-feed their infant were administered one tablet of NVP (200 mg) plus two tablets of TDF (300 mg)-FTC (200 mg) at the start of labor and one TDF-FTC daily tablet for 7 days postpartum. The protocol was approved by the Ethics Committee of the country (Cote d'Ivoire). The women and the children's fathers were asked to sign an informed consent form. Maternal blood and milk samples were collected concomitantly after drug administration on days 1, 2, 3, and 7 after delivery. A liquid-liquid extraction procedure was performed using 300 l of methanol-dichloromethane (10/16, vol/vol) containing 0.1% hydrochloric acid added to 100 l of milk samples. After vortexing and centrifugation at 20,000 ϫ g at ϩ4°C for 20 min, the upper phase was withdrawn and evaporated under nitrogen to dryness. The sample was then reconstituted with 100 l of mobile phase, and 40 l of the extract was injected in the analytical system. TFV and FTC concentrations were measured using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method previously described (9) and adapted for FTC. Limits of quantitation were 4.9 and 9.5 ng/ml for TFV and FTC, respectively. Maximal and minim...