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Contains fulltext : 152455.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum. METHODS: HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and >/=2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated. RESULTS: Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60-.88) for the area under the curve over a dosing interval (AUCtau) and 0.70 (0.58-0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (Ctrough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03-0.56). The viral load close to delivery was

© The Author 2015. Published by Oxford University Press on behalf of the Infectious. Objective.To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum. Methods.HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and ≥2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated. Results.Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval,. 60-.88) for the area under the curve over a dosing interval (AUCtau) and 0.70 (0.58-0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (Ctrough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03-0.56). The viral load close to delivery was

Clindamycin is commonly prescribed to treat children with skin and skin structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus [CA-MRSA]), yet little is known about the pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving intravenous clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. Median age (range) was 3.3 years (0–20). Median dosing was 9.9 mg/kg/dose (3.8–15.1). A 1-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (L/h)=13.7*(weight/70)0.75*(PMA3.1/(43.63.1+PMA3.1)); V (L)=61.8*(weight/70). Maturation reached 50% adult CL values at ~44 weeks PMA. Our findings support age-based dosing.

Aim: To describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period. Methods: IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100mg twice daily during pregnancy through to 6-12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks post-partum. PK targets were the estimated 10thpercentile IDV AUC (12.9μgml-1h) in non-pregnant historical Thai adults and a trough concentration of 0.1μgml-1, the suggested minimum target. Results: Twenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12h) and Cmaxduring the second trimester and post-partum (ante:post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12h) and Cmaxratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml-1at delivery. All 26 infants were confirmed HIV negative. Conclusion: Indinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and ∼30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100mg twice daily may be preferable to ensure adequate drug concentrations. © 2013 The Authors.

Mannose binding lectin (MBL) activates complement pathway that leads to pathogen opsonization and phagocytosis. MBL deficiency is linked to HIV transmission and disease progression. We sought to determine the role of MBL in HIV encephalitis (HIVE) by evaluating its presence and distribution in the HIV-1-infected brain and by assessing its association with monocyte chemoattractant protein-1 (MCP-1) expression. This retrospective study utilized archived post-mortem brain tissues obtained from 35 individuals enrolled in a longitudinal study as part of the California NeuroAIDS Tissue Network. MBL, MCP-1 and brain cell markers in post-mortem brain tissues with or without HIVE were evaluated using immunocytochemistry, immunofluorescence, confocal microscopy, and western blots. MBL was expressed in neurons, astrocytes, microglia, and oligodendrocytes of the frontal cortex of the HIV-1-infected brain. Overall, there were 30% to 40% more MBL-positive brain cells in HIVE vs non-HIVE cases (P = 0.01, paired t-test). Specifically, there was an increased MBL expression in the neuronal axons of HIVE cases. Also, western blots showed 3- to 4-fold higher levels of 78 kD MBL trimers in HIVE vs non-HIVE cases. This MBL-HIVE link was further confirmed by MBL associated higher MCP-1 expression in HIVE vs non-HIVE cases. HIV negative healthy individuals and normal or the gp120 transgenic mice did not show any differential MBL expression. Increased MBL expression in the major brain cell types, specifically in the neuronal axons of HIVE brain, and MBL associated higher MCP-1 expression in HIVE suggest that MBL could cause neuroinflammation and neuronal injury through MBL complement activation pathway. © 2011 Singh et al, publisher and licensee Dove Medical Press Ltd.

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To investigate the association of single nucleotide polymorphisms (SNPs) with nevirapine concentrations following intra-partum single-dose nevirapine. Plasma and DNA samples were obtained from 330 HIV-infected Thai women who received intra-partum single-dose nevirapine in the PHPT-2 clinical trial to prevent perinatal HIV transmission. Nine SNPs within CYP2B6, CYP3A4 and ABCB1 were genotyped by real-time PCR. Nevirapine plasma concentrations were determined by HPLC and used in a population pharmacokinetic analysis. Higher nevirapine exposure was observed in women carrying the CYP2B6 516G > T polymorphism, but this did not reach statistical significance (P = 0.054). The TGATC CYP2B6 haplotype (g.3003T, 516G, 785A, g.18492T and g.21563C) was associated with increased nevirapine clearance and lower exposure (P = 0.0029). The median time for nevirapine concentrations to reach 10 ng/mL post-partum (nevirapine IC50 for HIV-1) was 14 days [interquartile range (IQR, 14-18)] for TGATC homozygotes, 16 days (14-20) for TGATC heterozygotes and 18 days (14-20) for non-TGATC homozygotes (P = 0.020). The CYP2B6 516G > T impact on nevirapine concentrations was less pronounced after intra-partum single-dose nevirapine than reported under steady-state conditions, perhaps due to lack of enzyme auto-induction at the time of dosing. Although the TGATC CYP2B6 haplotype may shorten the persistence of nevirapine post-partum, its practical implications for the prevention of HIV transmission or selection of resistance mutations are likely limited.

The main objective of this study was to determine reliability, validity, and reproducibility of the Italian version of the Tinnitus Handicap Inventory (THI) self-administered questionnaire aimed at evaluating the impact of tinnitus on the quality of life of subjects affected by this symptom. The questionnaire was presented to a sample of 443 subjects (285 men and 158 women; ages 19-86; mean age, 53) who were referred to our Tinnitus Centre in Rome and came from the entire national territory. All subjects reported as their main problem a tinnitus that had persisted for at least 6 months. Statistical analysis carried out on THI questionnaire results showed high internal consistency and reliability for the total scale (Cronbach's alpha = .94). Despite the poor number of items, the THI proved useful for the functional scale (0.86), the emotional scale (0.89), and the catastrophic scale (0.75).