RESUMEN
Placental transfers of the HIV nonnucleoside reverse transcriptase inhibitor rilpivirine were investigated in 8 term human cotyledons perfused with rilpivirine (400 ng/ml) in the maternal-to-fetal direction. The mean fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 15 to 90 min) was 26% ± 8% (mean ± standard deviation), and the clearance index (rilpivirine FTR/antipyrine FTR) was 61% ± 20%. This shows that rilpivirine crosses the placenta at a relatively high rate, suggesting that the fetus is exposed to the compound during treatment of the mother.
Asunto(s)
Placenta/metabolismo , Inhibidores de la Transcriptasa Inversa/metabolismo , Rilpivirina/metabolismo , Femenino , Humanos , Intercambio Materno-Fetal , EmbarazoRESUMEN
Placental transfer of the HIV protease inhibitor darunavir was investigated in 5 term human cotyledons perfused with darunavir (1,000 ng/ml) in the maternal to fetal direction. The mean (± the standard deviation [SD]) fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 15.0%±2.1%, and the mean (±SD) clearance index (darunavir FTR/antipyrine FTR) was 40.3%±5.8%. This shows that darunavir crosses the placenta at a relatively low rate, resulting in fetal exposure.
Asunto(s)
Inhibidores de la Proteasa del VIH/metabolismo , Intercambio Materno-Fetal , Placenta/metabolismo , Sulfonamidas/metabolismo , Transporte Biológico , Darunavir , Femenino , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Embarazo , Sulfonamidas/uso terapéuticoRESUMEN
: Data on placental transfer is lacking for the recent HIV integrase inhibitors, bictegravir and cabotegravir, although their future use in pregnancy is to be expected. The objective of this study was to determine their transplacental pharmacokinetics. Maternal-to-fetal transfer was investigated using the open-circuit ex-vivo dually perfused human cotyledon model. Cabotegravir or bictegravir was added to a maternal perfusate containing 2âg/l of human albumin and antipyrine, a marker to validate the cotyledon's viability, and cotyledons were dually perfused for up to 90âmin. For cabotegravir, in five experiments, the median (IQR 25-75) concentrations in the maternal and in the fetal compartments were, respectively, 550âng/ml (344-788) and 48âng/ml (37-54), with a maternal-to-fetal ratio of 10% (5-16) and a clearance index (in comparison with antipyrine transfer) of 22% (19-28). The median cotyledon accumulation index was 10% (2-21). For bictegravir, in six experiments, the median (IQR 25-75) concentrations in the maternal and in the fetal compartments were, respectively, 1650âng/ml (1455-1960) and 126âng/ml (112-142), with a maternal-to-fetal ratio of 7% (6-9.5) and a clearance index (in comparison with antipyrine transfer) of 21% (17-29). The median cotyledon accumulation index was 4% (3-5). Placental transfer of cabotegravir and bictegravir were low. This may not only limit the potential for fetal toxicities but also be a limit to their usefulness at the time of labor and delivery to reduce the risk of vertical HIV transmission. The safety and efficacy of these new integrase inhibitors in pregnancy require more investigation.
Asunto(s)
Cotiledón/metabolismo , Infecciones por VIH , Inhibidores de Integrasa VIH/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Intercambio Materno-Fetal , Placenta/metabolismo , Piridonas/farmacocinética , Amidas , Femenino , Feto/irrigación sanguínea , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Técnicas In Vitro , Modelos Biológicos , Perfusión , Piperazinas , Placenta/irrigación sanguínea , Embarazo , Piridonas/uso terapéuticoRESUMEN
OBJECTIVE: To determine the transplacental pharmacokinetics of the HIV integrase inhibitor dolutegravir. STUDY DESIGN: Maternal-to-fetal transfer across the term human placenta was investigated with the ex-vivo dually perfused cotyledon model, in 5 closed-circuit, recirculating experiments. Dolutegravir was added to a maternal perfusate containing antipyrine, a marker to validate the cotyledon's viability, and 2 g/liter of human albumin. RESULTS: After 3h of recirculating perfusion, the mean (± SD) DTG concentrations in the maternal and in the fetal compartments were respectively 2450 ± 286 ng/mL and 715 ± 369 ng/mL, with a fetal-to-maternal ratio of 34% ± 18% and a clearance index (in comparison with antipyrine transfer) of 79% ± 23%. The mean cotyledon accumulation index was 153% ± 25%. CONCLUSION: Fetal transplacental exposure to dolutegravir was considerable as well as accumulation in placental tissue. Whether this may lead to risks for the exposed fetus requires more investigation.
Asunto(s)
Inhibidores de Integrasa VIH/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Intercambio Materno-Fetal , Placenta/metabolismo , Antipirina/farmacocinética , Femenino , Inhibidores de Integrasa VIH/análisis , Compuestos Heterocíclicos con 3 Anillos/análisis , Humanos , Modelos Biológicos , Oxazinas , Perfusión , Piperazinas , Placenta/química , Embarazo , PiridonasRESUMEN
OBJECTIVE: To determine the transplacental pharmacokinetics of the HIV integrase strand transfer inhibitor elvitegravir and of cobicistat, a cytochrome P450 inhibitor used as a pharmacoenhancer in antiretroviral therapy. DESIGN AND METHODS: Maternal-to-fetal transfer across the term human placenta was investigated with the ex-vivo dually perfused cotyledon model, in seven open-circuit experiments and 10 closed-circuit (recirculating) experiments. Elvitegravir and cobicistat were added to a maternal perfusate containing 2âg/l of human serum albumin and antipyrine, as a marker to validate the cotyledon's viability. Elvitegravir and cobicistat concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. RESULTS: For elvitegravir, in open-circuit experiments the mean (±SD) fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90âmin) was 19â±â13% and the mean clearance index was 0.46â±â0.21; in the closed-circuit model, after 3âh of perfusion the FTR was 20â±â10% and the mean accumulation index was 12.28â±â5.57. For cobicistat, in the open perfusions the FTR was 23â±â13% and the mean clearance index was 0.63â±â0.34; in the closed perfusions after 3âh the fetal-to-maternal ratio of cobicistat was 21â±â11%. The mean accumulation index was 3.46â±â2.19 CONCLUSION:: The two models concurred to show moderate placental transfer of elvitegravir and cobicistat across the placenta as well as elvitegravir accumulation in the placenta tissue. Whether this may lead to toxicities and modifications in fetal or placental metabolism requires clinical studies.
Asunto(s)
Fármacos Anti-VIH/farmacología , Cobicistat/farmacocinética , Intercambio Materno-Fetal , Placenta/metabolismo , Quinolonas/farmacocinética , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Modelos Teóricos , Embarazo , Espectrometría de Masas en TándemRESUMEN
Effective cell cycle completion requires both Myc and E2F activities. However, whether these two activities interact to regulate cell survival remains to be tested. Here we have analysed survival of inducible c-Myc-overexpressing cell lines derived from U2OS human osteosarcoma cells, which carry wild-type pRb and p53 and are deficient for p16 and ARF expression. Induced U2OS-Myc cells neither underwent apoptosis spontaneously nor upon reconstitution of the ARF-p53 axis and/or serum-starvation. However, they died massively when concomitantly exposed to inhibitors of E2F activity, including a constitutively active pRb (RbDeltacdk) mutant, p16, a stable p27 (p27T187A) mutant, a dominant-negative (dn) CDK2, or dnDP-1. Similar apoptotic effect was observed upon down-modulation of endogenous E2Fs through overexpression of E2F binding site oligonucleotides in U2OS-Myc cells, upon expression of RbDeltacdk or dnDP-1 in the Myc-amplified HL-60 (ARF-; p53-) human leukemia cells, and upon co-transfection of Myc and RbDeltacdk in SAOS-2 (ARF+; p53-) human osteosarcoma cells but not in human primary fibroblasts. Consistent with these results, a dnp53 mutant did not abrogate the Myc-induced apoptotic phenotype, which instead strictly depended on caspase-3-like proteases and on Myc transcriptional activity. Our data indicate that in contrast to normal cells, Myc-overexpressing human cancer cells need E2F activity for their survival, regardless of their ARF and p53 status, a notion that may have important implications for antineoplastic treatment strategies.
Asunto(s)
Apoptosis/fisiología , Neoplasias Óseas/metabolismo , Proteínas de Unión al ADN , Oligonucleótidos/farmacología , Osteosarcoma/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factores de Transcripción/metabolismo , Proteína p14ARF Supresora de Tumor/metabolismo , Western Blotting , Neoplasias Óseas/patología , Caspasa 3 , Inhibidores de Caspasas , Caspasas/metabolismo , Ciclo Celular/fisiología , Proteínas de Ciclo Celular/metabolismo , División Celular/fisiología , Células Cultivadas , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Regulación hacia Abajo , Factores de Transcripción E2F , Inhibidores Enzimáticos/farmacología , Genes Dominantes/fisiología , Vectores Genéticos/genética , Humanos , Immunoblotting , Osteosarcoma/patología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteína de Retinoblastoma/metabolismo , Proteína de Retinoblastoma/farmacología , Factores de Tiempo , Factores de Transcripción/genética , Transfección , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Atazanavir/ritonavir (ATV/r) is a boosted protease inhibitor recommended to minimize the risk of mother-to-child HIV-1 transmission (MTCT). We aimed to assess the pharmacokinetics, safety and efficacy of ATV/r in HIV-1-infected pregnant women and their neonates. METHODS: A multicentre, cross-sectional, non-interventional cohort of HIV-1-infected pregnant women receiving ATV/r (300/100 mg once daily) who delivered in three Paris hospitals from 2006 to 2013 was designed. We determined antiretroviral trough plasma concentrations using liquid chromatography-mass spectrometry at each of the three trimesters, delivery and post-partum. ATV concentrations at 24 h (C24h) were interpreted by the 150-850 ng/ml efficacy-tolerance thresholds. Safety data and newborn HIV status were recorded. A mother's virological failure was defined as two successive measurements of plasma HIV-1 RNA>50 copies/ml within the 2 months before delivery. RESULTS: 103 pregnant women were included, mostly from sub-Saharan Africa (88%). ATV C24h at each of the three trimesters and delivery remained similar to post-partum values. No dose adjustment was needed during pregnancy. The median plasma ratio of fetal/maternal ATV level was 0.19 (n=28). Only three patients showed two successive detectable viral loads but <400 copies/ml. Among 82 available newborn data, 16 were born preterm. Three in utero deaths occurred. Tolerance was good with one case of maternal grade 3 hyperbilirubinaemia, no cases in neonates at delivery and no clinically relevant adverse event. No case of MTCT was reported. CONCLUSIONS: In this population, an ATV/r-containing antiretroviral regimen demonstrated good pharmacokinetics, virological efficacy and safety. No significant impact of pregnancy on ATV C24h was found. No dose adjustment was required.