Follicular fluid high density lipoprotein-associated micronutrient levels are associated with embryo fragmentation during IVF

To investigate whether follicular fluid lipid-soluble micronutrients are associated with embryo morphology parameters during IVF. Follicle fluid and oocytes were obtained prospectively from 81 women. Embryo morphology parameters were used as surrogate markers of oocyte health. HDL lipids and lipid-soluble micronutrients were analyzed by high-pressure liquid chromatography. Non-parametric bi-variate analysis and multivariable ordinal logistic regression models were employed to examine associations between biochemical and embryo morphology parameters. Follicular fluid HDL cholesterol (r = −0.47, p < 0.01), α-tocopherol (r = −0.41, p < 0.01), δ-tocopherol (r = −0.38, p < 0.05) and β-cryptoxanthine (r = −0.42, p < 0.01) are negatively correlated with embryo fragmentation. Ordinal logistic regression models indicate that a 0.1 μmol/L increase in β-cryptoxanthine, adjusted for γ-tocopherol, is associated with a 75% decrease in the cumulative odds of higher embryo fragmentation (p = 0.010). Follicular fluid HDL micronutrients may play an important role in the development of the human oocyte as evident by embryo fragmentation during IVF

Switching to Tenofovir Alafenamide in Elvitegravir-Based Regimens: Pharmacokinetics and Antiviral Activity in Cerebrospinal Fluid.

BackgroundTenofovir alafenamide fumarate (TAF) co-formulated with elvitegravir (EVG; E), cobicistat (C), and emtricitabine (F), a recommended antiretroviral regimen, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF) as well as neurocognitive (NC) performance change in participants switching from E/C/F/tenofovir disoproxil fumarate (TDF) to E/C/F/TAF.MethodsThis was a 24-week, single-arm, open-label study in treatment-experienced adults living with human immunodeficiency virus (HIV). Nine participants switched from E/C/F/TDF (150/150/200/300 mg once daily) to E/C/F/TAF (150/150/200/10 mg once daily) at week 12. CSF and total plasma concentrations of EVG, TDF, TAF, tenofovir (TFV), and HIV RNA levels were measured at baseline and week 24. NC performance was estimated by the Montreal Cognitive Assessment.ResultsEVG concentrations in CSF and the CSF:plasma ratio remained stable (P = .203) over time. Following the switch, TFV concentrations in CSF and plasma declined (P = .004), although the TFV CSF:plasma ratio increased (P = .004). At week 24, median TAF plasma concentration was 11.05 ng/mL (range, 2.84-147.1 ng/mL) 2 hours postdose but was below assay sensitivity 6 hours after dosing. TAF was below assay sensitivity in all CSF specimens. HIV RNA was ≤40 copies/mL in all CSF and plasma specimens. Three participants (33%) had NC impairment at baseline and 2 (22%) remained impaired at week 24.ConclusionsSwitch to E/C/F/TAF was associated with reductions in TFV concentrations in CSF but stable EVG concentrations that exceeded the 50% inhibitory concentration for wild-type HIV, suggesting that EVG achieves therapeutic concentrations in the central nervous system. No virologic failure or significant NC changes were detected following the switch.Clinical trials registrationNCT02251236

Development and validation of a high performance liquid chromatography method to determine nevirapine in plasma in a resource-limited setting.

BACKGROUND: There are several instances where nevirapine pharmacokinetic monitoring may be useful, such as in special populations or pharmacokinetic drug interaction studies that require the ascertainment of nevirapine pharmacokinetics in the sub-Saharan region. OBJECTIVES: The main aim of this study was to produce a validated, sustainable and relevant nevirapine assay method that meets bio-analytical regulatory requirements. METHODS: The developed method utilised a Waters 2795 Alliance high performance liquid chromatography system with a 2996 photo diode array detector, an Atlantis dC18 5 micron, 3.9 mm × 150 mm analytical column and a gradient flow rate of 1 mL/min. Ultraviolet detection data were collected from 210 nm to 400 nm, extracted at 260 nm, and processed for nevirapine and internal standard peak height responses. RESULTS: The method proved to be linear (R2 0.995), precise (+1.92% - +9.69%) and accurate (-9.70% - 12.0%). Recovery for the analyte and internal standard was between 98.8% and 114%. The method showed good specificity as no interferences were caused by common African traditional medicines, anti-tuberculosis medications or other concomitant antiretrovirals nor endogenous components. CONCLUSION: The method is reproducible, relevant to our setting and uses considerably low plasma volumes with preservation of some consumables, a desirable key factor in a resource-limited setting

Effect of Experimental Kidney Disease on the Functional Expression of Hepatic Reductases Running Title: Effect of Kidney Disease on Hepatic Reduction in Rats

P450; K m , MichaelisMenten constant; NQO1, NADPH quinone oxidoreductase type 1; SDR, short-chain dehydrogenase reductase; UPLC-MS/MS, ultra-performance liquid chromatography-tandem mass spectrometry; V max , maximum reaction velocity. DMD # 61150 3 ABSTRACT Chronic kidney disease (CKD) affects the nonrenal clearance of drugs by modulating the functional expression of hepatic drug metabolizing enzymes and transporters. The impact of CKD on oxidative and conjugative metabolism has been extensively studied. However, its effect on hepatic drug reduction, an important Phase I drug metabolism pathway, has not been investigated. We aimed to assess the effect of experimental CKD on hepatic reduction using warfarin as a pharmacological probe substrate. Cytosolic and microsomal cellular fractions were isolated from liver tissue harvested from 5/6 th -nephrectomized and control rats (n=10 per group). The enzyme kinetics for warfarin reduction were evaluated in both fractions, and formation of warfarin alcohols was used as an indicator of hepatic reductase activity. Selective inhibitors were employed to identify reductases involved in warfarin reduction. Gene and protein expression of reductases were quantified using qRT-PCR and Western blotting, respectively. Formation of RS/SR-warfarin alcohol was decreased by 39% (P<0.001) and 43% (P<0.01) in cytosol and microsomes, respectively in CKD rats versus controls. However, RR/SS-warfarin alcohol formation was unchanged in the cytosol, and a trend toward its decreased production was observed in microsomes. Gene and protein expression of cytosolic carbonyl reductase 1 and aldo-keto reductase 1C3/18, and microsomal 11β-hydroxysteroid dehydrogenase type 1 were significantly reduced by >30% (P<0.05) in CKD rats compared to controls. Collectively, these results suggest that the functional expression of hepatic reductases is selectively decreased in kidney disease. Our findings may explain one mechanism for altered nonrenal clearance, exposure, and response of drugs in CKD patients