"Standing Up for Press Freedom." Media Asia, 21(1), pp. 43–44 Additional informationNotes on contributorsChristopher PattenRt. Hon. Christopher Patten is the Governor of Hong Kong.
There is an increase in electronic advertising billboards along major roads, which may cause driver distraction due to the highly conspicuous design of the electronic billboards. Yet limited research on the impact of electronic billboards on driving performance and driver behavior is available. The Swedish Transport Administration recently approved the installation of 12 electronic billboards for a trial period along a 3-lane motorway with heavy traffic running through central Stockholm, Sweden. The aim of this study was to evaluate the effect of these electronic billboards on visual behavior and driving performance.A total of 41 drivers were recruited to drive an instrumented vehicle passing 4 of the electronic billboards during day and night conditions. A driver was considered visually distracted when looking at a billboard continuously for more than 2 s or if the driver looked away from the road for a high percentage of time. Dependent variables were eye-tracking measures and driving performance measures.The visual behavior data showed that drivers had a significantly longer dwell time, a greater number of fixations, and longer maximum fixation duration when driving past an electronic billboard compared to other signs on the same road stretches. No differences were found for the factors day/night, and no effect was found for the driving behavior data.Electronic billboards have an effect on gaze behavior by attracting more and longer glances than regular traffic signs. Whether the electronic billboards attract too much attention and constitute a traffic safety hazard cannot be answered conclusively based on the present data.
Several human immunodeficiency virus (HIV) protease inhibitors, including atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, were tested for their potential to inhibit uridine 5′-diphospho-glucuronosyltransferase (UGT) activity. Experiments were performed with human cDNA-expressed enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) as well as human liver microsomes. All of the protease inhibitors tested were inhibitors of UGT1A1, UGT1A3, and UGT1A4 with IC50 values that ranged from 2 to 87 μM. The IC50 values found for all compounds for UGT1A6, 1A9, and 2B7 were >100 μM. The inhibition (IC50) of UGT1A1 was similar when tested against the human cDNA-expressed enzyme or human liver microsomes for atazanavir, indinavir, and saquinavir (2.4, 87, and 7.3 μM versus 2.5, 68, and 5.0 μM, respectively). By analysis of the double-reciprocal plots of bilirubin glucuronidation activities at different bilirubin concentrations in the presence of fixed concentrations of inhibitors, the UGT1A1 inhibition by atazanavir and indinavir was demonstrated to follow a linear mixed-type inhibition mechanism (Ki = 1.9 and 47.9 μM, respectively). These results suggest that a direct inhibition of UGT1A1-mediated bilirubin glucuronidation may provide a mechanism for the reversible hyperbilirubinemia associated with administration of atazanavir as well as indinavir. In vitro-in vivo scaling with [I]/Ki predicts that atazanavir and indinavir are more likely to induce hyperbilirubinemia than other HIV protease inhibitors studied when a free Cmax drug concentration was used. Our current study provides a unique example of in vitro-in vivo correlation for an endogenous UGT-mediated metabolic pathway.
Objective Development and characterization of a novel cell‐based transporter model to study regulatory agencies (USFDA/EMA) recommended and industry important SLC transporters. Methods Cryopreserved HEK293 cells which transiently overexpress OATP1B1*1a (wild‐type), OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2‐K, OATP1A2, OATP2B1, PEPT1, PEPT2, NTCP and empty vector, respectively, were thawed and plated on 24‐well Poly‐D‐Lysine coated plates, and then refed with plating media in the presence or absence of 2mM sodium butyrate at 3‐4 hours post plating. Uptake assays were performed at 24 hrs post plating. Following two washes, cells were pre‐equilibrated with HBSS buffer for 10min, MATE1 and MATE2‐K cells require extra incubation with HBSS buffer containing NH 4 Cl. The cells were then incubated with substrate or inhibitor for desired amount of time. After the assay was terminated, the cells were lysed and subjected to analysis. Results The novel SLC transporter model, including OATP1B1*1a (wild‐type), OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2‐K, OATP1A2, OATP2B1, PEPT1, PEPT2, and NTCP cells, was characterized for time and substrate concentration‐dependent uptake (Km and Vmax determinations) using prototypical substrates as well as known drug substrates. The model was also validated using selected prototypical transporter inhibitors recommended by regulatory agencies. The kinetic profiles of the selected substrates and IC 50 of selected inhibitors were comparable to the published literature and also consistent across independent laboratories. As an example, OATP1B1*1a Km comparison using various substrates is demonstrated below. OATP1B1*1a Substrates Estradiol‐17β‐Glucuronide Estrone‐3‐Sulfate Rosuvastatin Fluorescein Methotrexate K m (µM) using Corning® OATP1B1*1a Cells 6.2 0.4 14.2 5.2 K m (µM) reported in literature 6.3 0.46 13.1 3.8 Conclusions The data demonstrated this new SLC transporter model is a validated and compliant in vitro tool to study drug interactions with SLC transporters recommended by regulatory agencies (USFDA/EMA) and industry. This novel cell‐based transporter model eliminates the need for intensive cell culture and maintenance, as well as providing consistent lot‐to‐lot performance.
Flavonoids are widely occurring in our diet. In this study, the effects of nine flavonoids on acetaminophen (APAP) oxidation and related cytochrome P450 (P450) enzyme activities were investigated. With rat liver microsomes, APAP oxidation was stimulated 2- to 4-fold by 50 microM flavone or tangeretin and inhibited 65% by myricetin or quercetin. Only a slight inhibition of APAP oxidation was caused by naringenin. All the effects cited herein were from experiments with 50 microM flavonoids. With human liver microsomal samples that had high P450 3A4 activity, APAP oxidation was stimulated 1.6- to 3.0-fold by tangeretin, nobiletin, and flavone, but inhibited 40-60% by myricetin and quercetin. With human P450 1A2 expressed in Hep G2 cells, APAP oxidation was inhibited completely by flavone or quercetin. With expressed P450 3A4, this reaction was stimulated 4-fold by flavone, but inhibited 60% by quercetin. The expressed human P450 2E1-dependent APAP oxidation was only slightly affected by flavone and quercetin. The mechanisms of the inhibition and stimulation were complex and varied with the different P450 forms and flavonoids used in the system. The O-deethylation of ethoxyresorufin in rat liver microsomes was effectively inhibited by myricetin (IC50, 15 microM) and moderately inhibited by flavone, tangeretin, and quercetin (IC50, 50-80 microM); with P450 1A2 in Hep G2 cell microsomes, the activity was markedly inhibited by flavone (IC50, 2.5 microM). The microsomal P450s 2E1 and 3A activities were inhibited by myricetin (IC50, 85-90 microM), but not effectively inhibited by other flavonoids.(ABSTRACT TRUNCATED AT 250 WORDS)
Increasing evidence shows that drug transporters play an important role in drug‐induced hepatotoxicity and adverse drug‐drug interactions. Regulatory agencies (USFDA and EMA) recommend in their drug interaction guidelines to investigate clinically relevant transporters for new molecular entities. Here we report characterization of Corning HepatoCells (derived from primary human hepatocytes) for uptake transporter study, specifically OCT1, OATP1B1/1B3, and NTCP. When cultured on Corning BioCoat™ Collagen I coated tissue culture plates for 3‐4 days, Corning HepatoCells demonstrated time‐dependent and concentration‐dependent uptake of prototypical substrates of OCT1, OATP1B1/1B3, and NTCP, with Km values comparable to literature data. Multiple lots of Corning HepatoCells generated similar kinetic profiles. Inhibition assays were also performed and the results showed concentration dependent inhibition with similar profiles among multiple lots of cells, and IC50 values were in line with literature data from other test systems. In addition to active expression of uptake transporters, Corning HepatoCells also demonstrated bile canaliculi formation suggesting active expression of efflux transporters. In conclusion, the study demonstrated that Corning HepatoCells actively express functional uptake transporters, and this model represents a renewable source of human hepatic cells with consistent performance for uptake transporter study.
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