Translational methods for quantitative prediction of metabolic herbal product-drug interactions: case study with milk thistle

The misperception that herbal products are safe has perpetuated multibillion dollar sales of these products, exposing the public to potentially harmful herb-drug interactions when constituents in the herbal supplement inhibit drug metabolizing enzymes. Regulation of herbal products is not as rigorous as drug products. Consequently, evaluation of inhibitory properties of an herbal product typically is not requested before marketing. Traditional drug-drug interaction evaluation methods often are inadequate to evaluate herbal product interaction liability due to the mixture of bioactive constituents, high inherent variability between batches and manufacturers, and limited pharmacokinetic knowledge of constituents. Milk thistle was selected as an exemplar herbal product due to high usage rates in patient populations, particularly the hepatically-impaired; availability of isolated, purified constituents; and disparate effects between previous clinical interaction studies. Initial screens of inhibitory activity against the clinically relevant drug metabolizing enzymes, cytochrome P450 (CYP) 2C9 and CYP3A4, prioritized milk thistle constituents for further evaluation. The main constituents, silybin A and silybin B, inhibited CYP2C9 in a reversible manner (Ki, 10 and 4.8 μM, respectively) and CYP3A4 in an irreversible manner (KI, 110 and 89 μM, respectively). Incorporation of these in vitro kinetic parameters into a physiologically based pharmacokinetic (PBPK) model facilitated predictions of the interaction liability of milk thistle administration with FDA-recommended probe substrates of CYP2C9 (warfarin) and CYP3A4 (midazolam). Administration of large doses of the milk thistle product silibinin (1440 mg/day) was predicted to increase the peak concentration and systemic exposure of both warfarin and midazolam by roughly 5%. Proof-of-concept clinical evaluation of these silibinin-drug interactions confirmed the low interaction potential of the selected milk thistle product, as midazolam and warfarin exposure was increased modestly (9 and 13%, respectively). This mechanistic modeling and simulation approach facilitated prospective evaluation of interactions between a well-characterized herbal product and two widely used and clinically relevant probe substrates. This framework could be applied to other herbal products to predict the magnitude and likelihood of interactions with conventional drugs, guide pharmacotherapeutic decisions, and improve patient care.Doctor of Philosoph

Population and Noncompartmental Pharmacokinetics of Sodium Oxybate Support Weight‐Based Dosing in Children and Adolescents With Narcolepsy With Cataplexy

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Automated Control Systems and Methods for Underground Crop Harvesters

Methods and devices for automated adjustment of a digging implement during harvest of underground crops are described. Utilizing the devices, a digging implement, e.g., a blade, can be located and maintained at a desired depth as a harvester travels across a field. During use, the digging implement depth controls can be varied as the harvester travels within a single field under different operating conditions, e.g., different soil friability, consistency, etc., thereby preventing crop loss and improving crop yield

Impact mass flow sensor for monitoring peanut harvest yields

Yield monitoring systems for harvesting machines and methods that can provide yield monitoring of crops are described. Machines include those that pneumatically convey crop through the machine such as peanut harvesting machines. The yield monitoring system includes a force sensor that can be located in conjunction with a duct of the harvesting machine such that impact of the crop materials on an impact plate within the duct will be registered by the force sensor. This registration can be used to determine a mass flow rate for the crop, which can be correlated to yield of the crop. The systems can include additional components such as optical monitors, moisture sensors, and pressure sensors

Impact of volcanism on the sedimentary record of the Neuquén rift basin, Argentina: towards a cause and effect model

The analysis of volcano-sedimentary infill in sedimentary basins constitutes a challenge for basin analysis and hydrocarbon exploration worldwide. In order to understand the contribution of volcanism to the sedimentary record in rift basins, we study the Jurassic effusive-explosive volcanic infill of an inverted extensional depocentre at the Neuquén Basin, Argentina. A cause and effect model that evaluates the relationship between volcanism and sedimentation was devised to develop a conceptual model for the tectono-stratigraphic evolution of this volcanic rift basin. We show how the variations in the volcanism, coupled with the activity of extensional faults, determined the types of volcanic edifices (i.e., composite volcanoes, graben-calderas, and lava fields). Volcanic edifices controlled the stacking patterns of the volcanic units as well as sedimentary systems. The landform of the volcanic edifices, as well as the styles and scales of the eruptions governed the sedimentary input to the basin, setting the main variables of the sedimentary systems, such as provenance, grain size, transport and deposition and geometry. As a result, the contrasting volcaniclastic input, from higher volcaniclastic input to lower volcaniclastic input, associated with different subsidence patterns, determined the high-resolution syn-rift infill patterns of the extensional depocentre. The cause and effect model presented in this study isolates the variables of the volcanic environments that control the sedimentary scenarios. We suggest that, by adjusting the first order input parameters of the model, these cause and effect scenarios could be adapted to similar rift basins, in order to establish predictive facies models with stratigraphic controls, and the impact of volcanism on their stratigraphic records.Fil: D'Elia, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Geológicas. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Centro de Investigaciones Geológicas; ArgentinaFil: Martí, Joan. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias de la Tierra Jaume Almera; EspañaFil: Muravchik, Martin. University Of Bergen; Noruega. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bilmes, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Geología y Paleontología.; ArgentinaFil: Franzese, Juan Rafael. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Geológicas. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Centro de Investigaciones Geológicas; Argentin

Psychosocial working conditions and the utilization of health care services

<p>Abstract</p> <p>Background</p> <p>While there is considerable theoretical and empirical evidence on how job stress affects physical and mental health, few studies have examined the association between job related stress and health care utilization. Using data from the Canadian National Population Health Survey from 2000 to 2008, this paper examines the association between stressful working conditions, as measured by the job strain model, and the utilization of health care services.</p> <p>Methods</p> <p>A zero inflated negative binomial regression is used to examine the excess health care utilization due to job strain. Separate regressions are estimated for both males and females since studies have shown gender differences in health care utilization.</p> <p>Results</p> <p>Estimates for the whole population show that high or medium job strain has a positive and statistically significant association with the number of visits to both a general practitioner (GP) and a specialist (SP). On average, the number of GP visits is up to 26% more (IRR = 1.26, 95% CI = 1.19-1.31) for individuals with high strain jobs compared to those in the low job strain category. Similarly, SP visits are up to 27% more (IRR = 1.27, 95% CI = 1.14-142) for the high strain category. Results are quantitatively similar for males and females, save for medium strain. In general, findings are robust to the inclusion of workplace social support, health status, provincial and occupational-fixed effects.</p> <p>Conclusion</p> <p>Job strain may be positively associated with the utilization of health care services. This suggests that improving psychosocial working conditions and educating workers on stress-coping mechanisms could be beneficial for the physical and mental health of workers.</p

Enhanced Bioactivity of silybin B methylation Products

Abstract: Flavonolignans from milk thistle (Silybum marianum) have been investigated for their cellular modulatory properties, including cancer chemoprevention and hepatoprotection, as an extract (silymarin), as partially purified mixtures (silibinin and isosilibinin), and as pure compounds (a series of seven isomers). One challenge with the use of these compounds in vivo is their relatively short half-life due to conjugation, particularly glucuronidation. In an attempt to generate analogues with improved in vivo properties, particularly reduced metabolic liability, a semi-synthetic series was prepared in which the hydroxy groups of silybin B were alkylated. A total of five methylated analogues of silybin B were synthesized using standard alkylation conditions (dimethyl sulfate and potassium carbonate in acetone), purified using preparative HPLC, and elucidated via spectroscopy and spectrometry. Of the five, one was monomethylated (3), one was dimethylated (4), two were trimethylated (2 and 6), and one was tetramethylated (5). The relative potency of all compounds was determined in a 72 h growth-inhibition assay against a panel of three prostate cancer cell lines (DU-145, PC-3, and LNCaP) and a human hepatoma cell line (Huh7.5.1) and compared to natural silybin B. Compounds also were evaluated for inhibition of both cytochrome P450 2C9 (CYP2C9) activity in human liver microsomes and hepatitis C virus infection in Huh7.5.1 cells. The monomethyl and dimethyl analogues were shown to have enhanced activity in terms of cytotoxicity, CYP2C9 inhibitory potency, and antiviral activity (up to 6-fold increased potency) compared to the parent compound, silybin B. In total, these data suggested that methylation of flavonolignans can increase bioactivity. Graphical Abstract

Estimating cumulative pathway effects on risk for age-related macular degeneration using mixed linear models

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the elderly in developed countries and typically affects more than 10 % of individuals over age 80. AMD has a large genetic component, with heritability estimated to be between 45 % and 70 %. Numerous variants have been identified and implicate various molecular mechanisms and pathways for AMD pathogenesis but those variants only explain a portion of AMD’s heritability. The goal of our study was to estimate the cumulative genetic contribution of common variants on AMD risk for multiple pathways related to the etiology of AMD, including angiogenesis, antioxidant activity, apoptotic signaling, complement activation, inflammatory response, response to nicotine, oxidative phosphorylation, and the tricarboxylic acid cycle. While these mechanisms have been associated with AMD in literature, the overall extent of the contribution to AMD risk for each is unknown. METHODS: In a case–control dataset with 1,813 individuals genotyped for over 600,000 SNPs we used Genome-wide Complex Trait Analysis (GCTA) to estimate the proportion of AMD risk explained by SNPs in genes associated with each pathway. SNPs within a 50 kb region flanking each gene were also assessed, as well as more distant, putatively regulatory SNPs, based on DNaseI hypersensitivity data from ocular tissue in the ENCODE project. RESULTS: We found that 19 previously associated AMD risk SNPs contributed to 13.3 % of the risk for AMD in our dataset, while the remaining genotyped SNPs contributed to 36.7 % of AMD risk. Adjusting for the 19 risk SNPs, the complement activation and inflammatory response pathways still explained a statistically significant proportion of additional risk for AMD (9.8 % and 17.9 %, respectively), with other pathways showing no significant effects (0.3 % – 4.4 %). DISCUSSION: Our results show that SNPs associated with complement activation and inflammation significantly contribute to AMD risk, separately from the risk explained by the 19 known risk SNPs. We found that SNPs within 50 kb regions flanking genes explained additional risk beyond genic SNPs, suggesting a potential regulatory role, but that more distant SNPs explained less than 0.5 % additional risk for each pathway. CONCLUSIONS: From these analyses we find that the impact of complement SNPs on risk for AMD extends beyond the established genome-wide significant SNPs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12859-015-0760-4) contains supplementary material, which is available to authorized users