Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 ...polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.
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Experiment is performed to investigate the mechanism of the cellulose pyrolysis and the formation of the main products. The evolution of the gaseous products is examined by the 3-D FTIR spectrogram ...at the heating rate of 5–60
K/min. A pyrolysis unit, composed of fluidized bed reactor, carbon filter, vapour condensing system and gas storage, is employed to investigate the products of the cellulose pyrolysis under different temperatures (430–730
°C) and residence time (0.44–1.32
s). The composition in the bio-oil is characterized by GC–MS while the gases sample is analyzed by GC. The effects of temperature and residence time on the main products in bio-oil (LG, 5-HMF, FF, HAA, HA and PA) are examined thoroughly. Furthermore the possible routes for the formation of the products are developed from the direct conversion of cellulose molecules and the secondary reactions of the fragments. It is found that the formation of CO is enhanced with elevated temperature and residence time, while slight change is observed for the yield of CO
2.
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The co-primary objectives of this study were to determine the human pharmacokinetics (PK) of oral NR and the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels.
Though ...mitochondrial dysfunction plays a critical role in the development and progression of heart failure, no mitochondria-targeted therapies have been translated into clinical practice. Recent murine studies have reported associations between imbalances in the NADH/NAD+ ratio with mitochondrial dysfunction in multiple tissues, including myocardium. Moreover, an NAD+ precursor, nicotinamide mononucleotide, improved cardiac function, while another NAD+ precursor, nicotinamide riboside (NR), improved mitochondrial function in muscle, liver and brown adipose. Thus, PK studies of NR in humans is critical for future clinical trials.
In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed.
Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008).
Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases.
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Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are ...a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.
Clinical Pharmacology & Therapeutics (2014); 95 4, 376–382. doi:10.1038/clpt.2013.254
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Transparent wood composites, with their high strength and toughness, thermal insulation, and excellent transmissivity, offer a route to replace glass for diffusely transmitting windows. Here, ...conjugated‐polymer‐based electrochromic devices (ECDs) that switch on‐demand are demonstrated using transparent wood coated with poly(3,4‐ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) as a transparent conducting electrode. These ECDs exhibit a vibrant magenta‐to‐clear color change that results from a remarkably colorless bleached state. Furthermore, they require low energy and power inputs of 3 mWh m−2 at 2 W m−2 to switch due to a high coloration efficiency (590 cm2 C−1) and low driving voltage (0.8 V). Each device component is processed with high‐throughput methods, which highlights the opportunity to apply this approach to fabricate mechanically robust, energy‐efficient smart windows on a large scale.
Let there be light: Color‐changing electrochromic devices (ECDs) are demonstrated on transparent wood substrates for energy‐saving smart windows and roofing. Highly conducting poly(3,4‐ethylenedioxythiophene):poly(styrene sulfonate) electrodes are solution‐processed with a dilute acid post treatment. The transparent wood (TW)‐based ECDs show vibrant color‐to‐colorless switching with low energy and power consumption.
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There is currently a renaissance of interest in the many functions of cerebrospinal fluid (CSF). Altered flow of CSF, for example, has been shown to impair the clearance of pathogenic inflammatory ...proteins involved in neurodegenerative diseases, such as amyloid-β. In addition, the role of CSF in the newly discovered lymphatic system of the brain has become a prominently researched area in clinical neuroscience, as CSF serves as a conduit between the central nervous system and immune system.
This article will review the importance of CSF in regulating normal brain development and function, from the prenatal period throughout the lifespan, and highlight recent research that CSF abnormalities in autism spectrum disorder (ASD) are present in infancy, are detectable by conventional structural MRI, and could serve as an early indicator of altered neurodevelopment.
The identification of early CSF abnormalities in children with ASD, along with emerging knowledge of the underlying pathogenic mechanisms, has the potential to serve as early stratification biomarkers that separate children with ASD into biological subtypes that share a common pathophysiology. Such subtypes could help parse the phenotypic heterogeneity of ASD and map on to targeted, biologically based treatments.
SnSe is a promising thermoelectric material with record-breaking figure of merit. However, to date a comprehensive understanding of the electronic structure and most critically, the self-hole-doping ...mechanism in SnSe is still absent. Here we report the highly anisotropic electronic structure of SnSe investigated by angle-resolved photoemission spectroscopy, in which a unique pudding-mould-shaped valence band with quasi-linear energy dispersion is revealed. We prove that p-type doping in SnSe is extrinsically controlled by local phase segregation of SnSe
microdomains via interfacial charge transferring. The multivalley nature of the pudding-mould band is manifested in quantum transport by crystallographic axis-dependent weak localisation and exotic non-saturating negative magnetoresistance. Strikingly, quantum oscillations also reveal 3D Fermi surface with unusual interlayer coupling strength in p-SnSe, in which individual monolayers are interwoven by peculiar point dislocation defects. Our results suggest that defect engineering may provide versatile routes in improving the thermoelectric performance of the SnSe family.
Lignin is a key component in the biomass with a complex polymeric structure of the phenyl-C
3 alkyl units. The kraft lignin from the wood pulping process is tested in TG-FTIR and Py-GC-MS. The ...samples are pyrolyzed in TGA coupled with FTIR from 30 to 900
°C at the heating rate of 20 and 40
K/min. The evolution of phenolic compounds in the initial pyrolysis stage of lignin is determined by FTIR, while the second stage is mainly attributed to the production of the low molecular weight species. A bench-scale fast pyrolysis unit is employed to investigate the effect of temperature on the product yield and composition. It is found that the guaiacol-type and syringol-type compounds as the primary products of lignin pyrolysis are predominant in bio-oil, acting as the significant precursors for the formation of the derivatives such as the phenol-, cresol- and catechol-types. A series of free-radical chain-reactions, concerning the cracking of different side-chain structures and the methoxy groups on aromatic ring, are proposed to demonstrate the formation pathways for the typical compounds in bio-oil by closely relating lignin structure to the pyrolytic mechanisms. The methoxy group (–OCH
3) is suggested to work as an important source for the formation of the small volatile species (CO, CO
2 and CH
4) through the relevant free radical coupling reactions.
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Background
In vitro experiments suggest that circulating metabolites of oxycodone are opioid receptor agonists. Clinical and animal studies to date have failed to demonstrate a significant ...contribution of the O‐demethylated metabolite oxymorphone toward the clinical effects of the parent drug, but the role of other putative circulating active metabolites in oxycodone pharmacodynamics remains to be examined.
Methods
Pharmacokinetics and pharmacodynamics of oxycodone were investigated in healthy human volunteers; measurements included the time course of plasma concentrations and urinary excretion of metabolites derived from N‐demethylation, O‐demethylation, and 6‐keto‐reduction, along with the time course of miosis and subjective opioid side effects. The contribution of circulating metabolites to oxycodone pharmacodynamics was analyzed by pharmacokinetic‐pharmacodynamic modeling. The human study was complemented by in vitro measurements of opioid receptor binding and activation studies, as well as in vivo studies of the brain distribution of oxycodone and its metabolites in rats.
Results
Urinary metabolites derived from cytochrome P450 (CYP) 3A‐mediated N‐demethylation of oxycodone (noroxycodone, noroxymorphone, and α‐ and β‐noroxycodol) accounted for 45% ± 21% of the dose, whereas CYP2D6‐mediated O‐demethylation (oxymorphone and α‐ and β‐oxymorphol) and 6‐keto‐reduction (α‐ and β‐oxycodol) accounted for 11% ± 6% and 8% ± 6% of the dose, respectively. Noroxycodone and noroxymorphone were the major metabolites in circulation with elimination half‐lives longer than that of oxycodone, but their uptake into the rat brain was significantly lower compared with that of the parent drug. Pharmacokinetic‐pharmacodynamic modeling indicated that the time course of pupil constriction is fully explained by the plasma concentration of the parent drug, oxycodone, alone. The metabolites do not contribute to the central effects, either because of their low potency or low abundance in circulation or as a result of their poor uptake into the brain.
Conclusions
CYP3A‐mediated N‐demethylation is the principal metabolic pathway of oxycodone in humans. The central opioid effects of oxycodone are governed by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites.
Clinical Pharmacology & Therapeutics (2006) 79, 461–479; doi: 10.1016/j.clpt.2006.01.009
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Highlights • Baicalin prevents depressive-like behaviors induced by CORT. • Baicalin reverses the increased mRNA and protein expression of SGK1 in the hippocampus induced by CORT. • Baicalin ...increases the hippocampal protein expression of 11β-HSD2, GRα and BDNF in CORT-treated mice.
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