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  • 1
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    H2 evolution: [Ni(P2N2)2]2+ in acidic ionic liq./H2O [Chemistry] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-09-26
    Description: The electrocatalytic reduction of protons to H2 by (where in the highly acidic ionic liquid dibutylformamidium bis(trifluoromethanesulfonyl)amide shows a strong dependence on added water. A turnover frequency of 43,000–53,000 s-1 has been measured for hydrogen production at 25 °C when the mole fraction of water (χH2O) is 0.72. The same catalyst in...
    Keywords: Chemical Approaches to Artificial Photosynthesis: Solar Fuels Special Feature
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Catalyst for reversible H2 oxidation/production [Chemistry] (2014)
    National Academy of Sciences
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    Publication Date: 2014-11-19
    Description: Hydrogenases interconvert H2 and protons at high rates and with high energy efficiencies, providing inspiration for the development of molecular catalysts. Studies designed to determine how the protein scaffold can influence a catalytically active site have led to the synthesis of amino acid derivatives of [Ni(P2RN2R′)2]2+ complexes, [Ni(P2CyN2Amino acid)2]2+ (CyAA). It...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 3
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    Biodistribution of Etanercept to Tissues and Sites of Inflammation in Arthritic Rats [Articles] (2015)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2015-05-01
    Description: Many monoclonal antibodies (mAbs) and other protein drugs have targets usually residing within tissues, making tissue concentrations of mAbs relevant to their pharmacologic effects. Therefore, knowledge of tissue distribution kinetics is important to better understand their pharmacokinetics and pharmacodynamics. The tissue distribution of mAbs is affected by many physiologic factors that may be altered in disease status. In the present work, we studied the tissue distribution kinetics of the fusion protein etanercept in inflamed joint tissues and examined the impact of inflammation on the tissue distribution of etanercept. Etanercept concentration profiles in plasma, blister fluid, and different tissues were obtained from healthy and collagen-induced arthritic (CIA) rats by use of a fluorescence quantification method via IRDye800CW labeling. Stepwise minimal and full physiologically based pharmacokinetic (PBPK) approaches were applied to characterize the distribution kinetics of etanercept in tissues in healthy and diseased animals. Etanercept exhibited modest tissue access (tissue/plasma area under the concentration curve [AUC] ratios 0.03–0.15 and estimated tissue reflection coefficients [ ] of 0.6–1.0), but with good penetration into arthritic paws (tissue/plasma AUC ratio 0.23 and 0.36). Etanercept exposure in the inflamed paws of CIA rats was approximately 3-fold higher than in normal paws taken from either CIA or healthy rats (tissue/plasma AUC ratios 0.23 versus 0.07 and 0.36 versus 0.71). The tissue distribution kinetics of etanercept in arthritic paws were well characterized with PBPK modeling approaches. Etanercept shows good penetration to arthritic paws in CIA rats. Our study indicates that inflammation produced increased tissue distribution of etanercept in CIA rats.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 4
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    {Delta}-9,11 Modification of Glucocorticoids Dissociates Nuclear Factor-{kappa}B Inhibitory Efficacy from Glucocorticoid Response Element-Associated Side Effects [Cellular and Molecular] (2012)
    The American Society for Pharmacology and Experimental Therapeutics
    Details
    Publication Date: 2012-09-15
    Description: Glucocorticoids are standard of care for many inflammatory conditions, but chronic use is associated with a broad array of side effects. This has led to a search for dissociative glucocorticoids—drugs able to retain or improve efficacy associated with transrepression [nuclear factor-B (NF-B) inhibition] but with the loss of side effects associated with transactivation (receptor-mediated transcriptional activation through glucocorticoid response element gene promoter elements). We investigated a glucocorticoid derivative with a -9,11 modification as a dissociative steroid. The -9,11 analog showed potent inhibition of tumor necrosis factor-α-induced NF-B signaling in cell reporter assays, and this transrepression activity was blocked by 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU-486), showing the requirement for the glucocorticoid receptor (GR). The -9,11 analog induced the nuclear translocation of GR but showed the loss of transactivation as assayed by GR-luciferase constructs as well as mRNA profiles of treated cells. The -9,11 analog was tested for efficacy and side effects in two mouse models of muscular dystrophy: mdx (dystrophin deficiency), and SJL (dysferlin deficiency). Daily oral delivery of the -9,11 analog showed a reduction of muscle inflammation and improvements in multiple muscle function assays yet no reductions in body weight or spleen size, suggesting the loss of key side effects. Our data demonstrate that a -9,11 analog dissociates the GR-mediated transcriptional activities from anti-inflammatory activities. Accordingly, -9,11 analogs may hold promise as a source of safer therapeutic agents for chronic inflammatory disorders.
    Print ISSN: 0022-3565
    Electronic ISSN: 1521-0103
    Topics: Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics
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  • 5
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    Effect of Disease-Related Changes in Plasma Albumin on the Pharmacokinetics of Naproxen in Male and Female Arthritic Rats [Articles] (2017)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2017-04-06
    Description: Naproxen (NPX) is used in the treatment of rheumatoid arthritis (RA) for alleviation of pain and inflammation. In view of the extensive albumin binding of NPX, this study investigates whether chronic inflammation and sex influence the physiologic albumin concentrations, plasma protein binding, and pharmacokinetics (PK) of NPX. The PK of NPX was evaluated in a rat model of RA [collagen-induced arthritis (CIA) in Lewis rats] and in healthy controls. These PK studies included 1) NPX in female and male CIA rats that received 10, 25, or 50 mg/kg NPX i.p.; and 2) NPX in healthy female and male rats after i.p. dosing of NPX at 50 mg/kg. Plasma albumin concentrations were quantified by enzyme-linked immunosorbent assay, and protein binding was assessed using ultrafiltration. The NPX concentrations in plasma and filtrates were determined by liquid chromatography–tandem mass spectrometry (LC-MS/MS). Plasma concentration-time data of NPX were first assessed by noncompartmental analysis (NCA). Nonlinear PK as indicated by dose-dependent NCA clearances and distribution volumes was observed. A two-compartment model with a first-order absorption process incorporating nonlinear protein binding in plasma and tissues jointly described the PK data of all groups. Saturable albumin binding accounts for the nonlinearity of NPX PK in all rats as well as part of the PK differences in arthritic rats. The CIA rats exhibited reduced albumin concentrations, reduced overall protein binding, and reduced clearances of unbound NPX, consistent with expectations during inflammation. The net effect of chronic inflammation was an elevation of the C max and area under the plasma concentration-time curve (AUC) of unbound drug.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 6
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    Modeling Sex Differences in Pharmacokinetics, Pharmacodynamics, and Disease Progression Effects of Naproxen in Rats with Collagen-Induced Arthritis [Articles] (2017)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2017-04-06
    Description: Naproxen (NPX) is a frequently used nonsteroidal anti-inflammatory drug for rheumatoid arthritis (RA). Lack of quantitative information about the drug exposure–response relationship has resulted in empirical dosage regimens for use of NPX in RA. Few studies to date have included sex as a factor, although RA predominates in women. A pharmacokinetic, pharmacodynamic, and disease progression model described the anti-inflammatory effects of NPX in collagen-induced arthritic (CIA) male and female rats. Three groups of rats were included for each sex: healthy animals, CIA controls, and CIA rats given a single 50-mg/kg dose of NPX intraperitoneally. Paw volumes of healthy rats indicated natural growth, and disease status was measured by paw edema. An innovative minimal physiologically based pharmacokinetic (mPBPK) model incorporating nonlinear albumin binding of NPX in both plasma and interstitial fluid (ISF) was applied. Arthritic rats exhibited lower plasma and ISF albumin concentrations and reduced clearances of unbound drug to explain pharmacokinetic profiles. The unbound ISF NPX concentrations predicted by the mPBPK model were used as the driving force for pharmacological effects of NPX. A logistic growth function accounting for natural paw growth and an indirect response model for paw edema and drug effects (inhibition of k in ) was applied. Female rats showed a higher incidence of CIA, earlier disease onset, and more severe symptoms. NPX had stronger effects in males, owing to higher unbound ISF NPX concentrations and lower IC 50 values. The model described the pharmacokinetics, unbound NPX in ISF, time course of anti-inflammatory effects, and sex differences in CIA rats.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 7
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    Modeling Corticosteroid Pharmacogenomics and Proteomics in Rat Liver [Metabolism, Transport, and Pharmacogenomics] (2018)
    The American Society for Pharmacology and Experimental Therapeutics
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    Publication Date: 2018-09-19
    Description: Corticosteroids (CS) regulate the expression of numerous genes at the mRNA and protein levels. The time course of CS pharmacogenomics and proteomics were examined in livers obtained from adrenalectomized rats given a 50-mg/kg bolus dose of methylprednisolone. Microarrays and mass spectrometry-based proteomics were employed to quantify hepatic transcript and protein dynamics. One-hundred, sixty-three differentially expressed mRNA and their corresponding proteins (163 genes) were clustered into two dominant groups. The temporal profiles of most proteins were delayed compared with their mRNA, attributable to synthesis delays and slower degradation kinetics. On the basis of our fifth-generation model of CS, mathematical models were developed to simultaneously describe the emergent time patterns for an array of steroid-responsive mRNA and proteins. The majority of genes showed time-dependent increases in mRNA and protein expression before returning to baseline. A model assuming direct, steroid-mediated stimulation of mRNA synthesis was applied. Some mRNAs and their proteins displayed down-regulation following CS. A model assuming receptor-mediated inhibition of mRNA synthesis was used. More complex patterns were observed for other genes (e.g., biphasic behaviors and opposite directionality in mRNA and protein). Models assuming either stimulation or inhibition of mRNA synthesis coupled with dual secondarily induced regulatory mechanisms affecting mRNA or protein turnover were derived. These findings indicate that CS-regulated gene expression manifested at the mRNA and protein levels are controlled via mechanisms affecting key turnover processes. Our quantitative models of CS pharmacogenomics were expanded from mRNA to proteins and provide extended hypotheses for understanding the direct, secondary, and downstream mechanisms of CS actions.
    Print ISSN: 0022-3565
    Electronic ISSN: 1521-0103
    Topics: Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics
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  • 8
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    Mathematical modeling of the circadian dynamics of the neuroendocrine-immune network in experimentally induced arthritis (2016)
    The American Physiological Society (APS)
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    Publication Date: 2016-07-23
    Description: The circadian dynamics of important neuroendocrine-immune mediators have been implicated in progression of rheumatoid arthritis pathophysiology, both clinically as well as in animal models. We present a mathematical model that describes the circadian interactions between mediators of the hypothalamic-pituitary-adrenal (HPA) axis and the proinflammatory cytokines. Model predictions demonstrate that chronically elevated cytokine expression results in the development of adrenal insufficiency and circadian variability in paw edema. Notably, our model also predicts that an increase in mean secretion of corticosterone (CST) after the induction of the disease is accompanied by a decrease in the amplitude of the CST oscillation. Furthermore, alterations in the phase of circadian oscillation of both cytokines and HPA axis mediators are observed. Therefore, by incorporating the circadian interactions between the neuroendocrine-immune mediators, our model is able to simulate important features of rheumatoid arthritis pathophysiology.
    Print ISSN: 0193-1849
    Electronic ISSN: 1522-1555
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 9
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    Interrelationships between Infliximab and Recombinant Tumor Necrosis Factor-{alpha} in Plasma Using Minimal Physiologically Based Pharmacokinetic Models [Articles] (2017)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2017-06-10
    Description: The soluble cytokine tumor necrosis factor- α (TNF- α ) is an important target for many therapeutic proteins used in the treatment of rheumatoid arthritis. Biologics targeting TNF- α exert their pharmacologic effects through binding and neutralizing this cytokine and preventing it from binding to its cell surface receptors. The magnitude of their pharmacologic effects directly corresponds to the extent and duration of free TNF- α suppression. However, endogenous TNF- α is of low abundance, so it is quite challenging to assess the free TNF- α suppression experimentally. Here we have applied an experimental approach to bypass this difficulty by giving recombinant human TNF- α (rhTNF- α ) to rats by s.c. infusion. This boosted TNF- α concentration enabled quantification of TNF- α in plasma. Free rhTNF- α concentrations were measured after separation from the infliximab-rhTNF- α complex using Dynabeads Protein A. The interrelationship of infliximab and TNF- α was assessed with minimal physiologically based pharmacokinetic models for TNF- α and infliximab with a target-mediated drug disposition component. Knowledge of TNF- α pharmacokinetics allows reliable prediction of the free TNF- α suppression with either free or total TNF- α concentration profiles. The experimental and modeling approaches in our study may aid in the development of next-generation TNF- α inhibitors with improved therapeutic effects.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 10
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    Characterization and Interspecies Scaling of rhTNF-{alpha} Pharmacokinetics with Minimal Physiologically Based Pharmacokinetic Models [Articles] (2017)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2017-06-10
    Description: Tumor necrosis factor- α (TNF- α ) is a soluble cytokine and target of specific monoclonal antibodies (mAbs) and other biologic agents used in the treatment of inflammatory diseases. These biologics exert their pharmacological effects through binding and neutralizing TNF- α , and thus they prevent TNF- α from interacting with its cell surface receptors. The magnitude of the pharmacological effects is governed not only by the pharmacokinetics (PK) of mAbs, but also by the kinetic fate of TNF- α . We have examined the pharmacokinetics of recombinant human TNF- α (rhTNF- α ) in rats at low doses and quantitatively characterized its pharmacokinetic features with a minimal physiologically based pharmacokinetic model. Our experimental and literature-digitalized PK data of rhTNF- α in rats across a wide range of doses were applied to global model fitting. rhTNF- α exhibits permeability rate–limited tissue distribution and its elimination is comprised of a saturable clearance pathway mediated by tumor necrosis factor receptor binding and disposition and renal filtration. The resulting model integrated with classic allometry was further used for interspecies PK scaling and resulted in model predictions that agreed well with experimental measurements in monkeys. In addition, a semimechanistic model was proposed and applied to explore the absorption kinetics of rhTNF- α following s.c. and other routes of administration. The model suggests substantial presystemic degradation of rhTNF- α for s.c. and i.m. routes and considerable lymph uptake contributing to the overall systemic absorption through the stomach wall and gastrointestinal wall routes of dosing. This report provides comprehensive modeling and key insights into the complexities of absorption and disposition of a major cytokine.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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