Role of Nuclear Receptors in Lipid Dysfunction and Obesity-Related Diseases.

Role of Nuclear Receptors in Lipid Dysfunction and Obesity-related Diseases.

Filed under: Drug and Alcohol Rehabilitation

Drug Metab Dispos. 2012 Oct 4;
Swanson H, Wada T, Xie W, Renga B, Zampella A, Distrutti E, Fiorucci S, Kong B, Thomas AM, Guo GL, Narayanan R, Yepuru M, Dalton J, Chiang JY

This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 12 meeting in San Diego, CA. The presentations discussed the roles of a number of nuclear receptors in regulating glucose and lipid homeostasis, the pathophysiology of obesity-related disease states and the promise associated with targeting their activities to treat these diseases. While many of these receptors, in particular constitutive androstane receptor and pregnane X receptor and their target enzymes have been thought of as regulators of drug and xenobiotic metabolism, this symposium highlighted the advances made in our understanding of the endogenous functions of these receptors. Similarly, the advances made in our understanding of the mechanisms underlying bile acid signaling pathways in the regulation of body weight and glucose homeostasis illustrates the importance of using complementary approaches to elucidate this fascinating network of pathways. The observations that some receptors, like the farnesoid X receptor can function in a tissue specific manner via well defined mechanisms has important clinical implications particularly in the treatment of liver diseases. Finally, the novel findings that agents that selectively activate estrogen receptor ? can effectively inhibit weight gain in a high-fat diet model of obesity identifies a new role for this member of the steroid superfamily. Taken together, this symposium has revealed a number of significant findings that illustrate the promise associated with targeting a number of nuclear receptors for the development of new therapies to treat obesity and other metabolic disorders.
HubMed – drug

Metabolism and Disposition of Vilanterol, a Long Acting Beta2 Adrenoceptor Agonist, for Inhalation use in Human.

Filed under: Drug and Alcohol Rehabilitation

Drug Metab Dispos. 2012 Oct 4;
Harrell AW, Siederer SK, Bal J, Patel NH, Young GC, Felgate CC, Pearce SJ, Roberts AD, Beaumont C, Emmons AJ, Pereira AI, Kempsford RD

The metabolism and disposition of vilanterol, a novel long-acting beta(2) adrenoceptor agonist (LABA) for inhalation use, was investigated following oral administration to human. Single oral administrations of up to 500 ?g vilanterol were shown to be safe and well tolerated in two clinical studies using healthy male subjects. In a human radiolabel study, six healthy male subjects received a single oral dose of 200 ?g [(14)C] vilanterol (74 kBq). Plasma, urine and faeces were collected up to 168 hours post dose and analysed for vilanterol, metabolites and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O-dealkylation to metabolites which were mainly excreted in urine. Vilanterol represented a very small percentage (<0.5%) of the total drug-related material in plasma - indicative of extensive first-pass metabolism. Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacological activity. The therapeutic dose level for vilanterol is 25 ?g by the inhalation route. At this low dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible. In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human ADME for inhaled molecules - mainly related to the low chemical doses and complications associated with the inhalation route of administration. HubMed – drug

Therapeutic Effects of PPAR? Agonists on Diabetic Retinopathy in Type 1 Diabetic Models.

Filed under: Drug and Alcohol Rehabilitation

Diabetes. 2012 Oct 5;
Chen Y, Hu Y, Lin M, Jenkins AJ, Keech AC, Mott R, Lyons TJ, Ma JX

Retinal vascular leakage, inflammation, and neovascularization (NV) are features of diabetic retinopathy (DR). Fenofibrate, a peroxisome proliferator-activated receptor ? (PPAR?) agonist, has shown robust protective effects against DR in type 2 diabetic patients, but its effects on DR in type 1 diabetes have not been reported. This study evaluated the efficacy of fenofibrate on DR in type 1 diabetic models and determined if the effect is PPAR? dependent. Oral administration of fenofibrate significantly ameliorated retinal vascular leakage and leukostasis in streptozotocin-induced diabetic rats and in Akita mice. Favorable effects on DR were also achieved by intravitreal injection of fenofibrate or another specific PPAR? agonist. Fenofibrate also ameliorated retinal NV in the oxygen-induced retinopathy (OIR) model and inhibited tube formation and migration in cultured endothelial cells. Fenofibrate also attenuated overexpression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and vascular endothelial growth factor (VEGF) and blocked activation of hypoxia-inducible factor-1 and nuclear factor-?B in the retinas of OIR and diabetic models. Fenofibrate’s beneficial effects were blocked by a specific PPAR? antagonist. Furthermore, Ppar? knockout abolished the fenofibrate-induced downregulation of VEGF and reduction of retinal vascular leakage in DR models. These results demonstrate therapeutic effects of fenofibrate on DR in type 1 diabetes and support the existence of the drug target in ocular tissues and via a PPAR?-dependent mechanism.
HubMed – drug

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