8-11-14-eicosatrienoic-acid and Dermatitis--Contact

Endothelial-derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that was tested in two phase I studies.. Single escalating doses of GSK2256294 2-20 mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers. Once daily doses of 6 or 18 mg or placebo were administered for 14 days to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme inhibition and blood biomarkers. Single doses of GSK2256294 10 mg were also administered to healthy younger males or healthy elderly males and females with and without food. Data on safety, pharmacokinetics and biliary metabolites were collected.. GSK2256294 was well-tolerated with no serious adverse events (AEs) attributable to the drug. The most frequent AEs were headache and contact dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with a half-life averaging 25-43 h. There was no significant effect of age, food or gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was dose-dependent, from an average of 41.9% on 2 mg (95% confidence interval [CI] -51.8, 77.7) to 99.8% on 20 mg (95% CI 99.3, 100.0) and sustained for up to 24 h. There were no significant changes in serum VEGF or plasma fibrinogen.. GSK2256294 was well-tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Adult; Aged; Cohort Studies; Cross-Over Studies; Cyclohexylamines; Dermatitis, Contact; Double-Blind Method; Enzyme Inhibitors; Epoxide Hydrolases; Female; Half-Life; Headache; Healthy Volunteers; Humans; Male; Middle Aged; Obesity; Triazines; Young Adult

Coconut oil is used as a dietary oil worldwide, and its healthy effects are recognized by the fact that coconut oil is easy to digest, helps in weight management, increases healthy cholesterol, and provides instant energy. Although topical application of coconut oil is known to reduce skin infection and inflammation, whether dietary coconut oil has any role in decreasing skin inflammation is unknown. In this study, we showed the impact of dietary coconut oil in allergic skin inflammation by using a mouse model of contact hypersensitivity (CHS). Mice maintained on coconut oil showed amelioration of skin inflammation and increased levels of cis-5, 8, 11-eicosatrienoic acid (mead acid) in serum. Intraperitoneal injection of mead acid inhibited CHS and reduced the number of neutrophils infiltrating to the skin. Detailed mechanistic studies unveiled that mead acid inhibited the directional migration of neutrophils by inhibiting the filamentous actin polymerization and leukotriene B

Topics: 8,11,14-Eicosatrienoic Acid; Actins; Animals; Biomarkers; Capillary Permeability; Chemotaxis; Coconut Oil; Dermatitis, Atopic; Dermatitis, Contact; Dietary Fats, Unsaturated; Disease Models, Animal; Female; Immunohistochemistry; Immunophenotyping; Leukotriene B4; Lipid Metabolism; Mice; Neutrophils; Skin