benzofurans and Psoriasis

Psoriasis plaque tests (PPTs) are important tools in the early phases of antipsoriatic drug development. Two distinct PPT design variants (open vs. occluded drug application) are commonly used, but no previous work has aimed to directly compare and contrast their performance.. We compared the antipsoriatic efficacy of mapracorat 0.1% ointment and reference drugs reported in 2 separate studies, representing open and occluded PPT designs. The drug effect size was measured by sonography (mean change in echo-poor band thickness), chromametry, and standardized clinical assessment.. Antipsoriatic effects were detectable for the study drugs in both occluded and open PPTs. Differences between the potency of antipsoriatic drugs and vehicle were observable. The total antipsoriatic effect size appeared to be higher in the occluded PPT than the open PPT, despite the shorter treatment duration (2 vs. 4 weeks). Effect dynamics over time revealed greater differences between some study drugs in the open PPT compared to the occluded PPT.. Taking the higher technical challenges for the open PPT into account, we recommend the occluded PPT as a standard screening setting in early drug development. In special cases, considering certain drug aspects or study objectives that would require procedural adaptations, an open PPT could be the better-suited design. Finally, both PPT models show clear advantages: classification as phase I studies, small number of psoriatic subjects, relatively short study duration, excellent discrimination between compounds and concentrations, parallel measurement of treatment response, and go/no go decisions very early in clinical development.

Topics: Adult; Aged; Benzofurans; Dermatologic Agents; Double-Blind Method; Drug Design; Female; Humans; Male; Middle Aged; Models, Biological; Ointments; Pentanols; Psoriasis; Quinolines; Research Design; Treatment Outcome

Resveratrol was shown to exert anti-inflammatory effects in experimental models of psoriasis. Several natural oligomers of resveratrol have been extracted from plants. We investigated the antipsoriatic activity of topical administration of resveratrol oligomers and explored the effect of the number of resveratrol subunits on skin absorption to establish the structure-permeation relationship (SPR). Three oligomers, ε-viniferin (dimer), ampelopsin C (trimer) and vitisin A (tetramer), extracted from Vitis thunbergii root were compared to the resveratrol glycoside polydatin. Delivery to porcine skin was assessed in vitro using the Franz cell. Keratinocytes activated with imiquimod (IMQ) were utilized to evaluate cytokine/chemokine inhibition. Topical application of resveratrol and oligomers was characterized in vivo by assessing cutaneous absorption, skin physiology, proinflammatory mediator expression, and histopathology in IMQ-treated mice. Skin deposition decreased as the molecular size and lipophilicity of the permeants increased. Resveratrol exhibited highest absorption, followed by ε-viniferin. The monomers resveratrol and polydatin exhibited higher flux across skin than the larger oligomers. In silico modeling revealed the permeants that strongly interacted with stratum corneum (SC) lipids exhibited lower transport to viable skin and the receptor compartment. In vitro, resveratrol and its derivatives had comparable ability to inhibit IMQ-induced IL-1β, IL-6, and CXCL8 secretion in activated keratinocytes. In vivo, topically applied ε-viniferin accumulated at higher levels than resveratrol (0.067 versus 0.029 nmol/mg) in psoriasis-like mouse skin with impaired barrier capacity. Topical ε-viniferin alleviated psoriasiform symptoms and reduced IL-23 secretion (by 58% vs. 37%) more effectively than resveratrol. ε-Viniferin has potential as an anti-inflammatory agent to prevent or treat psoriasis.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Benzofurans; Chemistry, Pharmaceutical; Chemokines; Cytokines; Flavonoids; Glucosides; Inflammation Mediators; Keratinocytes; Mice; Phenols; Plant Extracts; Psoriasis; Resveratrol; Skin Absorption; Stilbenes; Swine

Topics: Animals; Benzofurans; Coumarins; Female; Furocoumarins; Imiquimod; Keratinocytes; Mice, Inbred BALB C; Mice, Nude; Phenols; Photochemotherapy; Psoralea; Psoriasis; PUVA Therapy; Skin; Skin Absorption; Swine; Ultraviolet Rays

A reversed-phase column liquid chromatographic (LC) method with electrochemical detection (ED) is described for the quantification of 2,3-dihydro-6-[3-(2-hydroxymethyl)phenyl-2-propenyl]-5-benzofuranol (compound 1), a new locally active dual inhibitor of leukotriene and prostaglandin synthesis, in plasma. After a single liquid-liquid extraction of the biological specimen, the extract was analyzed using a liquid chromatograph with an amperometric detector set at an oxidation potential of +0.55 V. The resulting chromatograms are free from endogenous interference and the limit of detection is 0.2 ng/ml. Several other analogous dihydrobenzofuranols were shown to be electrochemically active, permitting their determination using LC with ED. The described analytical method has been fully validated in the concentration range 0.5-20 ng/ml of plasma and utilized in the analysis of plasma samples from human clinical studies. The analytical methodology has also been adapted for analysis of compound 1 in human skin blister fluid after topical administration of 1.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Benzofurans; Blister; Chromatography, High Pressure Liquid; Dogs; Electrochemistry; Humans; Psoriasis; Spectrophotometry, Ultraviolet

Topics: Aged; Amiodarone; Benzofurans; Humans; Male; Psoriasis

Topics: Acrylates; Animals; Autoradiography; Benzofurans; DNA; Humans; In Vitro Techniques; Light; Male; Mice; Mice, Inbred Strains; Psoriasis; Skin; Thymidine; Tritium; Ultraviolet Rays; Ultraviolet Therapy

Topics: Administration, Oral; Adolescent; Adult; Anthracenes; Benzofurans; Humans; Middle Aged; Psoriasis; Remission, Spontaneous; Time Factors; Ultraviolet Rays

Topics: Administration, Oral; Adolescent; Adult; Anthracenes; Benzofurans; Humans; Middle Aged; Psoriasis; Remission, Spontaneous; Time Factors; Ultraviolet Rays

Topics: Administration, Oral; Adult; Benzofurans; Gout; Humans; Joint Diseases; Male; Psoriasis; Uric Acid

Topics: Allopurinol; Arthritis, Rheumatoid; Benzofurans; Diagnosis, Differential; Gout; Humans; Ketones; Psoriasis; Rheumatic Fever; Uric Acid