Search

This study was conducted to appraise the possible potential of synthetic isoflavones (SIFs) on psoriasis treatment. A practical and easy-to-operate approach was employed in synthesizing a series of SIFs, considering that acquiring flavonoids from natural resources is usually expensive, time-consuming, and non-eco-friendly. Seven SIFs derived from daidzein were produced with differences in the location of the hydroxyl groups and degree of methoxylation. The in vitro and in vivo skin absorption of topically applied SIFs was estimated. Further, keratinocytes (HaCaT) were employed as the model to investigate the anti-inflammatory activity of the isoflavones. The lipophilicity was increased from SIF-1 to -7. Noteworthily, there was a parabolic relationship between lipophilicity and skin absorption, with SIF-5 (4',7-dihydroxyisoflavone, daidzein) and SIF-6 (7-hydroxy-3',4'-dimethoxyisoflavone, cladrin) demonstrating the highest retention in pig skin. The methoxylated isoflavone SIF-5 showed the greatest permeation into barrier-deficient skin among the compounds tested, with a 6- and 8-fold increase after lipid and protein removal. The cell-based study exhibited the capability of SIFs to restrain the overexpressed IL-6, IL-8, and CXCL1 in stimulated HaCaT. The therapeutic index (TI) predicted the potential candidates of SIF-5 and SIF-6 for topical application to treat psoriatic inflammation. The imiquimod (IMQ)-driven psoriasiform murine model manifested the inhibition of hyperplasia and immune cell infiltration by topically administered SIF-5 and SIF-6. The epidermal thickness of IMQ-treated skin was decreased from 172 to 40 μm by both isoflavones. This effect was comparable with that of betamethasone, the positive control. The topical treatment of SIF-6 significantly reduced cytokine/chemokine upregulation by IMQ. The methoxylated isoflavone with dramatic anti-inflammatory activity is promising for the development of an antipsoriatic agent.

The purpose of this study was to evaluate the skin permeation of tricyclic antidepressants (TCAs) with propamine moiety to select candidates for the development of topical analgesics to treat cutaneous pain. We sought to establish the structure-permeation relationship (SPR) of topical TCAs. The lipophilicity, melting point, and aqueous solubility were determined to develop the physicochemical characterization. The TCA permeation into pig and nude mouse skins was estimated using Franz diffusion cell. TCAs and lidocaine were comparatively examined for cutaneous analgesia by pinprick assay. Cutaneous tolerance to TCAs was assessed using nude mouse skin. The skin deposition increased following the increase of lipophilicity after excluding the effect of solubility, with clomipramine exhibiting the highest skin retention. A contrary result was observed for TCA penetration into the receptor. Of the permeants tested, clomipramine demonstrated the best skin-targeting ability. Nortriptyline and clomipramine demonstrated selective uptake into the hair follicles, exhibiting a 2.5-fold higher follicular accumulation than desipramine. Replacement of nitrogen with carbon in the seven-member ring increased skin absorption. The tertiary amine TCAs demonstrated higher absorption than the secondary amine TCAs. The position of the double bond also affected skin transport. Topical clomipramine had a longer duration of analgesic action than lidocaine (240min versus 60min). Exploring the SPR revealed that clomipramine could be an analgesic candidate drug for future development.

The discrepancy in drug absorption between healthy and diseased skins is an issue that needs to be elucidated. The present study attempted to explore the percutaneous absorption of drugs via lesional skin by using atopic dermatitis (AD) as a model. Tape-stripping and ovalbumin (OVA) sensitization induced AD-like skin. The lesions were evaluated by physiological parameters, histology, cytokines, and differentiation proteins. The permeants of tacrolimus, 8-methoxypsoralen, methotrexate, and dextran were used to examine in vitro and in vivo cutaneous permeation. Transepidermal water loss (TEWL) increased from 5.2 to 27.4 g/m(2)/h by OVA treatment. AD-like lesions were characterized by hyperplasia, skin redness, desquamation, and infiltration of inflammatory cells. Repeated OVA challenge produced a T-helper 2 (Th2) hypersensitivity accompanied by downregulation of filaggrin, involucrin, and integrin β. Tacrolimus, the most lipophilic permeant, revealed an increase of cutaneous deposition by 2.7-fold in AD-like skin compared to intact skin. The transdermal flux of methotrexate and dextran, the hydrophilic permeants, across AD-like skin increased about 18 times compared to the control skin. Surprisingly, AD-like skin showed less skin deposition of 8-methoxypsoralen than intact skin. This may be because the deficient lipids in the atopic-affected stratum corneum (SC) diminished drug partitioning into the superficial skin layer. The fluorescence and confocal microscopic images demonstrated a broad and deep passage of small-molecular and macromolecular dyes into AD-like skin. The results obtained from this report were advantageous for showing how the lesional skin influenced percutaneous absorption.