desonide and Disease-Models--Animal

Although there is a variety of animal models available, neither a single assay system nor the results of the various assays permit absolute protection of relative anti-inflammatory potency. Equally, current clinical dose titration studies, although more reliable, provide only gross estimates of therapeutic potency when conducted in certain clinical situations in a double-blind randomized fashion. This paper delineated clinical means to titrate more objectively and accurately therapeutic potency in the patient. Moreover, it has submitted considerations as to how to assess therapeutic anti-inflammatory activity in the complex multi-component process of inflammation accompanying most dermatologic diseases that eventually may permit titration of specific anti-inflammatory compounds on certain tissue components of the inflammatory process.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Clinical Trials as Topic; Desonide; Disease Models, Animal; Drug Evaluation; Drug Evaluation, Preclinical; Edema; Eye Diseases; Female; Fibroblasts; Glucocorticoids; Humans; Inflammation; Mitosis; Psoriasis; Rabbits; Triamcinolone Acetonide; Vagina; Vasoconstrictor Agents

Identifying inhibitors of pathogenic proteins is the major strategy of targeted drug discoveries. This strategy meets challenges in targeting neurodegenerative disorders such as Huntington’s disease (HD), which is mainly caused by the mutant huntingtin protein (mHTT), an “undruggable” pathogenic protein with unknown functions. We hypothesized that some of the chemical binders of mHTT may change its conformation and/or stability to suppress its downstream toxicity, functioning similarly to an “inhibitor” under a broader definition. We identified 21 potential mHTT selective binders through a small-molecule microarray–based screening. We further tested these compounds using secondary phenotypic screens for their effects on mHTT-induced toxicity and revealed four potential mHTT-binding compounds that may rescue HD-relevant phenotypes. Among them, a Food and Drug Administration–approved drug, desonide, was capable of suppressing mHTT toxicity in HD cellular and animal models by destabilizing mHTT through enhancing its polyubiquitination at the K6 site. Our study reveals the therapeutic potential of desonide for HD treatment and provides the proof of principle for a drug discovery pipeline: target-binder screens followed by phenotypic validation and mechanistic studies.

Topics: Animals; Desonide; Disease Models, Animal; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Mutation; Protein Stability

Our group previously reported the photoinstability of some desonide topical commercial formulations under direct exposure to UVA radiation.. This study aimed to prepare and characterize a gel-cream containing desonide, with greater photostability than the commercial gel-cream (C-GC). Benzophenone-3 (BP-3) was used as a photostabilizing agent.. The gel-cream developed (D-GC) containing BP-3 at 0.1% was prepared and characterized regarding its pH, drug content, spreadability, viscosity, in vitro drug release and in vitro permeation. The in vivo anti-inflammatory effect was assessed by ear edema measurement, croton oil-induced acute skin inflammation and myeloperoxidase assay.. D-GC presented characteristics compatible with topical application, appropriate drug content and good spreadability, and non-Newtonian behavior with pseudoplastic flow. D-GC showed a good photostability profile, presenting a desonide content of 95.70% after 48 h of exposure to UVA radiation, and stability under room conditions during 60 days. The amount of desonide released from D-GC and C-GC was 57.8 and 51.7 µg/cm. D-GC represents a promising approach to treat dermatological disorders, since it presented satisfactory physicochemical characteristics, the same biological activity as C-GC and superior photostability, conferred by the addition of BP-3 at 0.1%.

Topics: Animals; Anti-Inflammatory Agents; Benzophenones; Chemistry, Pharmaceutical; Croton Oil; Dermatitis, Contact; Dermatologic Agents; Desonide; Disease Models, Animal; Ear; Gels; Glucocorticoids; Humans; Male; Mice; Skin; Skin Cream; Ultraviolet Rays