The ameliorative effects of topical gemifloxacin alone or in combination with clobetasol propionate on imiquimod-induced model of psoriasis in mice.

Psoriasis is a lifelong immune-driven skin condition characterized by excessive epidermal overgrowth and inflammatory cell infiltration. Gemifloxacin is a fourth-generation fluoroquinolone with improved immunomodulatory and anti-inflammatory properties that are believed to possess an attractive role in psoriasis via suppressing the production of cytokines, chemokines, and eosinophil and neutrophil chemotaxis. The aim of this research is to investigate the ameliorative effects of prolonged topical gemifloxacin (GMF) alone and combined with clobetasol propionate (CLO) on an imiquimod (IMQ)-induced mouse model of psoriasis. Forty-eight Swiss albino mice were divided into six groups of eight. All groups except the negative controls got 62.5 mg of IMQ 5% topically for 8 days. Mice in the control group (controls) got Vaseline instead. Following the induction in the IMQ 5% group, mice in treatment groups CLO 0.05, GMF 1%, GMF 3%, and CLO + GMF obtained clobetasol propionate 0.05%, GMF 1% and 3%, and a combination of both, respectively, for an additional 8 days, rendering the experiment 16 days long. Our results revealed that gemifloxacin alleviated erythematous, thickened, and scaly psoriatic lesions and inhibited the tissue level of inflammatory cytokines, including interleukin (IL)-8, IL-17A, IL-23, tumor necrosis factor-α (TNF-α), and transforming growth factor-ß1 (TGF-ß1). The anti-inflammatory effect also occurred by hindering nuclear factor-kappa B (NF-κB) signaling and reversing histopathological problems. Gemifloxacin acts effectively in mitigating psoriasis-associated lesions and restricting NF-κB-mediated inflammation, recommending gemifloxacin as a promising adjuvant candidate for additional studies on the long-term treatment of autoimmune and autoinflammatory dermatoses like psoriasis.

Accelerating topical formulation development for inflammatory dermatoses; an ex vivo human skin culture model consistent with clinical therapeutics.

Although animal models have been extensively used to evaluate human topical therapeutics, they exhibit marked physiological differences to human skin. Our objective was to develop a human ex vivo skin culture model to explore the pathophysiology of inflammatory dermatoses and for preclinical testing of potential therapeutic treatments. Ex vivo skin barrier integrity and metabolic activity was retained for 5 days and stimulation of T-helper cells (Th1), which produce proinflammatory cytokines, provided inflammatory responses similar to those reported from in vivo biopsy. Tissue responses to established therapies of pimecrolimus (Elidel) and clobetasol propionate (Dermovate) were evaluated using the human ex vivo skin culture, assessing pharmacodynamic changes in gene expression alongside the pharmacokinetics of drug penetration with both products showing time dependent efficacies. The translational utility of the human ex vivo skin culture model of inflammatory dermatoses was demonstrated through comparison with an in vivo clinical study, with similar reductions in inflammatory gene expression recorded for both drug treatments. Thus, this model can reduce, replace or refine animal testing and also mitigate the risk of failure in costly and time-consuming clinical trials associated with novel topical therapeutic development.

Clinical, Cellular, and Molecular Effects of Corticosteroids on the Response to Intradermal Lipopolysaccharide Administration in Healthy Volunteers.

The intradermal lipopolysaccharide (LPS) challenge in healthy volunteers has proven to be a valuable tool to study local inflammation in vivo. In the current study the inhibitory effects of oral and topical corticosteroid treatment on intradermal LPS responses were evaluated to benchmark the challenge for future investigational drugs. Twenty-four healthy male volunteers received a two-and-a-half-day twice daily (b.i.d.) pretreatment with topical clobetasol propionate 0.05% and six healthy volunteers received a two-and-a-half-day b.i.d. pretreatment with oral prednisolone at 0.25 mg/kg body weight per administration. Participants received one injection regimen of either 0, 2, or 4 intradermal LPS injections (5 ng LPS in 50 µL 0.9% sodium chloride solution). The LPS response was evaluated by noninvasive (perfusion, skin temperature, and erythema) and invasive assessments (cellular and cytokine responses) in suction blister exudate. Both corticosteroids significantly suppressed the clinical inflammatory response (erythema P = 0.0001 for clobetasol and P = 0.0016 for prednisolone; heat P = 0.0245 for clobetasol, perfusion P < 0.0001 for clobetasol and P = 0.0036 for prednisolone). Clobetasol also significantly reduced the number of monocytes subsets, dendritic cells, natural killer cells, and T cells in blister exudate. A similar effect was observed for prednisolone. No relevant corticosteroid effects were observed on the cytokine response to LPS. We successfully demonstrated that the anti-inflammatory effects of corticosteroids can be detected using our intradermal LPS challenge model, validating it for evaluation of future investigational drugs, as an initial assessment of the anti-inflammatory effects of such compounds in a minimally invasive manner.

Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing.

Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders.

Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs.

Synthetic mRNAs are an appealing platform with multiple biomedical applications ranging from protein replacement therapy to vaccination. In comparison with conventional mRNA, synthetic self-amplifying mRNAs (sa-mRNAs) are gaining interest because of their higher and longer-lasting expression. However, sa-mRNAs also elicit an innate immune response, which may complicate their clinical application. Approaches to reduce the innate immunity of sa-mRNAs have not been studied in detail. Here we investigated, in vivo, the effect of several innate immune inhibitors and a novel cellulose-based mRNA purification approach on the type I interferon (IFN) response and the translation and vaccination efficacy of our formerly developed sa-mRNA vaccine against Zika virus. Among the investigated inhibitors, we found that corticosteroids and especially topical application of clobetasol at the sa-mRNA injection site was the most efficient in suppressing the type I IFN response and increasing the translation of sa-mRNA. However, clobetasol prevented formation of antibodies against sa-mRNA-encoded antigens and should therefore be avoided in a vaccination context. Residual dsRNA by-products of the in vitro transcription reaction are known inducers of immediate type I IFN responses. We additionally demonstrate a drastic reduction of these dsRNA by-products upon cellulose-based purification, reducing the innate immune response and improving sa-mRNA vaccination efficacy.

Topical Corticosteroids a Viable Solution for Oral Graft Versus Host Disease? A Systematic Insight on Randomized Clinical Trials.

Background and Objectives: This research attempts to provide a clear view of the literature on randomized clinical trials (RCTs) concerning the efficacy of topical dexamethasone, clobetasol and budesonide in oral graft versus host disease (GVHD). Materials and Methods: An electronic search of the PubMed, Web of Science and Scopus databases was carried out for eligible RCTs. Studies were included if they had adult patients with oral GVHD treatment with topical corticosteroids, and if the RCT study was published in English. The Cochrane Risk of Bias tool was used to assess the quality of these studies. Overall, three RCTs were included (an Open, Randomized, Multicenter Trial; a Randomized Double-Blind Clinical Trial; and an Open-Label Phase II Randomized Trial). Results: The trials involved 76 patients, of which 44 patients received topical dexamethasone, 14 patients received topical clobetasol and 18 patients received topical budesonide. Topical agents were most frequently used when oral tissues were the sole site of involvement. It appears that the best overall response is present for budesonide with no difference between the four arms, followed by clobetasol, and then by dexamethasone. The limitation of the current study is mainly represented by the fact that overall response was derived in two of the studies from other parameters. Moreover, both budesonide and clobetasol were used in only one study each, while two assessed dexamethasone. Conclusions: Based on the clinical trials, all three agents seem to be effective in treating oral GVHD and had a satisfactory safety profile. There is still a need for assessing high quality RCTs to assess the efficacy of these therapies on a larger cohort.

Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5.

The human cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 metabolize most drugs and have high similarities in their structure and substrate preference. Whereas CYP3A4 is predominantly expressed in the liver, CYP3A5 is upregulated in cancer, contributing to drug resistance. Selective inhibitors of CYP3A5 are, therefore, critical to validating it as a therapeutic target. Here we report clobetasol propionate (clobetasol) as a potent and selective CYP3A5 inhibitor identified by high-throughput screening using enzymatic and cell-based assays. Molecular dynamics simulations suggest a close proximity of clobetasol to the heme in CYP3A5 but not in CYP3A4. UV-visible spectroscopy and electron paramagnetic resonance analyses confirmed the formation of an inhibitory type I heme-clobetasol complex in CYP3A5 but not in CYP3A4, thus explaining the CYP3A5 selectivity of clobetasol. Our results provide a structural basis for selective CYP3A5 inhibition, along with mechanistic insights, and highlight clobetasol as an important chemical tool for target validation.

EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP.

Remyelination in the adult brain relies on the reactivation of the Neuronal Precursor Cell (NPC) niche and differentiation into Oligodendrocyte Precursor Cells (OPCs) as well as on OPC maturation into myelinating oligodendrocytes (OLs). These two distinct phases in OL development are defined by transcriptional and morphological changes. How this differentiation program is controlled remains unclear. We used two drugs that stimulate myelin basic protein (MBP) expression (Clobetasol and Gefitinib) alone or combined with epidermal growth factor receptor (EGFR) or Retinoid X Receptor gamma (RXRγ) gene silencing to decode the receptor signaling required for OPC differentiation in myelinating OLs. Electrospun polystyrene (PS) microfibers were used as synthetic axons to study drug efficacy on fiber engagement. We show that EGFR inhibition per se stimulates MBP expression and increases Clobetasol efficacy in OPC differentiation. Consistent with this, Clobetasol and Gefitinib co-treatment, by co-regulating RXRγ, MBP and phosphatidylinositol 4,5-bisphosphate (PIP2) levels, maximizes synthetic axon engagement. Conversely, RXRγ gene silencing reduces the ability of the drugs to promote MBP expression. This work provides a view of how EGFR/ErbB inhibition controls OPC differentiation and indicates the combination of Clobetasol and Gefitinib as a potent remyelination-enhancing treatment.

Development of Halobetasol-loaded nanostructured lipid carrier for dermal administration: Optimization, physicochemical and biopharmaceutical behavior, and therapeutic efficacy.

Halobetasol propionate (HB) is considered a super potent drug in the group of topical corticosteroids. HB has anti-inflammatory activity, vasoconstriction properties, and due to its high skin penetration, it can cause systemic side effects. To improve its characteristics, enhance topical effectiveness and reduce penetration to systemic circulation, a study to optimize and characterize a HB-loaded lipid nanocarrier (HB-NLC) has been made by high-pressure homogenization method. The formulation is composed by HB, surfactant, glyceryl distearate and capric glycerides. The optimized HB-NLC containing 0.01% of HB and 3% of total lipid shows an average size below 200 nm with a polydispersity index ≪0.2 and an encapsulation efficiency ≫90%. The in vitro and in vivo tests indicate that the HB-NLC is not toxic, is well tolerated and has an anti-inflammatory effect because they decrease the production of Interleukins in keratinocytes and monocytes. HB-NLC is considered an alternative treatment for skin inflammatory disorders.

Study of the potential adverse effects caused by the dermal application of Dillenia indica L. fruit extract standardized to betulinic acid in rodents.

This study aimed to evaluate the potential adverse effects of the dermal administration of Dillenia indica Linnaeus (D. indica) fruit extract in healthy rodents; the extract was standardized to betulinic acid. In the initial phase, the acute effects were evaluated on the skin application site of a single extract dose. A skin irritation test was performed in male Wistar rats (n = 8/group) receiving the extract (50-150 mg/mL) with betulinic acid (0.5-1.5%, respectively). A photosensitivity test was performed in male BALB/c mice (n = 6/group) receiving the extract (150 mg/mL). Afterwards, other BALB/c mice (n = 20, male:female, 1:1) were used to assess the systemic alterations caused by 14 daily repeated doses (150 mg/mL) by monitoring the effects on mortality, body morphology, behavior, nutrition status, neuromotor reactions, organ morphology and weight, and blood tests. At this time, 0.5 mg/mL clobetasol was used as the positive control. The skin irritation index suggested that negligible skin irritation had occurred, even when the extract was applied to the rat skin at 150 mg/mL. However, the extract acted as a photosensitizer on mouse skin, showing a photosensitizing activity close to that of 10 mg/mL 5-methoxypsoralen. Repeated doses caused no mouse mortality, aggressiveness, piloerection, diarrhea, convulsions, neuromotor alterations or nutrition status changes. The mouse organ weights did not change, and the mice did not have alterations in their blood compositions. Clobetasol caused a reduction in the mononuclear leukocyte numbers. In general, the data suggest that the extract was safe in healthy rodents but indicate that caution should be taken with the photosensitizing activity; in addition, this activity should be further explored as it may be useful for phototherapeutic drug development.

Prurigo nodularis as a sweat gland/duct-related disorder: resolution associated with restoration of sweating disturbance.

Little attention has been given to the involvement of sweat glands/ducts in the pathogenesis of prurigo nodularis (PN). According to recent studies, PN is likely to develop under conditions characterized by dry skin, such as atopic dermatitis (AD), suggesting a strong impact of skin dryness on PN development. No therapeutic modalities produced complete resolution of PN without exacerbations. We previously reported that increases in skin dryness by sweating disturbance could initiate the development of AD. We investigated whether sweating responses were impaired in refractory PN lesions; and, if so, we asked whether the PN lesions could resolve by restoring sweating disturbance. Using the impression mold technique, which allows an accurate quantification of individual sweat gland/duct activity, we examined basal sweating under quiescent conditions and inducible sweating responses to thermal stimulus in PN lesions and normal-appearing skin in the same patients before and after treatment with a moisturizer or topical corticosteroids. Sweating disturbance, either basal or inducible, was most profoundly detected in the "hub" structure corresponding to the center of PN papule before the treatment. This sweating disturbance was immunohistochemically associated with the leakage of sweat into the dermis. This disturbance was restored by treatment with a moisturizer. Our limitations include a relatively small patient cohort and lack of blinding. Sweating disturbance could be one of the aggravating factors of PN development. Refractory PN with low skin hydration may resolve by restoring sweating disturbance.

Clobetasol Modulates Adult Neural Stem Cell Growth via Canonical Hedgehog Pathway Activation.

Sonic hedgehog (Shh) signaling is a key pathway within the central nervous system (CNS), during both development and adulthood, and its activation via the 7-transmembrane protein Smoothened (Smo) may promote neuroprotection and restoration during neurodegenerative disorders. Shh signaling may also be activated by selected glucocorticoids such as clobetasol, fluocinonide and fluticasone, which therefore act as Smo agonists and hold potential utility for regenerative medicine. However, despite its potential role in neurodegenerative diseases, the impact of Smo-modulation induced by these glucocorticoids on adult neural stem cells (NSCs) and the underlying signaling mechanisms are not yet fully elucidated. The aim of the present study was to evaluate the effects of Smo agonists (i.e., purmorphamine) and antagonists (i.e., cyclopamine) as well as of glucocorticoids (i.e., clobetasol, fluocinonide and fluticasone) on NSCs in terms of proliferation and clonal expansion. Purmorphamine treatment significantly increased NSC proliferation and clonal expansion via GLI-Kruppel family member 1 (Gli1) nuclear translocation and such effects were prevented by cyclopamine co-treatment. Clobetasol treatment exhibited an equivalent pharmacological effect. Moreover, cellular thermal shift assay suggested that clobetasol induces the canonical Smo-dependent activation of Shh signaling, as confirmed by Gli1 nuclear translocation and also by cyclopamine co-treatment, which abolished these effects. Finally, fluocinonide and fluticasone as well as control glucocorticoids (i.e., prednisone, corticosterone and dexamethasone) showed no significant effects on NSCs proliferation and clonal expansion. In conclusion, our data suggest that Shh may represent a druggable target system to drive neuroprotection and promote restorative therapies.

Glucocorticoid mixtures of fluticasone propionate, triamcinolone acetonide and clobetasol propionate induce additive effects in zebrafish embryos.

Many synthetic glucocorticoids from medical applications occur in the aquatic environment. Whether they pose a risk for fish health is poorly known. Here we investigate effects of glucocorticoids fluticasone propionate (FLU) and triamcinolone acetonide (TRI) as single steroids and as ternary mixtures with clobetasol propionate (CLO) in zebrafish embryos. Exposure to FLU and TRI in a range of concentrations between 0.099 and 120.08 µg/L led to concentration-related decrease in muscle contractions and increase in heart rate at 0.98 and 1.05 µg/L, respectively, and higher. Genes encoding for proteins related to glucose metabolism (g6pca, pepck1), immune system regulation (fkbp5, irg1l, socs3, gilz) and matrix metalloproteinases mmp-9 and mmp-13 showed expressional alterations, as well as genes encoding for the progestin receptor (pgr) and corticosteroid dehydrogenase (hsd11b2). FLU accelerated hatching and led to embryotoxicity (immobilization and edema). Ternary mixtures (FLU + TRI + CLO) induced the same physiological and toxicological effects at concentrations of individual glucocorticoids of 11.1-16.37 µg/L and higher. Heart rate was increased in the mixture at concentrations as low as 0.0885-0.11 µg/L of each steroid. Glucocorticoids in mixtures showed additive activity; the fold-changes of transcripts of 19 target genes were additive. Together, our data show that glucocorticoids act additively and their joint activity may be of concern for developing fish in contaminated environments.

Assessing the Synergistic Effect of a Fixed Combination Halobetasol Propionate 0.01% and Tazarotene 0.045% Lotion in Moderate-to-Severe Plaque Psoriasis

Background: Fixed combinations are commonplace in dermatology, providing significant efficacy and tolerability benefits. In some cases, two active ingredients complement each other providing a cumulative or additive effect. In rarer cases, a synergistic effect may be seen where the sum of the two active ingredients combined action is greater than the sum of the efficacy of the constituent parts. Objective: To determine whether a novel halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) fixed combination lotion provides a synergistic effect in the treatment of moderate-to-severe plaque psoriasis. Methods: Post hoc analysis of 212 patients with moderate-to-severe plaque psoriasis randomized (2:2:2:1) to HP/TAZ lotion, HP, TAZ or vehicle once-daily for 8 weeks, with a 4-week posttreatment follow-up. Treatment success was evaluated based on two outcomes: percent of patients achieving at least a 2-grade improvement in Investigator Global Assessment (IGA) and IGA score equating to 'clear' or 'almost clear'; and percent change from baseline in the IGAxbody surface area (BSA) score, an alternative to assessing response to therapy that is more sensitive to area change than the Psoriasis Area Severity Index (PASI). In addition, a clinically meaningful outcome was reported in patients who achieved a 75% reduction in IGAxBSA. Synergy was established when the benefit of combination HP/TAZ lotion was greater than benefit of HP plus TAZ, with a ratio (HP/TAZ divided by HP+TAZ) >1.0. Results: HP/TAZ lotion was synergistic at week 8, and four weeks posttreatment. At week 8, treatment success with HP/TAZ lotion relative to vehicle was 42.8% compared with 32.5% for HP plus TAZ (ratio 1.3); and percent change from baseline in IGAxBSA score relative to vehicle was 51.6% compared with 40.6% for HP plus TAZ (ratio 1.3). At week 12, treatment success with HP/TAZ lotion relative to vehicle was 31.3% compared with 20.0% for HP plus TAZ (ratio 1.6). Percent change from baseline in IGAxBSA score relative to vehicle was 47.3% compared with 34.2% for HP plus TAZ (ratio 1.4). HP/TAZ lotion also provided synergistic benefits in terms of achieving a clinically meaningful outcome, with a ratio of 1.3 and 2.0 at weeks 8 and 12. Conclusions: Halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) fixed combination lotion provides a synergistic benefit in the treatment of moderate-to-severe plaque psoriasis. In addition, by combining two agents into one once-daily formulation, this novel formulation reduces the number of product applications and may help patient adherence. J Drugs Dermatol. 2019;18(3):279-284.

Halobetasol 0.01%/Tazarotene 0.045% Lotion in the Treatment of Moderate-to-Severe Plaque Psoriasis: Maintenance of Therapeutic Effect After Cessation of Therapy.

BACKGROUND: Psoriasis is a chronic, immune-mediated disease that varies widely in its clinical expression. Topical corticosteroids (TCS) are the mainstay of treatment. Long-term safety remains a concern, limiting use, and posttreatment flare is common. Tazarotene has also been shown to be effective in psoriasis, with efficacy maintained several weeks posttreatment. Fixed combination therapy with TCS and tazarotene may improve psoriasis signs and minimize posttreatment flare or rebound. OBJECTIVE: To investigate the maintenance of effect posttreatment with a once-daily application of halobetasol propionate 0.01%/tazarotene 0.045% (HP/TAZ) lotion in comparison with its active ingredients and vehicle in patients with moderate-to-severe plaque psoriasis. METHODS: Multicenter, randomized, double-blind, vehicle-controlled Phase 2 study in moderate or severe psoriasis (N=212). Patients randomized (2:2:2:1 ratio) to receive HP/TAZ, individual active ingredients, or vehicle, once-daily for 8 weeks with a 4-week posttreatment follow-up. Efficacy assessments included treatment success (defined as at least a 2-grade improvement from baseline in the IGA score, and 'clear' or 'almost clear'), and impact on individual signs of psoriasis (erythema, plaque elevation, and scaling) at the target lesion. RESULTS: At the end of the 4-week posttreatment period, 38.2% of patients who had been treated with HP/TAZ were treatment successes; compared with 21.0%, 12.8% and 6.9% of patients who had been treated with HP (P=0.042), TAZ (P=0.004), or vehicle (P=0.002). HP/TAZ lotion was also superior in maintaining reductions in psoriasis signs of erythema, plaque elevation, and scaling at the target lesion. At the end of the 4-week posttreatment period, 49.1%, 54.5%, and 54.5% of patients, respectively, were treatment successes: compared with 38.7% (P=0.26), 48.4% (P=0.51), and 48.4% (P=0.51) of patients who had been treated with HP; 29.8% (P=0.049), 31.9% (P=0.022), and 23.4% (P=0.001) who had been treated with TAZ; and 13.8% (P=0.002), 20.7% (P=0.003), and 20.7% (P=0.003) who had been treated with vehicle. Side effects were minimal and tended to resolve during the posttreatment period. CONCLUSIONS: In conclusion, HP 0.01%/TAZ 0.045% lotion provides synergistic efficacy following 8 weeks' therapy that is sustained after a 4-week posttreatment period. J Drugs Dermatol. 2018;17(7):723-726.

Pre-clinical evaluation of novel mucoadhesive bilayer patches for local delivery of clobetasol-17-propionate to the oral mucosa.

Oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS) are chronic inflammatory conditions often characterised by erosive and/or painful oral lesions that have a considerable impact on quality of life. Current treatment often necessitates the use of steroids in the form of mouthwashes, creams or ointments, but these are often ineffective due to inadequate drug contact times with the lesion. Here we evaluate the performance of novel mucoadhesive patches for targeted drug delivery. Electrospun polymeric mucoadhesive patches were produced and characterised for their physical properties and cytotoxicity before evaluation of residence time and acceptability in a human feasibility study. Clobetasol-17-propionate incorporated into the patches was released in a sustained manner in both tissue-engineered oral mucosa and ex vivo porcine mucosa. Clobetasol-17 propionate-loaded patches were further evaluated for residence time and drug release in an in vivo animal model and demonstrated prolonged adhesion and drug release at therapeutic-relevant doses and time points. These data show that electrospun patches are adherent to mucosal tissue without causing tissue damage, and can be successfully loaded with and release clinically active drugs. These patches hold great promise for the treatment of oral conditions such as OLP and RAS, and potentially many other oral lesions.

Effect of Different Skin Penetration Promoters in Halobetasol Propionate Permeation and Retention in Human Skin.

Halobetasol propionate (HB) is a potent synthetic corticosteroid used against inflammatory skin diseases, such as dermatitis, eczema, and psoriasis, among others. The aim of this study is to define how the presence of different skin penetration enhancers (nonane, menthone, limonene, azone, carene, decanol, linoleic acid and cetiol) affects the penetration and retention in skin of HB. To determine drug penetration through skin, 5% of each promoter was used in an ex vivo system with human skin on Franz cells. The results showed that the highest permeation occurs in the presence of menthone, followed by nonane. Permeation parameters were determined. The in vivo test was assessed, and the formulation containing HB-menthone presented better anti-inflammatory efficacy. These results are useful to generate a specific treatment according to each patient's needs, and the inflammatory characteristics of the disease.

A Randomized, Double-Blind, Placebo-Controlled Study of the Vasoconstrictor Potency of Topical 0.25% Desoximetasone Spray: A High to Super High Range of Potency (Class I to Class II) Corticosteroid Formulation.

BACKGROUND: Topical corticosteroids offer great efficacy in controlling a wide variety of dermatoses. Traditional ointment vehicles are messy and difficult to apply, which might limit adherence. Alternative vehicle formulations such as topical sprays might improve adherence due to their ease of application. The potency of desoximetasone spray is not fully characterized. OBJECTIVE: To evaluate the relative vasoconstrictive potency of desoximetasone 0.25% topical spray formulation. METHODS: This is a randomized, blinded, single-center study comparing the vasoconstrictive properties of desoximetasone 0.25% topical spray to placebo and seven other known potency topical corticosteroid formulations. The primary endpoint was the degree of vasoconstriction measured using a colorimeter device. RESULTS: Thirty-two healthy subjects met eligibility criteria. Desoximetasone 0.25% topical spray (REGWQ Grouping = A) showed a trend toward greater vasoconstrictive potency compared to clobetasol propionate 0.05% spray (REGWQ Grouping = A). No adverse or serious events were reported. LIMITATIONS: The trial enrolled 90% females, which may affect the external validity of the study. Different populations may respond differently to desoximetasone spray. CONCLUSIONS: Desoximetasone 0.25% topical spray is a high to super high range of potency (Class I to Class II) steroid formulation. Given the cosmetic acceptability of spray products, we anticipate that this type of product would be highly effective for the treatment of inflammatory diseases in clinical practice.

J Drugs Dermatol. 2017;16(10):972-975.

Effects of glucocorticoids on stratum corneum lipids and function in human skin-A detailed lipidomic analysis.

BACKGROUND: Topical glucocorticoids (GCs) are known to induce atrophy of human skin including thinning of epidermal and dermal compartments by influencing keratinocyte proliferation and synthesis of extracellular matrix proteins. GCs are also known to reduce skin barrier integrity but little is known about the changes in lipid composition in human skin following topical administration of GCs. OBJECTIVE: This study investigated the effects of GCs on stratum corneum (SC) function and lipid profile of human skin in vivo. METHOD: Over a period of 4 weeks, 16 healthy volunteers were treated on the forearms once daily with topical clobetasol proprionate (CP), betamethasone diproprionate (BDP) or vehicle. One day after last application (Day 29) SC lipids were collected by tape stripping and analysed by a high sensitivity liquid chromatography-mass spectrometry method. Gene expression was analysed in skin biopsies. The full skin, epidermal and SC thickness were assessed by ultrasound, optical coherence tomography and confocal microscopy, respectively, and barrier integrity was assessed by measuring transepidermal water loss (TEWL). RESULTS: Compared to vehicle controls, GCs induced significant alterations in SC lipid profiles. CP caused a reduction in 98 lipids of 226 analysed while BDP treatment only resulted in a significant change of 29 lipids. Most pronounced changes occurred among long chain, ester-linked, ceramide classes while other ceramide classes were much less affected. Almost the complete profile of triacylglycerols (TGs) was significantly decreased by CP while more modest changes were observed in free fatty acids. Topical GCs reduced the thickness of skin layers and increased TEWL. GC treatment also induced changes in expression of genes coding for extracellular markers and enzymes involved in lipid synthesis. CONCLUSIONS: This study shows a reduction in specific SC lipid classes following topical GC treatment of human skin and contributes to the characterisation of the barrier disruption in human skin induced by topical steroids.

In vivo characterization of structural changes after topical application of glucocorticoids in healthy human skin.

Topical glucocorticoids (GC) are known to induce changes in human skin with the potential to develop skin atrophy. Here, atrophogenic effects and subsequent structural changes in the skin after topical application of GC were investigated in vivo. Sixteen healthy volunteers were topically treated daily on the forearms with clobetasol propionate, betamethasone dipropionate, and the petrolatum vehicle for 4 weeks. All treated skin areas and a nontreated control area were examined by ultrasound, optical coherence tomography, confocal laser scanning microscopy, multiphoton tomography (MPT), and resonance Raman spectroscopy at baseline 1 day after last application and 1 week after last application. Investigated parameters included stratum corneum thickness, epidermal, and full skin thickness, keratinocyte size and density, keratinocyte nucleus-to-cytoplasm ratio, skin surface classification, relative collagen and elastin signal intensity, second-harmonic generation-to-autofluorescence aging index of dermis (SAAID), and the antioxidant status of the skin. A reduction in epidermal and dermal skin thickness was observed in GC treated as well as in vehicle-treated and untreated skin areas on the volar forearm. MPT analysis showed an increased epidermal cell density and reduced cell size and nucleus-to-cytoplasm ratio and a significant increase of SAAID after GC treatment indicating a restructuring or compression of collagen fibers clinically being observed as atrophic changes.