Technical approaches to select high-performance instant skin smoothing formulations: Correlation of in vitro and in vivo assessment methods.

BACKGROUND: Contractile films that smooth the surface of skin upon drying are popular among consumers due to their "instant" effect and perceivable smoothing benefits. The objective of our study was to correlate an in vitro measurement of contractile force with in vivo smoothing performance, thereby enabling rapid screening of film-forming technologies for impactful cosmetic results. METHODS: We introduce and characterize an in vitro method to measure drying stress of film-containing formulations. This method is used to measure the drying stresses of seven different cosmetic film formulations. We then evaluate these formulas in a blinded clinical study, measuring their effect on under-eye and Crow's Feet area smoothing through bioinstrumentation (3D PRIMOS imaging) and blinded expert grading of images. RESULTS: The in vitro drying stress measurement was found to be repeatable and sensitive enough to detect differences between formulations with typical amounts of film-forming agents. Significant correlation was found between the in vitro drying stress measurements and under-eye smoothing measured by 3D imaging (R2  = 0.71). Expert grading confirmed that film formulas deliver perceivable smoothing in the under-eye and Crow's Feet regions 15 minutes after application. CONCLUSION: The in vitro method described here can be used to predict the efficacy of formulations that deliver smoothing benefits to consumers. For consumer use, the esthetic properties of a formula should be balanced with film performance, guided by this model which predicts skin smoothing efficacy.

Cost-Effectiveness of Targeted Pharmacotherapy for Moderate to Severe Plaque Psoriasis.

BACKGROUND: Newer classes of targeted drugs for moderate to severe plaque psoriasis are more effective and more expensive than older classes, posing a difficult and potentially costly decision about whether to use them as initial targeted treatments. OBJECTIVE: To estimate the clinical and economic outcomes of initial targeted treatment for the following drugs: adalimumab, etanercept, and infliximab (TNFα inhibitors); apremilast (PDE4 inhibitor); ustekinumab (IL-12/23 inhibitor); and ixekizumab, secukinumab, and brodalumab (IL-17 inhibitors). METHODS: We developed a Markov model to simulate patient outcomes as measured by quality-adjusted life-years (QALYs) and health care costs over a 10-year period. We assumed that patients who fail initial targeted treatment either proceed to subsequent therapy or discontinue targeted treatment. Effectiveness estimates for initial treatment were defined as improvement in Psoriasis Area and Severity Index (PASI) from baseline and derived from a 2018 network meta-analysis. Wholesale acquisition drug costs were discounted by a class-specific, empirically derived rebate percentage off of 2016 costs. We conducted one-way and probabilistic sensitivity analyses to assess uncertainty in results. RESULTS: The incremental benefits compared with no targeted treatment were, in descending order: ixekizumab 1.68 QALYs (95% credible range [CR] = 1.11-2.02), brodalumab 1.64 QALYs (95% CR = 1.08-1.98), secukinumab 1.51 QALYs (95% CR = 1.00-1.83), ustekinumab 1.43 QALYs (95% CR=0.94-1.74), infliximab 1.27 QALYs (95% CR = 0.89-1.55), adalimumab 1.15 QALYs (95% CR = 0.76-1.44), etanercept 0.97 QALYs (95% CR = 0.61-1.25), and apremilast 0.87 QALYs (95% CR = 0.52-1.17). Costs of care without targeted treatment totaled $66,451, and costs of targeted treatment ranged from $137,080 (apremilast) to $255,422 (ustekinumab). Probabilistic sensitivity analysis results indicated that infliximab and apremilast are likely to be the most cost-effective initial treatments at willingness-to-pay thresholds around $100,000 per QALY, while IL-17 drugs are more likely to be cost-effective at thresholds approaching $150,000 per QALY. Acquisition cost of the initial targeted drug and utility of clinical response were the most influential parameters. CONCLUSIONS: Our findings suggest that initial targeted treatment with IL-17 inhibitors is the most effective treatment strategy for plaque psoriasis patients who have failed methotrexate and phototherapy. Apremilast, brodalumab, infliximab, ixekizumab, and secukinumab are cost-effective at different willingness-to-pay thresholds. Additional research is needed on whether the effectiveness of targeted agents changes when used after previously targeted agents. DISCLOSURES: Funding for this study was contributed by the Institute for Clinical and Economic Review (ICER). Ollendorf, Chapman, Pearson, and Kumar are current employees, and Loos and Liu are former employees, of ICER, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California HealthCare Foundation. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Alnylam, AstraZeneca, Blue Shield of California, Cambia Health Solutions and MedSavvy, CVS Caremark, Editas, Express Scripts, Genentech, GlaxoSmithKline, Harvard Pilgrim Health Care, Health Care Service Corporation, OmedaRx, United Healthcare, Johnson & Johnson, Kaiser Permanente, Premera Blue Cross, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Lilly, Humana, Prime Therapeutics, Sanofi, and Spark Therapeutics. Linder owns stock in Amgen, Biogen, and Eli Lilly; has contingent value rights in Sanofi Genzyme (related to alemtuzumab for multiple sclerosis); has received grant support from Astellas Pharma not related to this study and Clintrex, which was supported by AstraZeneca on an unrelated topic; and has received an honorarium from the Society of Healthcare Epidemiology of America (SHEA) as part of the SHEA Antimicrobial Stewardship Research Workshop Planning Committee, an educational activity supported by Merck. No other authors have potential conflicts of interest.

Mechanistic and pharmacological assessment of murine IL-23 mediated psoriasiform dermatitis; implications for drug discovery.

BACKGROUND: Animal models of Psoriasis (PsO) are important for our understanding of the pathophysiology of human disease but rarely manifest all features of the disease. In order to facilitate greater understanding of the underlying biology of PsO it is key that we understand the strengths and limitations of models used. OBJECTIVE: While humanized mouse models are available for PsO they remain technically challenging, expensive, require prolonged timelines and require a continued source of human tissue. Another approach is to focus on developing mechanistic models which recapitulate key features of human PsO. The role of the IL-23/IL-17 pathway as a key driver of human PsO is both well characterized and clinically validated. The goal of this manuscript is to provide a comprehensive disease and pharmacological assessment of IL-23 driven skin inflammation and its similarity to human psoriatic skin. METHODS: Intradermal injection of IL-23 has been used to study the IL-23 pathway in rodents, and this current study further characterizes pathology, cellular infiltrate, and gene signature kinetics, as well as the modulation of disease features by clinically relevant agents. RESULTS: Our results indicate that IL-23 triggers an early and robust activation of the immune system resulting in accumulation of T cell and monocyte/macrophage populations. It also supports changes in gene expression that parallel those observed in human PsO samples and is responsive to biologics commonly used to treat PsO in the clinic. CONCLUSIONS: Collectively, our studies indicate that a 5 day model of IL-23 psoriasiform dermatitis can be used to assess the pharmacology of novel small molecules/biologics in the treatment of PsO.

Preparation and efficacy assessment of malva nut polysaccharide for skin hydrating products.

INTRODUCTION: Scaphium scaphigerum or malva nut has long been served in Chinese medicine. However, the use of this herb in modern health care applications has, to date, been rarely reported. MATERIALS AND METHODS: Maceration of the herb in water afforded malva nut polysaccharide which was standardized. Safety and skin hydrating efficacy of the polysaccharide and products were evaluated in human volunteers. RESULTS: Malva nut polysaccharide (41.71±0.64%) having 36.58±0.51% total sugar content was isolated, with further analysis quantifying ash, carbohydrate, reducing sugar and moisture contents to be 6.05±0.00, 40.06±1.00, 12.20±0.05 and 12.64±0.31%, respectively. The polysaccharide exhibited swelling and hydrating capacities of 0.46±0.01% and 54.46±0.02g/g, with L*, a* and b* of 52.56±0.04, 9.02±0.06 and 18.42±0.03, respectively, and a viscosity of 1263.00±2.00 cps. Accelerated testing indicated the biopolysaccharide to be stable, resulting in no skin irritation in 15 human volunteers. The skin hydrating efficacy as assessed via a randomized single-blind, placebo-controlled study in 24 volunteers highlighted the superior performance of malva nut over the vehicle (moisture retainment for 70min as examined by Corneometer® CM 825). A stable skin moisturizing gel containing malva nut was developed and was shown to exhibit improved performance over benchmark tamarind and algae polysaccharide gels (after 180min observation). CONCLUSION: Malva nut polysaccharide has potential as a key ingredient in skin hydrating products, which should encourage its further development.

The importance of minipigs in dermal safety assessment: an overview.

The use of miniature swine as a non-rodent species in safety assessment has continued to expand for over a decade and their use has become routine, particularly in pharmacology as a model for human integumentary diseases. Translational preclinical swine study data are now favorably compared and contrasted to human data, and miniature swine models provide important information in dermal safety assessment and skin pharmacology. For example, the miniature swine model has been well-accepted for cutaneous absorption and toxicity studies due to swine integument being morphologically and functionally similar to human skin. Subsequently, this model is important to dermal drug development programs, and it is the animal model of choice for assessment of dermal absorption, local tolerance and systemic toxicity following dermal exposures. In conclusion, the miniature swine model has an important role to play in the safety assessment of pharmaceutical products and in multiple aspects of human dermal drug development.

Psoriasis Therapy: Breakthroughs in Pharmacogenomics or in Pharmacology?

As the cost of psoriasis therapies skyrockets, it becomes increasingly important to find biomarkers that predict which patients will respond to expensive medications. The ability to predict response to a specific therapy is particularly important for medications that are effective in only a small portion of the population. As we develop medications that clear most patients, the need for a predictive biomarker diminishes. Nevertheless, the importance of pharmacogenomics is likely to increase as the cost of drugs continues to rise.

Clinical and economic review of secukinumab for moderate-to-severe plaque psoriasis.

Secukinumab represents the first IL-17A antagonist among the available biologic therapies approved for moderate-to-severe plaque psoriasis management. Secukinumab demonstrated greater efficacy over placebo, etanercept and ustekinumab in patients that had limited benefit from non-biologic systemic therapies and phototherapy. Despite standard-of-care systemic therapies being more likely to be cost-effective at this time, a Canadian cost-utility analysis found secukinumab to display benefit in quality-of-life gains in moderate-to-severe plaque psoriasis patients, and greater cost-effectiveness when compared to other biologic systemic therapies. Determination of the true economic value of secukinumab amongst the available therapies for moderate-to-severe plaque psoriasis will require continued economic evaluation.

Assessment of in vitro antipsoriatic activity of selected Indian medicinal plants.

CONTEXT: Phyllanthus simplex Retz. (Phyllanthaceae), Crotolaria juncea Linn. (Leguminosae), Leucas aspera Linn. (Lamiaceae), and Vitex glabrata R.Br. (Verbenaceae) are well-known Indian medicinal plants. Different parts of these plants are used for healing purposes traditionally in the treatment of psoriasis and various other disorders. This prompted us to assess the antipsoriatic activities of these plants. OBJECTIVES: Petroleum ether and ethanol extracts of the selected plants, i.e., P. simplex (whole plant), C. juncea (seeds), L. aspera (aerial parts), and V. glabrata (leaves) were investigated for their in vitro antipsoriatic activity. MATERIALS AND METHODS: Antipsoriatic activity of the extracts was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, using HaCaT cells. About 200 µl of different concentrations (25, 50, 100, 200, and 400 µg/ml) of test samples were prepared in the cell culture medium and incubated for 24 h before MTT assay to determine the viable cells. The effect of these extracts on nitric oxide (NO) production and lipid peroxidation was also evaluated. RESULTS: Our findings revealed that these plants showed promising skin keratinocyte antiproliferative activity. However, the petroleum ether extract of C. juncea (CJPE) and ethanol extract of L. aspera (LAEE) were found to exhibit significant activity (IC50 value = 45.45 and 55.36 µg/ml, respectively). DISCUSSION AND CONCLUSIONS: The inhibitory action against NO production and lipid peroxidation in HaCaT cells suggested that the antipsoriatic activity of the extracts was mediated by an antioxidant mechanism. These findings validate the claims of the use of these plants in the treatment of psoriasis.

Non-invasive short-term assessment of retinoids effects on human skin in vivo using multiphoton microscopy.

BACKGROUND: The occlusive patch test developed for assessing topical retinoids activity in human skin has been extended as a short-term screening protocol for anti-ageing agents. In this model, biopsies are performed at the end of the occlusion period for morphological and immuno-histochemistry analysis. Multiphoton microscopy is a recent non-invasive imaging technique that combined with image processing tools allows the in vivo quantification of human skin modifications. OBJECTIVE: To validate with gold standards of anti-ageing that are retinoids, the relevance of multiphoton microscopy for kinetic and quantitative assessment in this model. METHODS: Twenty women, aged 50-65 years, were enrolled. Retinol 0.3% (RO) and Retinoic acid 0.025% (RA) were applied to the dorsal photo-damaged side of their forearm under occlusive patches for 12 days. A patch alone was applied to a third area as control. Evaluation was performed at day D0, D12 (end of treatment), D18 and D32 using multiphoton microscopy. Epidermal thickness, normalized area of the dermal-epidermal junction (DEJ) and melanin density were estimated using 3D image processing tools. RESULTS: Main significant results are: Epidermal thickening at D12, D18 and D32 with RO and at D12, D18 with RA vs. baseline and vs. CONTROL: Increased DEJ undulation at D32 with RO and at D12 with RA vs. baseline and vs. CONTROL: Decreased melanin content with RO (at D12 and D18 vs. baseline and at D32 vs. baseline and vs. control) and with RA (at D12 vs. baseline). CONCLUSIONS: This study shows that multiphoton microscopy associated to specific 3D image processing tools allows cutaneous effects induced by topical retinoids in this in vivo model to be non-invasively detected, quantified and followed over time. This innovative approach could be applied to the evaluation of other active compounds.

The European Medicines Agency approval of ingenol mebutate (Picato) for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults: summary of the scientific assessment of the Committee for Medicinal Products for Human Use (CHMP).

BACKGROUND: The European Commission has recently issued a marketing authorisation valid throughout the European Union for ingenol mebutate (Picato) in the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults. OBJECTIVES: The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the EU. The full scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (www.ema.europa.eu). MATERIAL & METHODS: The application was supported by 25 clinical studies, of which 18 were performed in patients with actinic keratosis. RESULTS: The active substance is a pure ingenol angelate obtained from the aerial parts of the plant species Euphorbia peplus by extraction and purification. One tube of ingenol mebutate 150 mcg/g gel or 500 mcg/g gel should be applied once daily to the affected area for 3 or 2 consecutive days on the 'face and scalp' or 'trunk and extremities', respectively. Complete response rate is 42.2% on the 'face and scalp' and 34.1% on the 'trunk and extremities'. The most common side effects are local skin responses including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration at the application site. CONCLUSIONS: The benefits of ingenol mebutate are its ability to improve the complete response rate of actinic keratosis, the short duration of treatment and the ease of self-application.

Neuromodulatory and anti-inflammatory ingredient for sensitive skin: in vitro assessment.

The manifestation of sensitive skin occurs as a consequence of increased permeability of the Stratum corneum, besides the involvement of neuro-immune-endocrine system. In this study, we evaluated the effects of an active ingredient SensC on the production of neuropeptides substance P (SP), enkephalin and ß-endorphin; eicosanoids prostaglandin E2 (PGE2) and leukotriene B4 (LTB4); histamine, transient receptor potential vanilloid subfamily member 1 (TRPV1), and envelope proteins filaggrin and involucrin, using an in vitro model of human cell culture. Our results demonstrated that treatment of keratinocyte cultures with SensC prevented the increase of all evaluated inflammatory mediators induced by interleukin-1 alpha (IL-1α). As the same way, SensC provides decrease in the synthesis of TRPV1. Regarding the synthesis of envelope proteins, SensC promoted increases for filaggrin and involucrin levels, when compared to control group. Considering the absence of appropriate treatment, the availability of ingredients, such as SensC, with antiinflammatory and protective barrier properties can be a significant tool for preventing neurosensorial symptoms associated with sensitive skin.

Cosmeceutical vehicles.

Consumers will pay a premium for high-performance skin and hair care products. The demand exists, and in return for the high cost, consumers expect the product to perform as claimed and to meet aesthetic standards beyond many products found in the mass market. To be successful in this highly competitive market, products must function as claimed or consumers will not repurchase. Effective contemporary high-end products must be properly formulated in nonirritating vehicles that consumers will perceive as elegant.

An evidence-based assessment of treatments for cellulite.

Cellulite, a skin surface change that is nearly ubiquitous in women, is a condition that remains elusive to treatment. In fact, no treatment is completely successful as none are more than mildly and temporarily effective. Despite the lack of evidence to support efficacy, treatment options continue to proliferate. This article will briefly review the currently available data about cellulite treatments including noninvasive devices such as massage, radiofrequency, and laser and light-based treatments; invasive modalities including liposuction, mesotherapy, and subcision; and other treatments including topical creams and carboxy therapy.

Patient receipt and understanding of written information provided with isotretinoin and estrogen prescriptions.

BACKGROUND: Medication guides (MG) and mandatory patient package inserts (MPPI) are required with some prescription medications. OBJECTIVE: We sought to determine how many patients receive, read, and understand these mandated materials. DESIGN AND PARTICIPANTS: A total of 3,620 patients were identified as filling prescriptions for isotretinoin or selected estrogen products from February 2004 to January 2005. Patients were surveyed to gauge receipt and understanding of the MG for isotretinoin and the MPPI for estrogen. MEASUREMENTS AND MAIN RESULTS: A total of 500 patients completed the survey, with 186 (93%) of the 200 isotretinoin patients and 258 (86%) of the 300 estrogen patients reporting receipt of the MG/MPPI with their most recent prescription. The majority of respondents reported confidence in their knowledge of their medication (86% for isotretinoin and 75% for estrogen). However, the mean score on 5 questions assessing recognition of medication risks was only slightly better than the score expected from guessing (3.1 vs 2.5, P < .01 for both isotretinoin and estrogen). CONCLUSIONS: Despite receiving the information and reporting confidence in medication knowledge, patients' understanding of major risks with these medications was poor. This finding highlights the need to develop better risk communication strategies to improve the safe and effective use of prescription medications.

Dermal microdialysis in the dog: in vivo assessment of the effect of cyclosporin A on cutaneous histamine and prostaglandin D2 release.

Dermal microdialysis, a relatively noninvasive technique, allows investigation of the changes in cellular mediators released during cutaneous allergic responses. This technique was used to evaluate the effect of cyclosporin A, an immunosuppressive drug used for treatment of canine atopic dermatitis, on the cutaneous release of two pro-inflammatory mediators following intradermal allergen challenge. Four beagle dogs spontaneously sensitized to Ascaris suum were treated for 1 month with oral cyclosporin A. At days 0, 15 and 30 of the treatment, dialysis probes were inserted into the skin of the back, and 20 microL of A. suum antigen was injected intradermally at each site. At timed intervals, dialysate was collected and assayed for histamine and prostaglandin D(2) and the wheal area was measured. Mean histamine concentration and wheal area were significantly lower at days 15 and 30 of treatment, compared with day 0. However, prostaglandin D(2) concentration was not significantly reduced. The inhibition in histamine release after intradermal challenge, by cyclosporin, confirms its anti-inflammatory action in the dog. Dermal microdialysis provides a useful tool for investigating canine allergic reactions and their modulation by drugs.

Temporary dermal scatter reduction: quantitative assessment and implications for improved laser tattoo removal.

BACKGROUND AND OBJECTIVES: Temporary dermal clearing, i.e., reduction in the attenuation coefficient of the dermis and epidermis, may lead to improved laser tattoo removal by providing increased efficiency of laser delivery to embedded ink particles and enabling the use of shorter wavelength visible lasers more effective on certain inks. STUDY DESIGNS/MATERIALS AND METHODS: In a hairless guinea pig model of human tattoo, we tested both intradermal and transdermal application of glycerol, using visual inspection, spectral analysis, and optical coherence tomography techniques to assess effectiveness. In controlled experiments, we compared the outcomes of single laser treatment sessions for both cleared and uncleared tattoo sites using Q-switched 755 and 532 nm lasers on three different inks. RESULTS: Intradermal injection of clearing agents induced dermal clearing but resulted in necrosis and scar. Transdermal application of clearing agents resulted in moderate reversible clearing, which was localized to the superficial layers of the skin and did not result in complications. Statistically significant differences in laser treatment outcome were observed relative to a number of treatment parameters including the treatment of certain tattoos by short wavelength lasers. CONCLUSIONS: Temporary clearing of superficial skin layers may be performed in an apparently safe and reliable manner. Clearing should lead to increased penetration of laser light to tattoos and should, therefore, increase treatment efficiency. Further study is needed to determine the degree to which this change is of clinical value.

Pharmaceutical and clinical assessment of hydroquinone ointment prepared by extemporaneous nonsterile compounding.

Ointments of the skin depigmentation agent hydroquinone (HQ) have been prepared by extemporaneous nonsterile compounding in Japan by imitating skin lightening creams commercially available in the U.S.A. and European Union. In our hospital, HQ ointments consisting of 5 or 10% HQ, 1.6% L(+)-ascorbic acid (AsA), 0.5% (w/w) Na2SO3, 10% (v/w) glycerin and hydrophilic ointment have been prepared. However, various problems have been observed including chromatic aberration of HQ ointments, relatively large variability of efficacy, and undesirable side effects although they were mild. Herein, the pharmaceutical and clinical properties of the HQ ointments were evaluated. HQ ointments were highly effective for treatment of various types of skin pigmentation. Chromatic aberration occurred during 3 months of storage, but this could be suppressed by storage at 4 degrees C. Chromatic aberration was independent of prescribed HQ content, and was not explained by alterations of HQ or p-benzoquinone (p-BQ) contents. Unexpectedly, removal of both antioxidants resulted in suppression of chromatic aberration, but an increase in p-BQ content. Acidification by removal of Na2SO3 only was further effective for the suppression of chromatic aberration, but with a decrease of p-BQ content except in the initial period. Chromatic aberration was due to water soluble material and insoluble material both formed by co-existence of HQ and p-BQ at a molecular ratio of 5:3 to 1:1. 1H-NMR analysis elucidated that the water soluble material was not HQ or p-BQ, and the insoluble material was a complex of HQ and p-BQ with non-covalent binding.