Advances in Topical Management of Adolescent Facial and Truncal Acne: A Phase 3 Pooled Analysis of Safety and Efficacy of Trifarotene 0.005% Cream.

PURPOSE: Acne vulgaris is very common among adolescents and young adults. It is important for clinicians who provide care to these patients to have a plan of action for assessing and managing acne in daily practice. METHODS: Post-hoc analysis of two large-scale phase 3 pivotal trials of trifarotene 0.005% cream, focusing on efficacy, safety, and tolerability in the subgroup of subjects aged 12 to 17, inclusive. RESULTS: Trifarotene was effective and well tolerated on both the face and trunk in patients ages 12-17 with moderate acne. There was a low and acceptable rate of adverse events and tolerability was favorable. CONCLUSIONS: Trifarotene monotherapy was associated with good clinical efficacy, safety, and tolerability. Once-daily application offers convenience for patients, and the low concentration of trifarotene makes it well-suited to use on large skin areas such as the trunk. J Drugs Dermatol. 2022;21(6):582-586. doi:10.36849/JDD.6778.

Remyelination in humans due to a retinoid-X receptor agonist is age-dependent.

Remyelination efficiency declines with advancing age in animal models, but this has been harder to demonstrate in people with multiple sclerosis. We show that bexarotene, a putatively remyelinating retinoid-X receptor agonist, shortened the visual evoked potential latency in patients with chronic optic neuropathy aged under 42 years only (with the effect diminishing by 0.45 ms per year of age); and increased the magnetization transfer ratio of deep gray matter lesions in those under 43 years only. Addressing this age-related decline in human remyelination capacity will be an important step in the development of remyelinating therapies that work across the lifespan.

A Clinician's Guide to Topical Retinoids.

Retinoids are defined as molecules that bind to and activate retinoic acid receptors to influence the proliferation and differentiation of cells. Topical retinoids have evolved over the past several decades, being used in multiple dermatological conditions. This review aims to differentiate between synthetic and natural retinoids, discuss the pharmacology behind topical retinoids, highlight clinical applications, and categorize all the commercially available agents, including combination products. Understanding retinoid affinities for unique receptor subtypes can impact clinical decisions, resulting in optimizing treatment and enhancing patient adherence.

Management of Acne Vulgaris: A Review.

IMPORTANCE: Acne vulgaris is an inflammatory disease of the pilosebaceous unit of the skin that primarily involves the face and trunk and affects approximately 9% of the population worldwide (approximately 85% of individuals aged 12-24 years, and approximately 50% of patients aged 20-29 years). Acne vulgaris can cause permanent physical scarring, negatively affect quality of life and self-image, and has been associated with increased rates of anxiety, depression, and suicidal ideation. OBSERVATIONS: Acne vulgaris is classified based on patient age, lesion morphology (comedonal, inflammatory, mixed, nodulocystic), distribution (location on face, trunk, or both), and severity (extent, presence or absence of scarring, postinflammatory erythema, or hyperpigmentation). Although most acne does not require specific medical evaluation, medical workup is sometimes warranted. Topical therapies such as retinoids (eg, tretinoin, adapalene), benzoyl peroxide, azelaic acid, and/or combinations of topical agents are first-line treatments. When prescribed as a single therapy in a randomized trial of 207 patients, treatment with tretinoin 0.025% gel reduced acne lesion counts at 12 weeks by 63% compared with baseline. Combinations of topical agents with systemic agents (oral antibiotics such as doxycycline and minocycline, hormonal therapies such as combination oral contraception [COC] or spironolactone, or isotretinoin) are recommended for more severe disease. In a meta-analysis of 32 randomized clinical trials, COC was associated with reductions in inflammatory lesions by 62%, placebo was associated with a 26% reduction, and oral antibiotics were associated with a 58% reduction at 6-month follow-up. Isotretinoin is approved by the US Food and Drug Administration for treating severe recalcitrant nodular acne but is often used to treat resistant or persistent moderate to severe acne, as well as acne that produces scarring or significant psychosocial distress. CONCLUSIONS AND RELEVANCE: Acne vulgaris affects approximately 9% of the population worldwide and approximately 85% of those aged 12 to 24 years. First-line therapies are topical retinoids, benzoyl peroxide, azelaic acid, or combinations of topicals. For more severe disease, oral antibiotics such as doxycycline or minocycline, hormonal therapies such as combination oral conceptive agents or spironolactone, or isotretinoin are most effective.

50 Years of Topical Retinoids for Acne: Evolution of Treatment.

Since the US Food and Drug Administration (FDA) approved tretinoin in 1971, retinoids alone or combined with other agents have become the mainstay of acne treatment. Retinoids act through binding to retinoic acid receptors, altering expression levels of hundreds of cellular proteins affecting multiple pathways involved in acne pathogenesis. Retinoids have evolved from first-generation agents, such as tretinoin, through chemical modifications resulting in a second generation (etretinate and acitretin for psoriasis), a third generation (adapalene and tazarotene) and, most recently, a fourth (trifarotene). For all topical retinoids, local irritation has been associated with poor tolerability and suboptimal adherence. Efforts to improve tolerability have utilized novel delivery systems and/or novel agents. This qualitative literature review summarizes the evolution of the four topical single-agent retinoids available for the treatment of acne in the US today and their various formulations, presenting the rationale behind their development and data from key studies.

Trifarotene for the Treatment of Facial and Truncal Acne.

OBJECTIVE: This article reviews clinical trials to assess the efficacy, safety, and clinical application of trifarotene 0.005% cream (Aklief). DATA SOURCES: A systematic review of the literature was performed using the terms trifarotene OR Aklief OR CD5789 in MEDLINE (PubMed) and EMBASE databases. Articles prior to May 2020 were considered for inclusion. Bibliographies and ClinicalTrials.gov were also searched to identify further studies. STUDY SELECTION AND DATA EXTRACTION: Relevant English language and human studies related to pharmacology, clinical trials, and safety were considered. DATA SYNTHESIS: In the 52-week phase III trial, treatment success rates for facial acne (Investigator Global Assessment [IGA] rating of no or almost no acne) and truncal acne (Physician's Global Assessment [PGA] rating of no or almost no acne) were 65.1% and 66.9%, respectively. Overall success rates (IGA and PGA success in the same patient) were 57.9%; 52.8% of patients had a Dermatology Quality of Life Index score of 0 or 1, compared with 22.6% at baseline. Trifarotene was well tolerated, with pruritus, irritation, and sunburn as the most common adverse effects. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Trifarotene is a newly Food and Drug Administration-labeled fourth-generation topical retinoid that shows particular promise in the treatment of facial and truncal acne vulgaris. It is an effective and safe addition to currently available retinoids. CONCLUSION: Trifarotene is effective and safe for treatment of facial and truncal acne. Future trials should compare its efficacy and tolerability with that of the older, clinically established retinoids. Despite efficacy, cost may be a prohibitive factor.

Topical Over-the-Counter Antiaging Agents: An Update and Systematic Review.

Over-the-counter antiaging formulations aim to prevent or minimize the signs of aging skin, and to maintain the benefits obtained from different cosmetic procedures. Even though a huge selection of such products is available on the market, evidence and good clinical practice of the data supporting their use are oftentimes lacking. In this systematic review, the authors reviewed scientific data available in the published literature on the most common ingredients used in antiaging cosmetics, with a particular focus on in vivo studies.

Hydroquinone: myths and reality.

Hydroquinone has pharmacological uses in disorders of pigmentation because of its ability to competitively inhibit the enzyme tyrosinase. Our contemporary review presents the strongest evidence supporting the use of hydroquinone with the most effective and tolerable formulations combining hydroquinone, retinoid and corticosteroid (modified Kligman formula or 'triple combination cream'). The risk of exogenous ochronosis is low if prescribed concentrations of ≤ 5 for a limited period with regular monitoring. Dermatologists should reassure patients that with controlled use, hydroquinone can be well-tolerated and safe for a range of hyperpigmentary conditions.

Preventive action of retinoids in metabolic syndrome/type 2 diabetic rats fed with citrus functional food enriched in ß-cryptoxanthin.

Citrus fruits are known for their beneficial health effects associated with the prevention of metabolic syndrome/type 2 diabetes that is mainly attributed to flavonoids. Few investigations have reported the potential anti-diabetic effects of retinoids from the bioconversion of ß-cryptoxanthin (bcx), a citrus carotenoid. Therefore, the present study explored the anti-diabetic effect of a citrus functional food, obtained by membrane eco-technology of a citrus clementina juice, especially enriched in bcx but also in flavonoids and pectin. We assessed the in vivo effect of citrus bcx absorption and its bioconversion into retinoids in metabolic syndrome/type 2 diabetic fructose rats. Fructose-fed rats were used as a prediabetic control, and a prediabetic group was treated with the citrus concentrate for 8 weeks. The citrus-based food treatment improved glucose tolerance, dyslipidemia and blood pressure, in prediabetic rats. Although these effects were in part due to the synergy between enriched phytonutrients (bcx, hesperidin, pectin) of the citrus matrix, the role of bcx and its bioconversion into retinoids were highlighted. We showed that prediabetic rats absorbed less bcx and the bioconversion was less efficient. Bcx from citrus-based food was able to restore vitamin A status in prediabetic rats suggesting that the absorption/bioconversion of bcx may have a key role in improvement of metabolic syndrome/type 2 diabetes.

Identification and verification immune-related regulatory network in acne.

Acne is a common inflammatory skin disease with the dysregulation of innate and adaptive immunity. However, the underlying mechanism of acne has not been completely elucidated. In this study, we identified gene signatures and the immune-related regulatory network in acne using integrated bioinformatics methods. Here, 303 Differentially expressed genes (DEGs) and 28 Hub genes were identified in acne (GSE53795 and GSE108110), which were associated with the inflammation-related signaling pathway. Subsequently, the CIBERSORT algorithm revealed the increased proinflammatory cells in acne. Moreover, we identified 3 kinases (FGR, HCK and LYN) and 2 transcription factors (TFs) (IRF8 and ZBTB16) from DEGs as the key genes, which regulated immune cell infiltration via targeting immune-related genes in acne. The upregulated 3 kinases (FGR, HCK and LYN) and IRF8, and the downregulated ZBTB16 were also confirmed in GSE6475 and in Acne mice. Based on the expression levels of these key genes, the tissues could be divided into 2 clusters using consensus cluster analysis. GSEA analysis showed that inflammation-related signaling pathways significantly enriched in cluster 2, indicating the important role of kinase and TFs on immune regulation in acne. Finally, we found that isotretinoin and trifarotene (CD5789) treatment repressed the expression of immune genes but not the expression of the kinases and TFs, indicating that kinases and TFs may be novel therapeutic target for acne. In conclusion, 3 kinases and 2 TFs were identified and validated as key regulators in the immune-related regulatory networks in acne, providing a more comprehensive understanding and novel therapeutic targets of acne.

Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine.

Retinoids regulate a wide spectrum of cellular functions from the embryo throughout adulthood, including cell differentiation, metabolic regulation, and inflammation. These traits make retinoids very attractive molecules for medical purposes. In light of some of the physicochemical limitations of retinoids, the development of drug delivery systems offers several advantages for clinical translation of retinoid-based therapies, including improved solubilization, prolonged circulation, reduced toxicity, sustained release, and improved efficacy. In this Review, we discuss advances in preclinical and clinical tests regarding retinoid formulations, specifically the ones based in natural retinoids, evaluated in the context of regenerative medicine, brain, cancer, skin, and immune diseases. Advantages and limitations of retinoid formulations, as well as prospects to push the field forward, will be presented.

Retinoic acid receptor-targeted drugs in neurodegenerative disease.

INTRODUCTION: Neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by progressive neuronal loss and currently lack effective treatments that block the degenerative process. It has been suggested that retinoids, a class of vitamin A-derived compounds, may hold potential as future therapeutics for these disorders. AREAS COVERED: In this review, we explore the role of retinoids in modulating various signaling pathways in the brain which influence pathologically relevant processes such as cellular differentiation, immune and antioxidant response, neurite outgrowth and neurite regeneration. These actions are predominantly mediated by the retinoic acid receptors and we discuss the developmental history of ligands for these receptors, assessing how refinements in receptor binding specificity and improved pharmacokinetic properties may influence the management of off-target effects. EXPERT OPINION: New approaches to understanding retinoid's mechanisms of action, including non-genomic pathways, and how these mechanisms interact may prove vital in the development of future retinoid-based neurodegenerative disease treatments.