Adverse Pregnancy and Child Outcomes in Oral Retinoid-Exposed Pregnancies: A Nationwide Population-Based Study.

BACKGROUND: Oral retinoids are used to treat various dermatological conditions, and their use is increasing in women of childbearing age. However, there is limited knowledge on the incidence of adverse outcomes after retinoid exposure during pregnancy. We aimed to evaluate the risk of adverse outcomes associated with oral retinoid exposure during pregnancy. METHODS: We conducted a retrospective cohort study using the NHIS mother-child linked healthcare database in South Korea. We included all women who gave live birth from April 1, 2009 to December 31, 2020 and their children. The exposure was defined as having ≥ 1 prescription of isotretinoin, alitretinoin, and acitretin from one month before pregnancy to the delivery. The outcomes of interest were adverse child outcomes including major congenital malformations, low birth weight, and neurodevelopmental disorders (autism spectrum disorder and intellectual disorder), and adverse pregnancy outcomes including gestational diabetes mellitus, preeclampsia, and postpartum hemorrhage. Propensity score-based matching weights were used to control for various potential confounders. For congenital malformation, low birth weight, and adverse pregnancy outcomes, we calculated relative risk (RR) with 95% confidence interval (CI) using a generalized linear model and for neurodevelopmental disorders, we estimated hazard ratio (HR) with 95% CI using the Cox proportional hazard model. RESULTS: Of 3,894,184 pregnancies, we identified 720 pregnancies (0.02%) as the oral retinoid-exposed group. The incidence of major congenital malformation was 400.6 per 10,000 births for oral retinoid-exposed group and 357.9 per 10,000 births for unexposed group and the weighted RR was 1.10 (95% CI, 0.65-1.85) in oral retinoid-exposed group compared with unexposed group. The neurodevelopmental disorder showed a potential increased risk, with the weighted HR of 1.63 (95% CI, 0.60-4.41) for autism spectrum disorder and 1.71 (95% CI, 0.60-4.93) for the intellectual disorder, although it did not reach statistical significance. For low birth weight and adverse pregnancy outcomes, no association was observed with oral retinoid exposure during pregnancy. CONCLUSION: This study found no significantly increased risk of congenital malformations, autism spectrum disorders, and intellectual disability associated with oral retinoid exposure during pregnancy; however, given the limitations such as including only the live births and increased point estimate, potential risk cannot be fully excluded.

A review of the topical management of acne and its associated sequelae in the Asia-Pacific region with a spotlight on trifarotene.

Acne, a highly prevalent skin disease, can be particularly bothersome for patients of Asian background because of its impact on self-confidence and social interactions. In addition to active acne lesions, some patients may develop sequelae such as scarring, macular/postinflammatory hyperpigmentation, or erythema. The tendency of Asian skin to develop sequelae because of its increased susceptibility to irritation, cultural preferences for lighter skin phototypes, and differences in skincare regimens may all contribute to the increased burden of acne. Moreover, many Asia-Pacific countries do not have their own guidelines for acne management, and those that do often have no schedule in place for regular updates. In this article, we provide a critical review of the published guidance for the management of acne and its sequelae in the Asia-Pacific region, identifying gaps in current recommendations that could be addressed to enhance standards of acne care in Asia-Pacific countries. Along with highlighting the importance of a comprehensive skincare regimen to increase treatment efficacy and adherence, we discuss topical retinoids and retinoid combination options in the acne armamentarium that may be beneficial for sequelae prevention and management, such as adapalene 0.3% ± benzoyl peroxide 2.5%, tretinoin 0.05%, tazarotene 0.1%, and trifarotene 0.005%. In particular, trifarotene 0.005% has been observed to significantly reduce acne scar counts in a Phase 4 study. The recent data highlight the need to establish up-to-date guidance for acne and acne sequelae management in Asia-Pacific countries to provide optimal care to Asian patients.

Topical Treatments for Melasma and Post-inflammatory Hyperpigmentation.

BACKGROUND: Dyschromia is one of the most common reasons for patients to seek dermatological care, especially among individuals with skin of color. Most cases present as melasma or post-inflammatory hyperpigmentation (PIH); both are chronic issues requiring long-term treatment. While many pharmaceutical (topical or systemic) or procedural (lasers/chemical peels) options are available, some treatments are not safe/tolerable for long-term use or can induce/exacerbate PIH.  Methods: This qualitative review provides an overview of topical treatments for melasma and PIH, including recent data from an investigator-initiated trial of the retinoid tazarotene.  Results: Topical hydroquinone (HQ) in the form of triple combination HQ 4%/tretinoin 0.05%/fluocinolone acetonide 0.01% cream is the gold-standard treatment for melasma and PIH but should not be used long-term due to safety concerns. Efficacy data for OTC/cosmeceutical products are limited or lacking. Topical retinoids are efficacious and safe, though dose and formulation differences may affect tolerability. Tazarotene 0.045% polymeric emulsion lotion demonstrated good efficacy, safety, and tolerability over 24 weeks in adult female patients with moderate-to-severe melasma and/or PIH. CONCLUSIONS: There are multiple topical treatments available for dyspigmentation. However, many are lacking efficacy data and others are limited by tolerability or safety concerns. Retinoids, such as tazarotene, may be an efficacious and safe treatment for melasma or PIH. J Drugs Dermatol. 2023;22(11):1118-1123     doi:10.36849/JDD.7754.

Topical Treatments for Photoaged Skin.

BACKGROUND: Photoaging due to cumulative lifetime ultraviolet light exposure is the greatest contributing factor to facial aging. With the continued growth of the population of individuals aged ≥65 years and over, demand for safe and effective photoaging treatments will likely increase. METHODS: This qualitative review provides an overview of efficacy and safety of over-the-counter (OTC) and prescription topical treatments for photoaging, including recent data from an investigator-initiated trial of the topical retinoid tazarotene. RESULTS: OTC and cosmeceutical products comprise the majority of treatment options for photoaging, although clinical data in support of their efficacy are generally lacking. Topical retinoids have been shown to increase collagen and elastic fibers and normalize melanocytes and keratinocytes, yielding improvements in wrinkling, texture, elasticity, and skin tone. Prescription topical retinoids (adapalene, tazarotene, tretinoin) are the most studied and efficacious treatments for photoaging, though their use is typically associated with adverse effects such as erythema, peeling, dryness, and burning/stinging in a concentration-dependent manner. In a 12-week, open-label study, lower-dose tazarotene 0.045% lotion led to significantly reduced signs and severity of photoaging vs baseline. CONCLUSION: Prescription topical retinoids are the most potent treatment option for photoaging, though their use may be limited by irritation concerns. Tazarotene 0.045% polymeric emulsion lotion has recently demonstrated significant photoaging improvements with 12 weeks of once-daily treatment, with a favorable safety and tolerability profile. CITATION: Sadick N, Pannu S, Abidi Z, et al. Topical treatments for photoaged skin. J Drugs Dermatol. 2023;22(9):867-873. doi:10.36849/JDD.7753.

Acne characteristics in Latin American patients and the potential role of trifarotene.

BACKGROUND: Individualization of treatment based on acne type and severity, location, disease burden, and patient preference is required to maximize efficacy, safety, and adherence to therapy. Latin American populations have unique attributes that must be considered as part of this process to improve clinical success and achieve patient goals. Acne is more common among patients with darker skin phototypes, in whom it is often associated with postinflammatory hyperpigmentation and scarring-the most important acne sequelae-potentially due to more frequent and more severe underlying inflammatory processes in this population. DISCUSSION: These data argue for an early and proactive approach to managing acne in these patients with agents that target the inflammatory processes that underlie acne and its sequelae. As a class, retinoids offer a spectrum of activity that may be useful in addressing the unique needs of Latin American populations. CONCLUSION: Trifarotene, a novel, selective retinoid, has been evaluated in relevant patient populations.

A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis.

Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.

The synergistic effect of retinyl propionate and hydroxypinacolone retinoate on skin aging.

BACKGROUND: Aging is responsible for the majority of skin and soft tissue remolding in humans. Retinol and its derivatives or retinoids effectively intervene skin aging process. Nevertheless, retinoids usually induce skin intolerance, especially among the Chinese, and thus, their application to prevent skin aging is yet to be well accepted. The study of optimal composition and concentration of retinoids is necessary to offer strong antiaging efficacies with minimum irritations. Therefore, a better understanding of retinol and its derivatives is acutely needed to develop strategies to combat skin aging. OBJECTIVE: In this study, we aimed to determine the optimal ratio of two retinol derivatives-hydroxypinacolone retinoate (HPR) and retinyl propionate (RP) in terms of dermal remodeling and skin aging prevention-and to investigate their synergistic antiaging effects both in vitro and in vivo. METHODS: An in vitro human foreskin fibroblast (HFF-1) cell model was established to evaluate the cell viability of HPR and/or RP treatment. In addition, the antiaging and retinol receptor genes expressions in HFF-1 cells cotreated with HPR and RP were quantified. The in vivo adverse reaction evaluation of skincare serums containing various levels of retinol or the optimal HPR and RP combination termed Gravi-A was performed by 24 h patch tests in 33 subjects prior to the clinical research. Last but not the least, clinical research with 42 Chinese urban women was conducted to assess the in vivo antiaging efficacy of the skincare serum containing this optimal retinoid combination. RESULTS: The combination of HPR and RP at the weight ratio of 5:9 was shown to achieve the optimal in vitro antiaging performance. Coadministration of 5 µg/mL HPR and 9 µg/mL RP to HFF-1 cells promoted their proliferation at 24 h and synergistically enhanced the expressions of type IV collagen, CRBP-I, and RARB genes. In addition, the skincare serum containing HPR and RP combination at 5:9 weight ratio demonstrated superior in vivo anti-wrinkle and skin elasticity improvement benefits without any adverse reactions, while retinol in the same concentration exerted much higher adverse effect. Skin wrinkles, skin smoothness, TEWL, skin elasticity R2 and R5 were improved by 8.3%, 11.9%, 25.7%, 14.5%, and 22.6%, respectively, after 8-week use. CONCLUSION: Our results indicated the advanced antiaging effect of HPR and RP combination both in vitro and in vivo. In addition, little adverse effect was observed in this study, in comparison with retinol. This combination named as Gravi-A is a potential therapeutic strategy to prevent skin aging, especially for Chinese women.

Efficacy and Tolerability of a Retinoid Eye Cream for Fine to Moderate Wrinkles of the Periorbital Region.

INTRODUCTION: The periorbital region is susceptible to premature skin aging and among the first areas to manifest age-related changes. Retinoids are highly effective but can be irritating, limiting use in this vulnerable area. A hydrating formulation comprised of a double-conjugated retinoid/alpha hydroxy acid (lactic acid; AHARet-EM) has been developed to address photoaging of the periorbital area. This study evaluated the efficacy, tolerability, and subject satisfaction of nightly application of AHARet-EM, and a regimen that included application of a peptide-rich eye cream (InF-E; AM) and AHARet-EM (PM). DESIGN: A 12-week, dual-center, open-label study evaluated nightly application of AHARet-EM in subjects 35 to 65 years of age with fine to moderate lines/wrinkles in the periorbital area (3-7 score based on the Fitzpatrick Classification Wrinkle Scale [FCWS]). A subset of subjects applied AHARet-EM (PM) and InF-E (AM). Investigator assessments at baseline and weeks 4, 8, and 12 were based on the 9-point FCWS for lines/wrinkles (1 [Fine Wrinkles] to 9 [Deep Wrinkles]) and a 6-point scale (0 [None] to 5 [Severe]) for texture, erythema, and under-eye darkness, puffiness, and dryness. Subject satisfaction and adverse events (AEs) were captured over 12 weeks. RESULTS: Twenty-six subjects, Fitzpatrick skin type III-VI, completed the study. Subjects applying AHARet-EM (n=16) demonstrated significant improvements from baseline at week 12 in the appearance of lines/wrinkles (33%; P<.0001), texture (37%, P<.0001), erythema (37%, P=.004), under-eye darkness (41%; P<.001), puffiness (55%, P<.0001) and dryness (94%, P<.0001). Significant improvements from baseline were demonstrated in subjects using the AM/PM regimen (n=10) at week 12 in the appearance of texture (33%; P=.002), erythema (68%; P=.001), under-eye darkness (32%; P=.007), puffiness (64%; P=.01) and dryness (90%; P<.0001). No AEs occurred related/possibly related to use of the study products. High levels of subject satisfaction were reported over 12 weeks. CONCLUSION: Nightly application of a hydrating, double-conjugated retinoid eye cream demonstrated significant improvements in the appearance of lines/wrinkles, under-eye darkness, puffiness, and dryness of the periorbital area at week 12. Morning application of a peptide-rich eye cream afforded additional benefits. The study products were non-irritating, and subjects reported high levels of satisfaction throughout the study. J Drugs Dermatol. 2022;21(9):932-937. doi:10.36849/JDD.6815.

Emerging drugs for the treatment of acne: a review of phase 2 & 3 trials.

INTRODUCTION: Acne vulgaris is one of the commonest dermatoses encountered in a dermatology clinic. Although the inflammatory processes are centered around the pilosebaceous unit, a myriad of external factors that alter the pathogenesis have been hypothesized. Newer therapies are focused on targeting these as possible scaffolds for drug development. Existing topical and oral medications have considerable overlap between pharmacotherapy and cosmeceuticals directed toward acne treatment making new drug development extremely competitive and financially burdening. Teratogenicity associated with retinoids, cutaneous adverse effects of topical anti-acne medications, and lack of long-term remission induction are a few hindrances that have to be tackled by novel therapies. AREAS COVERED: Numerous topical and systemic medications for acne vulgaris are undergoing clinical trials presently. The review has dealt with anti-acne drugs undergoing phase II and III clinical trials with emphasis on the rationale of various combinations in tandem with the complex pathogenesis of the disease. EXPERT OPINION: The current strategies in new drug development target sebocyte function, neo-inflammatory mediators, and methods combatting drug resistance while broadening the anti-microbial spectrum against Cutibacterium acnes. A holistic approach is pivotal to strengthen the management protocol for acne to achieve precision dermatological practice.

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.

A systematic review of oral retinoids for treatment of acneiform eruptions induced by epidermal growth factor receptor inhibitors.

Epidermal growth factor receptor inhibitors (EGFRi) are now standard of care in patients with EGFR mutations in non-small cell lung cancer (NSCLC) and are increasingly being used in other EGFR mutated cancers, including gastrointestinal, and head and neck. However, EGFRi are well known to cause acneiform eruptions, which are shown to positively correlate with tumor response to treatment, but may be severe enough to cause interruption of their treatment. Although most guidelines call for the use of tetracyclines to treat these acneiform eruptions, there is mounting evidence for the use of systemic retinoids instead. The objective of this review is to summarize available data on the use of systemic retinoids for management of acneiform eruptions on EGFRi. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE and EMBASE were searched from database inception until December 10th, 2021. All articles were screened and relevant data extracted independently in duplicate by two reviewers. In total, 16 case reports, case series and retrospective reviews were included. Forty-three patients were treated with retinoids for their acneiform eruption due to EGFRi. The majority (77%) noted moderate to significant improvement after treatment initiation with minimal adverse events (16%). The findings of this systematic review suggest that systemic retinoids are a safe and effective therapy for the management of acneiform eruptions induced by EGFRi.

Tazarotene 0.045% Lotion: A Novel Retinoid Formulation.

OBJECTIVE: The aim of this study is to review the available data on efficacy and tolerability of tazarotene 0.045% lotion. DATA SOURCES: A literature search of MEDLINE (PubMed) and EMBASE databases was completed in November 2021. STUDY SELECTION AND DATA EXTRACTION: Articles that discussed efficacy, tolerability, and pharmacology of tazarotene 0.045% lotion, written in English and published before mid-November 2021, were assessed. DATA SYNTHESIS: In two, 12-week phase III clinical trials, tazarotene 0.045% lotion had higher rates of treatment success (study 1: 25.5% and study 2: 29.6%) than individuals who received the vehicle (study 1: 13.0% and study 2: 17.3%) (both Ps < 0.001). Participants treated with tazarotene 0.045% lotion had greater least squares mean reduction in inflammatory (study 1: 55.5% and study 2: 59.5%) and noninflammatory (study 1: 51.4% and study 2: 60%) acne lesions when compared with vehicle (inflammatory acne lesions, study 1: 45.7% and study 2:49%; noninflammatory acne lesions, study 1: 41.5% and study 2: 41.6%) (P < 0.001 for studies 1 and 2). Tazarotene 0.045% lotion was well tolerated. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Retinoids are first-line therapy in the treatment of acne vulgaris. However, many patients experience cutaneous irritation, which can decrease patient adherence and efficacy. Tazarotene 0.045% lotion is the first retinoid to utilize polymeric emulsion technology (PET) to efficiently distribute the medication across the skin, decreasing adverse effects while maintaining efficacy. CONCLUSIONS: Tazarotene 0.045% lotion is an effective and well-tolerated retinoid recently approved by the US Food and Drug Administration (FDA) for treating acne vulgaris in individuals 9 years of age and older.

A2E-induced inflammation and angiogenesis in RPE cells in vitro are modulated by PPAR-α, -ß/δ, -γ, and RXR antagonists and by norbixin.

N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing angiogenesis and inflammation. A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-α. Here we show that A2E binds and transactivates also peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR). 9'-cis-norbixin, a di-apocarotenoid is also a ligand of these nuclear receptors (NR). Norbixin inhibits PPAR and RXR transactivation induced by A2E. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-κB and AP-1 transactivation and mRNA expression of the inflammatory interleukins (IL) -6 and -8 and of vascular endothelial growth factor (VEGF) enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression in response to A2E. Selective PPAR-α, -ß/δ and -γ antagonists inhibit the expression of IL-6 and IL-8 while only the antagonist of PPAR-γ inhibits the transactivation of NF-κB following A2E exposure. In addition, a cocktail of all three PPARs antagonists and also HX531, an antagonist of RXR reproduce norbixin effects on inflammation. Altogether, A2E's deleterious biological effects could be inhibited through PPAR and RXR regulation. Moreover, the modulation of these NR by norbixin may open new avenues for the treatment of AMD.

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 and systemic retinoids for the treatment of cutaneous viral warts: A systematic review and meta-analysis.

Cutaneous viral warts (CVW), caused by human papillomavirus, often have a self-limited course. However, some patients experience a recalcitrant disease despite treatment. Retinoids are considered the mainstay of therapy in many dermatologic diseases. Data on their use for viral warts are limited. To systematically review the published evidence on the efficacy and safety of retinoids for the treatment of CVW. A systematic review and meta-analysis of topical or systemic retinoid treatment for CVW was performed in accordance with the PRISMA statement. The primary outcome was clinical response; secondary outcomes were recurrence rate and adverse events. Fourteen publications including 399 patients treated exclusively with retinoids (65% topical, 35% systemic) were evaluated. The complete response rate was 64% (95% CI, 46-78%; I2 =80%) for topical treatment and 61% (95% CI, 44-76%; I2 =69%) for systemic treatment. The most common side effects were irritant contact dermatitis and cheilitis, respectively. Relapse rates were 6% and 17%, respectively. The reviewed studies were considerably heterogenous and most lacked a control group. Both topical and systemic retinoids are effective and safe as monotherapy for CVW. Further studies are required to determine their exact role in this setting.

Teratogen update: Topical use and third-generation retinoids.

The first pharmaceutical retinoids approved by the U.S. Food and Drug Administration were given black-box warnings against their use in pregnancy due to potential teratogenic effects. These first- and second-generation retinoids were initially formulated for oral dosing and are structurally very similar to vitamin A, which has beneficial effects on skin as well as plays a vital role in driving healthy embryogenesis. Some of these early retinoids have since been reformulated for topical application, which has resulted in their diminished potential for systemic exposures. Additionally, rational drug design has been applied to create today's third-generation retinoids (adapalene, tazarotene, and bexarotene). These compounds include aromatic rings within their molecular cores to provide structural rigidity that contrasts with the flexible aliphatic backbone of vitamin A and the earlier generations of retinoids, and thus limits their off-target activity. As a result of these design features, the teratogenic potential in animals of the third-generation retinoids and those reformulated for topical use is generally less than seen with oral administration of earlier generations of retinoids. The available, but limited, epidemiologic data further show little-to-no teratogenic potential associated with real-life use of these compounds in humans. Given the paucity of epidemiologic data available at this time, however, it is recommended that the use of topical retinoids during pregnancy be avoided. However, in circumstances when inadvertent exposure in pregnancy may occur, the available data provide some reassurance that adverse pregnancy outcomes are unlikely.

Adverse events related to topical drug treatments for acne vulgaris.

Introduction: Acne vulgaris is a widespread skin disease. Topical therapy is a standard treatment for mild to moderate acne. Given the complex pathophysiology of acne, various agents with complementary action are nowadays frequently combined to increase the efficacy of therapy.Area covered: This review focus on safety profile of topical agents used for the treatment of acne vulgaris, including topical retinoids, benzyl peroxide, azelaic acid, topical antibiotic, and combined agents. Data from clinical trials but also metanalyses, systematic reviews, and other secondary analyses are presented.Expert opinion: In general, topical agents used for acne vulgaris have a favorable safety profile. The most commonly reported AEs were associated with local skin irritation, usually mild to moderate in intensity, intermittent, and rarely led to the cessation of therapy. Irritative potential seems to be highest for BPO and topical retinoids. Due to the possibility of development of Cutibacterium acnes resistance, topical antibiotics should not be used in monotherapy but as a part of combination therapy. In female adolescent and adults of childbearing potential, topical retinoids should be used with caution, because they are contraindicated in pregnant females (FDA Pregnancy category) C (adapalene, tretinoin) and X (tazarotene).