A Review of Topical Tapinarof for the Treatment of Plaque Psoriasis.

OBJECTIVE: This article reviews the efficacy and safety of 1% tapinarof cream for plaque psoriasis. DATA SOURCES: A literature search was conducted from August 2022 to February 2023. The terms tapinarof, VTAMA, benvitimod, GSK2894512, DMVT-505, and WBI-1001 were queried in PubMed. ClinicalTrials.gov was searched to identify ongoing or unpublished studies. STUDY SELECTION AND DATA EXTRACTION: All clinical trials written in English and relevant to pharmacology, efficacy, and safety were included. DATA SYNTHESIS: In two 12-week phase III clinical trials, disease severity assessed by a Physician's Global Assessment (PGA) score of clear or almost clear and a 2-point PGA improvement was 35.4% and 40.2% at week 12 in the 2 trials, respectively. In the 40-week, open-label extension trial, the efficacy and safety results were similar: 40.9% of patients achieved a PGA of 0 at least once during the trial, and 58.2% of patients with PGA ≥ 2 achieved PGA 0/1 at least once. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Tapinarof is a topical aryl hydrocarbon receptor agonist and a first-in-class, potentially promising treatment for plaque psoriasis recently approved by the U.S. Food and Drug Administration. CONCLUSION: Compared with placebo, tapinarof may be an effective and safe topical treatment for mild to severe plaque psoriasis. Head-to-head trials to compare the efficacy and adverse effect profile of tapinarof to other topical treatments are still needed, as are investigation in patients with recent or current use of phototherapy or biologic or nonbiologic systemics. Cost and adherence to treatment may be barriers for treatment efficacy.

A Review of Topical Sirolimus for the Treatment of Facial Angiofibromas in Tuberous Sclerosis Complex.

OBJECTIVE: This article assesses the efficacy, safety, pharmacology, and clinical applications of topical sirolimus 0.2% gel for the treatment of tuberous sclerosis complex (TSC)-associated facial angiofibromas. DATA SOURCES: A review of the literature was conducted using the Medline (PubMed) and EMBASE databases using the keywords topical sirolimus, rapamycin, Hyftor, and tuberous sclerosis. STUDY SELECTION AND DATA EXTRACTION: Articles written in English and relevant to the topic were included. DATA SYNTHESIS: In the phase 2 trial, the mean improvement factor, a composite measure of improved tumor size and redness, was achieved in all patient groups (P < 0.001) with significant responses among the adult and pediatric subgroups at week 12. There were no serious adverse events recorded. In the phase 3 trial, 60% of participants responded to treatment in the sirolimus group compared with 0% in the placebo group with different response rates between the adult and pediatric subgroups at week 12. Sirolimus gel had no serious adverse events, and dry skin was the most common adverse reaction. Patients who had completed the 12-week trials were then enrolled in a long-term trial; angiofibromas had response rates of 78.2% to 0.2% sirolimus gel. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Topical sirolimus 0.2% is a first-in-class, newly Food and Drug Administration (FDA)-approved, mammalian target of rapamycin (mTOR) inhibitor that is a promising and safe, noninvasive alternative to surgical procedures for TSC-associated angiofibromas. CONCLUSIONS: Topical sirolimus 0.2% gel is a moderately effective treatment for TSC-associated facial angiofibromas with an adequate safety profile.

A Review of Topical Roflumilast for the Treatment of Plaque Psoriasis.

OBJECTIVE: This article reviews clinical trials to assess the efficacy, safety, and clinical application of once-daily roflumilast 0.3% cream for the treatment of plaque psoriasis. DATA SOURCES: A systematic review of the literature was performed using the terms roflumilast OR Zoryve OR ARQ-151 in MEDLINE (PubMed) and EMBASE databases between January 2012 and October 2022. Bibliographies and the ClinicalTrials.gov website were also searched to identify further studies. STUDY SELECTION AND DATA EXTRACTION: Studies written in English and relevant to pharmacology, clinical trials, and safety were considered for inclusion. DATA SYNTHESIS: In two 8-week phase III clinical trials, disease severity as assessed by a score of "clear" or "almost clear" and a 2-point improvement on Investigator Global Assessment (IGA) was 42.4% and 37.5% at week 8 in DERMIS-1 and DERMIS-2, respectively, compared to 6.1% and 6.9% in the control groups. In the 52-week phase III trial, treatment success rates for plaque psoriasis and intertriginous psoriasis were similar to the 8-week data with 45% of patients in the treatment group were evaluated as an IGA of "clear" or "almost clear" at week 52. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Roflumilast is a new US Food and Drug Administration (FDA)-approved topical phosphodiesterase inhibitor that shows promise for the treatment of mild-severe plaque psoriasis. It is an effective and safe topical nonsteroidal alternative to currently available topical corticosteroids, but there are currently no comparative studies with other psoriasis treatments. CONCLUSION: Roflumilast is effective and safe for the treatment of plaque psoriasis and intertriginous psoriasis. Future trials should compare its efficacy and tolerability with that of the older, clinically established topical corticosteroids. Prohibitive factors may include limited patient adherence to topical treatments and cost.

Using the BacMam Baculovirus System to Study Expression and Function of Recombinant Efflux Drug Transporters in Polarized Epithelial Cell Monolayers.

The ATP-binding cassette (ABC) transporter superfamily includes several membrane-bound proteins that are critical to drug pharmacokinetics and disposition. Pharmacologic evaluation of these proteins in vitro remains a challenge. In this study, human ABC transporters were expressed in polarized epithelial cell monolayers transduced using the BacMam baculovirus gene transfer system. The purpose of the study was to evaluate the efficacy of BacMam baculovirus to transduce cells grown in monolayers. In a porcine kidney cell line, LLC-PK1 cells, baculoviral transduction is successful only via the apical side of a polarized monolayer. We observed that recombinant ABC transporters were expressed on the cell surface with post-translational modification. Furthermore, sodium butyrate played a critical role in recombinant protein expression, and preincubation in the presence of tunicamycin or thapsigargin enhanced protein expression. Cells overexpressing human P-glycoprotein (P-gp) showed vectorial basolateral-to-apical transport of [(3)H]-paclitaxel, which could be reversed by the inhibitor tariquidar. Similarly, coexpression of human P-gp and ABCG2 in LLC-PK1 cells resulted in higher transport of mitoxantrone, which is a substrate for both transporters, than in either P-gp- or ABCG2-expressing cells alone. Taken together, our results indicate that a high level of expression of efflux transporters in a polarized cell monolayer is technically feasible with the BacMam baculovirus system.

Uptake of compounds that selectively kill multidrug-resistant cells: the copper transporter SLC31A1 (CTR1) increases cellular accumulation of the thiosemicarbazone NSC73306.

Acquired drug resistance in cancer continues to be a challenge in cancer therapy, in part due to overexpression of the drug efflux transporter P-glycoprotein (P-gp, MDR1, ABCB1). NSC73306 is a thiosemicarbazone compound that displays greater toxicity against cells expressing functional P-gp than against other cells. Here, we investigate the cellular uptake of NSC73306, and examine its interaction with P-gp and copper transporter 1 (CTR1, SLC31A1). Overexpression of P-gp sensitizes LLC-PK1 cells to NSC73306. Cisplatin (IC50 = 77 µM), cyclosporin A (IC50 = 500 µM), and verapamil (IC50 = 700 µM) inhibited cellular accumulation of [(3)H]NSC73306. Cellular hypertoxicity of NSC73306 to P-gp-expressing cells was inhibited by cisplatin in a dose-dependent manner. Cells transiently expressing the cisplatin uptake transporter CTR1 (SLC31A1) showed increased [(3)H]NSC73306 accumulation. In contrast, CTR1 knockdown decreased [(3)H]NSC73306 accumulation. The presence of NSC73306 reduced CTR1 levels, similar to the negative feedback of CTR1 levels by copper or cisplatin. Surprisingly, although cisplatin is a substrate of CTR1, we found that CTR1 protein was overexpressed in high-level cisplatin-resistant KB-CP20 and BEL7404-CP20 cell lines. We confirmed that the CTR1 protein was functional, as uptake of NSC73306 was increased in KB-CP20 cells compared to their drug-sensitive parental cells, and downregulation of CTR1 in KB-CP20 cells reduced [(3)H]NSC73306 accumulation. These results suggest that NSC73306 is a transport substrate of CTR1.

Monitoring adherence to vulvar lichen sclerosus treatment - a prospective study.

Background: Vulvar lichen sclerosus treatment consists of topical corticosteroids followed by maintenance therapy. Self-reported adherence to topical corticosteroids in vulvar lichen sclerosus is approximately 66-70.4% and adherence to chronic topical medications is poor.Objective: To measure treatment adherence for vulvar lichen sclerosus.Methods: Adults with vulvar lichen sclerosus who were receiving or who were candidates to receive treatment with topical clobetasol propionate 0.05% ointment twice daily received medication tubes equipped with adherence monitors capturing the time and amount of dose dispensed. After 2 months, monitors were returned, and patients were surveyed regarding their adherence.Results: Ten patients participated for a median (range) of 8.5 (7-11) weeks. Eight (80%) and 7 (70%) caps captured medication timing and dosing events, respectively. Median (interquartile range) adherence was 65% (42-77) and median (interquartile range) medication dispensed per use was 0.15 (0.14 - 0.5) grams. Of the 8 patients using active adherence monitors, 2 did not clinically improve; adherence rates and mean quantity dispensed for these two patients were 31% and 0.13 grams, and 9% and 0.74 grams, respectively.Conclusion: Poor adherence to both twice daily application and prescribed medication quantity occurred frequently. Factors related to self-reported non-adherence included perceived greater efficacy, inconvenience, and time-constraints. Patient adherence to recommended treatment and clinical outcomes are areas for improvement in patients with vulvar lichen sclerosus.

"Pick" wisely: An approach to diagnosis and management of pathologic skin picking.

Manipulation of the skin is ubiquitous in most individuals along a spectrum of extent and severity. Skin picking that results in clinically evident changes or scarring to the skin, hair, and nails or significantly impairs intrapsychic, psychosocial, or occupational function is considered pathological picking. Several psychiatric conditions are associated with skin picking, including obsessive-compulsive disorder, body-focused repetitive behaviors, borderline personality disorder, and depressive disorder. It is also associated with pruritus and other dysesthetic disorders. Although pathologic skin picking, also known as excoriation disorder, is a distinct diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM5), this review attempts to further classify the diagnosis into the following 11 picker categories: organic/dysesthetic, obsessive-compulsive, functionally autonomous/habit, anxious/depressed, attention deficit hyperactivity disorder, borderline, narcissistic, body dysmorphic, delusional, guilty, and angry picker. An organized conceptualization of skin picking can guide providers toward a constructive management approach, ultimately increasing the likelihood of successful therapeutic outcomes.

Concurrent Atopic Dermatitis and Psoriasis Successfully Treated With Dual Biologic Therapy.

Atopic dermatitis (AD) and psoriasis are chronic inflammatory skin conditions with clinical and histopathologic features that often overlap, representing an underlying immunopathological spectrum of disease that can complicate the proper diagnosis and treatment of both conditions. We report the case of a patient with longstanding concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with dupilumab and guselkumab. Our case highlights the importance of considering coexisting AD and psoriasis in patients with treatment-resistant disease and the utility of dual biologic therapy. We also review an established but rare incidence of overlap between AD and psoriasis and highlight diagnostic challenges and the importance of assessing patients comprehensively. Our case also demonstrates the utility of patch testing and tissue diagnosis in patients with concurrent AD and psoriasis, as well as the importance of considering both diagnostic testing and clinical response in clinical decision-making.

Recommendations for Cost-Conscious Treatment of Basal Cell Carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) affects 3.3 million Americans annually. Treatment modalities for BCC include many surgical and nonsurgical options. The cost of BCC treatment can pose a substantial burden to patients and the healthcare system. Cost can be an important consideration in BCC treatment planning. OBJECTIVE: We present an approach to the management of BCC when cost reduction is a priority. METHODS: A PubMed literature search identified studies on effectiveness of current BCC therapies. Treatment prices were obtained from the Medicare National Fee Schedule, GoodRx, and pharmaceutical companies. The American Academy of Dermatology's (AAD) guidelines for treating BCC were used to develop recommendations for cost-reductive treatment. RESULTS: The cost of treating a primary superficial BCC < 0.5 cm arising on Area M (cheeks, forehead, scalp, neck, jawline, pretibial surface) was $143 with curettage and electrodesiccation (C&E), $143 with cryosurgery, $210 with standard excision and simple reconstruction (SE), $1221 with Mohs Micrographic Surgery (MMS) and simple reconstruction, $472 with imiquimod, $186 with 5-fluorouracil (5-FU), and $354-$371 for photodynamic therapy (PDT). The cost of treating a primary nodular BCC 1.1-2 cm arising on Area L (trunk and extremities, excluding pretibial surface, hands, feet, nail units and ankles) was $183 with C&E, $183 with cryosurgery, $251 with SE and simple reconstruction, $1163-1351 with MMS and simple reconstruction, $472 with imiquimod, $186 with 5-FU, and $354-$371 for photodynamic therapy (PDT). The cost of treating a giant BCC (BCC > 10 cm with aggressive behavior) was $465-3311 with radiation, $139,560 with vismodegib, $144,452 with sonidegib, ~ $44.5 with cisplatin (medication cost only), and at least $184,836 with cemiplimab-rwlc. CONCLUSIONS: For a primary superficial BCC < 0.5 cm arising on Area M, the cost-conscious algorithm prioritizes C&E or cryosurgery. For a primary nodular BCC 1.1-2 cm arising on Area L, the cost-conscious algorithm prioritizes C&E, cryosurgery, or 5-FU. For a giant BCC, the cost-conscious algorithm identifies superficial radiation therapy as first line.

Understanding the Medical Dictionary for Regulatory Activities (MedDRA) reporting of herpes simplex virus (HSV) adverse events in atopic dermatitis clinical trials.

Drug efficacy is best evaluated by randomized, controlled, double-blind clinical trials; however, safety is harder to assess. The Medical Dictionary for Regulatory Activities (MedDRA) is used to track and categorize adverse events (AE) during clinical trials. Recent atopic dermatitis (AD) clinical trials were reviewed to illustrate how an understanding of MedDRA may be helpful when evaluating the rates and nature of adverse events related to herpes simplex virus (HSV) infection. All completed AD clinical trials (excluding phase I studies) with results on clinicaltrials.gov (01/01/2018-01/31/2023) were queried in January 2023. MedDRA version, preferred term (PT) for AEs captured as "HSV", PTs for other AEs possibly related to HSV, frequency thresholds for reporting non-serious AEs, and route of treatment were recorded. Of the 46 clinical trials, 17 had PTs for AEs captured as "HSV". Among all studies, 11 different versions of MedDRA were utilized, from versions 10 to 24.1. In all studies, PTs for AEs captured as "HSV" were listed in the Infections and Infestations system organ class (SOC) classification of MedDRA. PTs varied from "herpes simplex", "herpes virus infection", "herpes ophthalmic", "ophthalmic herpes simplex", "nasal herpes", "oral herpes", "herpes dermatitis", "eczema herpeticum", "genital herpes simplex", and "genital herpes." While one clinical trial of dupilumab (NCT03359356) simply reported the PT "oral herpes" as an AE, a clinical trial of DS107 (NCT03817190) reported the PTs "oral herpes", "herpes simplex", and "herpes virus infection" separately. In the DS107 clinical trial, it is unclear if the same adverse event was reported under multiple PTs or if multiple HSV-related AEs occurred. Although the definition of HSV is unchanged from 2018 to 2023 and there are few changes between MedDRA versions, coding for HSV is complex. HSV events can be reported in different ways, which may impact the interpretation of a drug's safety profile.