Pharmacokinetics of tazarotene and acitretin in psoriasis

Introduction: Psoriasis is a prevalent cutaneous condition with severe physical and psychological manifestations. Since the advent of biologics, clinical outcomes in psoriasis have improved. However, retinoids are useful in the correct clinical context. Tazarotene and acitretin are currently the only US Food and Drug Administration approved retinoids for treatment of psoriasis. Both topical tazarotene and oral acitretin act on retinoic acid receptors and retinoid-X-receptors, resulting in altered gene expression of inflammatory cytokines and inhibition of keratinocyte proliferation.

Areas covered: This article provides an in-depth pharmacologic and clinical review on the use of tazarotene and acitretin in psoriasis. The PubMed database was searched using combinations of keywords: acitretin, bioavailability, dosing, efficacy, etretinate, interactions, mechanism, pharmacodynamics, pharmacokinetics, pharmacogenetics, psoriasis, safety, tazarotene, tolerability, and toxicity.

Expert opinion: Tazarotene and acitretin are effective treatments for psoriasis. Benefits include lack of immunosuppression and success treating inflammatory psoriasis. When combined with other topical and systemic agents, both retinoids improve clinical efficacy while lowering the treatment threshold. However, topical adherence and bothersome side effects can limit retinoid use. Acitretin and tazarotene both improve outcomes through a unique mechanism that especially benefits subsets of patients, despite side effects and limitations.     

经全反维甲酸诱导和未诱导的HL-60细胞基因的差异展示分析

目的 对经全反维甲酸诱导和未诱导的HL-60细胞差异表达基因进行初探。方法 提取早幼粒白血病细胞株中总RNA,经由锚定引物介导的逆转录反应(RT)获得cDNA;以cDNA为模板采用相同锚定引物和另一上游引物进行PCR扩增,然后将PCR扩增产物在非变性聚丙烯酰胺凝胶上进行电泳分离,比较两组细胞的基因表达情况。结果 经由24种引物组合对经全反维甲酸诱导和未诱导的HL-60细胞进行差异展示分析,扩增出541条片段,平均每泳道显带数23条,发现差异明显片段36条。结论 mRNA差异展示技术能有效地反映出经全反维甲酸诱导和未诱导的HL-60细胞多个基因差异表达情况。     

Histological effects of tazarotene 0.1% cream vs. vehicle on photodamaged skin: a 6-month, multicentre, double-blind, randomized, vehicle-controlled study in patients with photodamaged facial skin

BACKGROUND: Topical tazarotene has been shown to offer efficacy in ameliorating multiple effects of photodamage. OBJECTIVES: To evaluate the histological effects of tazarotene cream on photodamaged skin. METHODS: In this multicentre, double-blind, randomized, vehicle-controlled study, 50 patients with photodamaged facial skin (at least mild fine wrinkling and mottled hyperpigmentation, with at least one of these being moderate) were randomized to apply tazarotene 0.1% cream or vehicle cream to their face, once daily for 24 weeks. RESULTS: Blinded assessments showed that tazarotene was less likely than vehicle to be associated with an increase in keratinocytic and melanocytic atypia, and more likely than vehicle to be associated with a reduction in atypia. Between-group comparisons in distribution of change from baseline categories of severity were in favour of tazarotene (P = 0.055 for keratinocytic atypia, P = 0.034 for melanocytic atypia, and P < 0.001 for the number of granular cell layers). Compared with vehicle, tazarotene was associated with an increase in epidermal polarity (P = 0.008) and epidermal thickness (P = 0.012), and a tendency for stratum corneum compaction. Tazarotene was also associated with widened intercellular spaces (reported as epidermal oedema) relative to vehicle (P < 0.001). CONCLUSIONS: Treatment of photodamaged skin with tazarotene is associated with an amelioration of keratinocytic and melanocytic atypia, an improvement in epidermal polarity, and an increase in epidermal thickness.     

Knockdown of lecithin retinol acyltransferase increases all‐trans retinoic acid levels and restores retinoid sensitivity in malignant melanoma cells

Retinoids such as all‐trans retinoic acid (ATRA) influence cell growth, differentiation and apoptosis and may play decisive roles in tumor development and progression. An essential retinoid‐metabolizing enzyme known as lecithin retinol acyltransferase (LRAT) is expressed in melanoma cells but not in melanocytes catalysing the esterification of all‐trans retinol (ATRol). In this study, we show that a stable LRAT knockdown (KD) in the human melanoma cell line SkMel23 leads to significantly increased levels of the substrate ATRol and biologically active ATRA. LRAT KD restored cellular sensitivity to retinoids analysed in cell culture assays and melanoma 3D skin models. Furthermore, ATRA‐induced gene regulatory mechanisms drive depletion of added ATRol in LRAT KD cells. PCR analysis revealed a significant upregulation of retinoid‐regulated genes such as CYP26A1 and STRA6 in LRAT KD cells, suggesting their possible involvement in mediating retinoid resistance in melanoma cells. In conclusion, LRAT seems to be important for melanoma progression. We propose that reduction in ATRol levels in melanoma cells by LRAT leads to a disturbance in cellular retinoid level. Balanced LRAT expression and activity may provide protection against melanoma development and progression. Pharmacological inhibition of LRAT activity could be a promising strategy for overcoming retinoid insensitivity in human melanoma cells.     

Novel anti‐wrinkle effect of cosmeceutical product with new retinyl retinoate microsphere using biodegradable polymer

Background: The novel hybrid retinoid, retinyl retinoate, is a synthetic material that was designed to reduce the side effects of retinoic acid and to increase the stability of retinol. The formulation of the retinyl retinoate, however, is required to enhance skin permeation, and thus to increase the anti‐wrinkle effect. Aim: To identify the efficacy of retinyl retinoate microsphere using biodegradable polymer as an anti‐aging agent of cosmetics in treating females over 30 years old with periorbital wrinkles. Methods: The retinyl retinoate microsphere was prepared using the biodegradable polymer; polylactic acid (PLA). We also conducted two clinical studies with a total of 44 Korean women for 12 weeks. In the first clinical study, 20 patients completed a 12‐week trial of cream A [3% PLA‐retinyl retinoate (2%) microsphere] applied twice daily to the face. In the second clinical study, 24 patients completed a 12‐week trial of cream B (0.06% retinyl retinoate) applied twice daily to the face. Efficacy was based on a global photodamage score, photographs, and image analysis using replicas and Visiometers every 4 weeks. Results: The PLA‐retinyl retinoate microsphere was more effective for the permeation of retinyl retinoate than retinyl retinoate in itself. The cream A, which contains 3% PLA‐retinyl retinoate (2%) microsphere, showed a statistically significant improvement in facial wrinkles (P<0.05) in 20 volunteers after only 4 weeks of application in a clinical trial test. The visual wrinkle improvement and the maximum roughness improvement rate (R2) for cream A was 6.05%, 8.03% higher than that of cream B which contains 0.06% retinyl retinoate, after 4 weeks. Conclusion: Retinyl retinoate has a potent anti‐wrinkle activity, and the PLA‐retinyl retinoate microsphere could be a useful cosmeceutical product for anti‐aging purposes.     

Melatonin treatment in fetal and neonatal diseases

This literature review aims to address the main scientific findings on oxidative stress activity in different gestational disorders, as well as the function and application of melatonin in the treatment of fetal and neonatal changes. Oxidative stress has been associated with the etiopathogenesis of recurrent miscarriages, preeclampsia, intrauterine growth restriction, and stillbirth. Both, the exacerbated consumption of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and the increased synthesis of reactive oxygen species, such as superoxide, peroxynitrite, and hydrogen peroxide, induce phospholipid peroxidation and endothelial dysfunction, impaired invasion and death of trophoblast cells, impaired decidualization, and remodeling of maternal spiral arteries. It has been postulated that melatonin induces specific biochemical responses that regulate cell proliferation in fetuses, and that its antioxidant action promotes bioavailability of nitric oxide and, thus, placental perfusion and also fetal nutrition and oxygenation. Therefore, the therapeutic action of melatonin has been the subject of major studies that aim to minimize or prevent different injuries affecting this pediatric age group, such as intrauterine growth restriction, encephalopathy, chronic lung diseases, retinopathy of prematurity Conclusion: the results antioxidant and indicate that melatonin is an important therapy for the clinical treatment of these diseases.