A Randomized, Placebo-Controlled, Double-Blind, Dose Escalation, Single Dose, and Steady-State Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers.

9cUAB30 is a synthetic analogue of 9-cis retinoic acid with chemoprevention activity in cell lines and animal models. The purpose of this phase I placebo-controlled, double-blinded, dose escalation study of 9cUAB30 was to evaluate its safety, pharmacokinetics, and determine a dose for future phase II studies. Participants received a single dose of study drug (placebo or 9cUAB30) on day 1 followed by a 6-day drug-free period and then 28 days of continuous daily dosing starting on day 8. Fifty-three healthy volunteers were enrolled into five dose cohorts (20, 40, 80, 160, and 240 mg). Participants were randomized within each dose level to receive either 9cUAB30 (n = 8) or placebo (n = 2). 9cUAB30 was well tolerated, with no dose limiting toxicities reported and no evidence of persistent elevations in serum triglycerides or cholesterol. Treatment-emergent grade 3 hypertension occurred in 1 of 8 participants at the 20 mg dose level and in 2 of 8 at the 240 mg dose level, all considered unlikely related to study agent; no other grade 3 adverse events were observed. The AUC increased, as expected, between day 1 (single dose) and day 36 (steady state). Pharmacokinetics were linear in dose escalation through 160 mg. 9cUAB30 administered by daily oral dosing has a favorable safety and pharmacokinetic profile. On the basis of the observed safety profile and lack of linearity in pharmacokinetics at doses greater than 160 mg, the recommended phase II dose with the current formulation is 160 mg once daily.

Synergistic and additive effect of retinoic acid in circumventing resistance to p53 restoration.

TP53 mutations occur in ∼50% of all human tumors, with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant p53-targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation-based therapies. Here, we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting that it will unlikely be effective as a monotherapy. Through gene expression profiling of p53R172H -mutant lymphomas, we identified retinoic acid receptor gamma (RARγ) as an actionable target and demonstrated that pharmacological activation of RARγ with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.

Peretinoin as an adjuvant therapy for hepatocellular carcinoma.

INTRODUCTION: The current curative treatment modalities for hepatocellular carcinoma (HCC) are unfortunately fraught with high rates of HCC recurrence. Hence there is a need to prevent or reduce HCC recurrence after initial curative therapy. Peretinoin is a synthetic oral retinoid showing significant reduction in the incidence of recurrent or new HCC in patients who had received curative HCC therapy. Areas covered: Peretinoin is analysed against the background of molecular pathogenesis of the different causes of HCC. Publications related to peretinoin since 1996 are reviewed, covering clinical characteristics, safety and tolerance profile as well as the current status of clinical development. Expert commentary: Early phase studies are promising but we need to await the results of the ongoing phase III study of peretinoin in hepatitis C related HCC. Long term impact of peretinoin may be diminished by the foreseeable near eradication of hepatitis C by the direct acting antivirals.

Are topical retinoids teratogenic?

Retinoic acid is a physiological compound of human blood. Blood levels range from 1000 to 7000 pg/mL (usually 1500-5000 pg/mL). Results of studies on absorption of topical retinoic acid in laboratory animals, although rather conflicting, demonstrate that it induces plasma concentrations which are well below concentrations caused by non-teratogenic oral doses. In humans, minimal percutaneous absorption of tretinoin was observed after topical applications. Neither single dose nor long-term treatment with topical tretinoin affect the endogenous levels of retinoic acid or its metabolites. Topical application of tretinoin at doses used in acne unlikely induces systemic effects. Although some clinical cases of suspected tretinoin-related embryotoxicity have been described, three prospective cohort studies clearly demonstrated the safety of topical tretinoin as an embryotoxic agent.

Transcriptional regulation of human and murine short-chain dehydrogenase/reductases (SDRs) - an in silico approach.

Numerous physiological functions of the body are controlled by endogenous (e.g. steroids, retinoids, lipid mediators) or exogenous molecules (e.g. drugs, xenobiotics) that bind to transcription factors (TF). The biosynthesis and catabolism of these signaling molecules depend, apart from CYPs, on enzymes belonging to the short-chain dehydrogenase/reductase (SDR) superfamily. Moreover, the contribution of SDRs to the metabolism of therapeutic drugs and xenobiotics is increasingly recognized. However, only scarce information exists regarding the transcriptional regulation of most SDR proteins. This work aims to illustrate the role of nuclear receptors (NR) and TF related to oxidative stress, inflammation, hypoxia, and xenobiotics in the regulation of selected human and murine SDRs that play crucial roles in steroid, retinoid, eicosanoid, fatty acid, and xenobiotic metabolism. These include, for example, 17ß-hydroxysteroid dehydrogenases, retinol dehydrogenases, and carbonyl reductases. Because existing experimental data are limited, an in silico analysis (TRANSFAC(®) Professional database) of the 5'-upstream sequences for putative response elements was performed. Experimental and in silico data suggest that pharmaceutical, environmental, or dietary NR ligands may alter SDR-mediated retinoid, steroid, and xenobiotic metabolism, likely affecting basic cellular events like energy expenditure, cell proliferation/differentiation, or aging processes. Also, some SDRs are possibly induced by their own substrates. Further experimental work is urgently needed to fully understand the NR-mediated transcriptional regulation of SDRs. This is essential for deducing their possible involvement in drug side effects and will help to identify new substrates and further physiological functions of these SDRs.

Potential Therapeutic Agents Against Retinal Diseases Caused by Aberrant Metabolism of Retinoids.

The retinoid (visual) cycle is a complex enzymatic pathway that operates in the retina for the regeneration of 11-cis-retinal (11-cis-Ral), the inherent visual chromophore indispensable for vision. Deficiencies in the retinoid metabolism are involved in pathologic mechanisms of several forms of retinal diseases including age-related macular degeneration, Stargardt's disease, and Leber's congenital amaurosis, for which no effective cures presently exist. Nevertheless, the interference of abnormal retinoid metabolism with chemicals has been considered to be a promising strategy aimed at alleviating these retinal dysfunctions. Moreover, since gene therapy is gaining increasing importance in clinical practice, the modulation of key enzymes implicated with the retinoid cycle at a genetic level will hold great promise for the treatment of patients with degenerative diseases of the retina.

Skin metabolism established with the use of MetaSite for selected retinoids employed in topical and systemic treatment of various skin disorders and found in cosmeceuticals.

PURPOSE: Besides being widely used in cosmetics, retinoids are potent therapeutic agents used topically and systemically as anti-acne agents. The aim of this study was to predict with the use of MetaSite the skin metabolism of selected retinoids employed in treatment of skin disorders and found in cosmeceuticals. The following compounds were studied: retinol, retinaldehyde, retinoic acid, retinyl acetate, retinyl palmitate, acitretin, etretinate, adapalene and bexarotene. METHODS: MetaSite, Molecular Discovery Ltd. is a computational model that enables prediction of cytochrome P450-dependant metabolism. This software indicates atoms in the molecule structure that are mostly vulnerable to metabolic changes and predicts the metabolite structures. RESULTS: MetaSite indicated that retinol and retinal metabolites were obtained through hydroxylation of the methyl group located in the position 3 of the aliphatic chain, whereas retinoic acid biotransformation would occur principally in the carbon atom situated in the position 4 in the cyclohexene ring. In acitretin molecule, carbon atom of the methoxy group attached to the benzene ring displayed the highest probability of biotransformation. In etretinate, metabolic reactions would occur principally on the carbon atom of the final ethyl group of the molecule. CONCLUSIONS: MetaSite metabolism predictions for retinoic acid, acitretin, etretinate, adapalene and bexarotene were in agreement with experimental findings. In case of compounds being converted by catalysts other than cytochrome P450 enzymes, the primary metabolites predicted by MetaSite differ from those reported previously. In conclusion, MetaSite is a useful tool that can aid identification of the major metabolites of compounds being administered topically.

In vivo pharmacokinetics, biodistribution and antitumor effect of amphiphilic poly(L-amino acids) micelles loaded with a novel all-trans retinoic acid derivative.

Poly(amino acid)s are well-known as biodegradable and environmentally acceptable materials. In this study, a series of poly(L-aspartic acid)-b-poly(L-phenylalanine) (PAA-PPA) compounds with different degrees of polymerization were used to prepare copolymer micelles for a poorly water-soluble drug 4-amino-2-trifluoromethyl-phenyl retinate (ATPR, a novel all-trans retinoic acid derivative) and in vivo pharmacokinetics, biodistribution and antitumor efficacy of ATPR delivered by PAA-PPA micelles were evaluated. The area under the plasma concentration time curve AUC0→∞ of ATPR-loaded PAA20PPA20 micelles was 2.23 and 1.97 times higher than that of ATPR solution and ATPR CrmEL solution, respectively; In addition, the mean residence time (MRT) was increased 1.67 and 1.97-fold, respectively and the total body clearance (CL) was reduced 2.25 and 1.98-fold, respectively. The biodistribution study indicated that most of the ATPR in the ATPR-M group was distributed in the liver and there was delayed liver aggregation compared with the ATPR solution and ATPR CrmEL solution groups. Furthermore, the antitumor efficacy of ATPR-loaded PAA20PPA20 micelles was demonstrated in in vivo antitumor models involving mice inoculated with the human gastric cancer cell line SGC-7901. At the same dose of 7mg/kg, the ATPR-loaded micelles group demonstrated a better tumor growth inhibition and induced differentiation than the groups given ATPR solution and ATPR CrmEL solution. Therefore, the ATPR-loaded PAA-PPA micelles appear to be a potentially useful drug delivery system for ATPR and suitable for the chemotherapy of gastric cancer.

Nutrient supplementation with n3 polyunsaturated fatty acids, lutein, and zeaxanthin decrease A2E accumulation and VEGF expression in the retinas of Ccl2/Cx3cr1-deficient mice on Crb1rd8 background.

The Age-Related Eye Diseases Study 2 (AREDS2) clinical trial is assessing the effects of higher dietary xanthophyll (lutein and zeaxanthin) and long-chain n3 polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake on progression to advanced age-related macular degeneration (AMD). This study's purpose was to examine the retinal effects of the AREDS2 formulation on Chemokine (C-C motif) ligand 2 (Ccl2(-/-))/CX3C chemokine receptor 1 (Cx3cr1(-/-)) mice on Crumbs homolog 1 retinal degeneration phenotype 8 (Crb1(rd8)) background (DKO), which develop focal retinal lesions with certain features similar to AMD. DKO and C57BL/6N rd8 background mice (WT) were bred and randomized into 4 groups. Two groups, WT mice on AREDS2 diet (A-WT) and DKO mice on AREDS2 diet (A-DKO), were supplemented daily with 1.76 µmol of lutein, 35.1 µmol of zeaxanthin, 215 µmol EPA, and 107 µmol of DHA, and 2 control groups, WT mice on control diet (C-WT) and DKO mice on control diet (C-DKO), were fed an isocaloric diet. All mice had monthly fundus photos and were killed after 3 mo for biochemical and histologic analyses. After 3 mo, 81% of A-DKO mice had lesion regression compared with 25% of C-DKO mice (P < 0.05). Toxic retinal 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetra-enyl]-1-(2-hydroxyethyl)-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl) 1E,3E,5E,7E-hexatrienyl]-pyridinium (A2E) concentrations were significantly lower in A-DKO compared with C-DKO mice. The outer nuclear layer thickness in A-DKO mice was significantly greater than that in C-DKO mice. Retinal expression of inducible nitric oxide synthase (iNos) tumor necrosis factor-α (Tnf-α), Cyclooxygenase-2 (Cox-2), interleukin1beta (IL-1ß), and vascular endothelial growth factor (Vegf) was significantly lower in A-DKO compared with C-DKO mice. Xanthophylls and LCPUFAs have antiinflammatory, neuroprotective, and antiangiogenic properties. Our data provide potential mechanisms by which the AREDS2 formula has a protective effect on retinal lesions in DKO mice.

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.

The effect of food preparation on the bioavailability of carotenoids from carrots using intrinsic labelling.

A strategy to reduce the incidence of vitamin A deficiency is to improve precursor bioavailability from meals. Since vitamin A precursors are fat-soluble, we noted that carotenoids are more easily absorbed from food if prepared in such a way that the food matrix containing provitamin A (ß-carotene) is sufficiently fat rich. To quantify this effect, we have developed a stable isotope methodology. By regular watering with 2H-labelled water, we were able to produce several kg of intrinsically labelled carrots, with carotenoids labelled to 0.63 % excess 2H. These were divided into 100 g portions and fed to a small group of healthy subjects both raw and stir-fried. To normalise for inter-individual variation in absorption and subsequent metabolism, small quantities of extrinsically 13C-labelled ß-carotene and 2H-labelled retinol acetate were also incorporated into the meal. After ingestion of the carrots, blood lipids were monitored for a period of 3 d in order to determine the kinetics of ß-carotene and retinol. From kinetic data, it was estimated that the bioavailability of carrot-derived ß-carotene compared with pure ß-carotene was about 11 % for raw carrots, but 75 % when the carrots were stir-fried. Conversely, there was a slight reduction in the bioconversion to retinol from ß-carotene when the latter was derived from the stir-fried meal compared with that from raw carrots. When these two factors are combined, the yield of retinol from the carotene in carrots was found to be enhanced by a factor of 6.5 by stir-frying.

Phototoxicity and photocarcinogenesis associated with voriconazole.

The antifungal voriconazole was given its marketing authorization in 2002. Several kinds of adverse effects have been reported, including acute and chronic cutaneous adverse effects, mainly due to a phototoxicity mechanism. More recently, some authors have reported that voriconazole was involved in the occurrence of multiple and often-aggressive cutaneous squamous cell carcinomas if the treatment was maintained for a long time. According to safety data in studies assessing voriconazole effectiveness, 8% of outpatients may experience phototoxic events. An overview of the different types of phototoxicity and of the concerned population was given by the 61 published case reports of photo-induced voriconazole-related skin adverse events (including 18 cases of squamous cell carcinomas). The most likely mechanisms may be phototoxicity directly related to either voriconazole or to its N-oxide main metabolite, and an interaction with retinoid metabolism; moreover, immunodeficiency may enhance the risk of skin cancer. Several issues remain to be investigated, and studies are needed concerning the phototoxicity and photocarcinogenesis of voriconazole and the prognosis of chronic non-malignant skin lesions. Voriconazole prescription must be associated with strict photoprotection; in case of a phototoxic adverse event, another azole may be recommended.

Alitretinoína oral: tratamiento específicio del eczema crónico de manos grave refractario a corticoides / Oral alitretinoin: specific therapy for severe chronic eczema of the hands refractory to corticosteroids

El eczema de manos (ECM) es la dermatosis más frecuente de la manos, y se trata de un importante (..) (AU)

Eczema of the hands (EOH) is the most prevalent hand dermatosis and represents and important healthcare, social (..) (AU)

[Retinoids: mechanisms of action]. / Rétinoïdes: mécanismes d'action.

Retinoids, vitamin A derivatives, are natural or synthetic molecules with pleiotropic effects, which regulate cell differentiation, proliferation and apoptosis. In target cell, the active natural metabolites retinoic acid (RA) and 9-cis-retinoic acid are synthetized from retinol by a two-step process with intermediate metabolite retinaldehyde. In 1987, the identification of the nuclear retinoic acid receptors that belong to the superfamily of nuclear receptors led to a significant progress in the comprehension of the mechanism of action of retinoids. There are two families of Retinoid Nuclear Receptors (RNR), the RA receptors (RAR), which natural ligand is RA, and the Retinoid X Receptors (RXR), which natural ligand is 9-cis-retinoic acid. Among synthetic retinoids, isotretinoin, acitretin, tazarotene and adapalene are ligands of the RAR, bexarotene is the first rexinoid (ligand of the RXR), alitretinoin the first panagonist (RAR+ RXR). For each family, there are 3 isotypes (α, ß, γ), and for each isotype several isoforms. Each NRR is composed of 6 regions (A-F). 3 regions are of importance: the A/B region has a ligand-independent transcriptional activation function, the C region harbors the DNA binding domain, the E region harbors the ligand binding domain. To regulate the expression of target genes, NRR have to dimerize. RXR are obligatory in dimers (heterodimers RAR-RXR, homodimers RXR-RXR). Dimers binds specific sequences of DNA, present in the promoters of target genes. When the ligand, natural or synthetic, bind to RNR, coactivators are recruited and transcription factors are activated. In target cell, retinoids not utilized are degradated in polar metabolites by enzymes of cytochrome P450.

Vitamin A supplementation for different periods alters rat vascular redox parameters

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Vitamin A plays physiological and antioxidants properties and is associated with protective effects on arterial level. However, deleterious effects have been reported, including those observed by our group, which has demonstrated pro-oxidant properties in other systems. Therefore, it is needed to better understand the redox effects of retinoids on arterial system. Thus, our aim was to compare vascular redox parameters among animals supplemented or not with vitamin A. Eighty-five adult male rats were treated with different retinyl palmitate (..) (AU)

The neurobehavioral teratology of retinoids: a 50-year history.

This review of the central nervous system (CNS) and behavioral teratology of the retinoids over the last 50 years is a commemorative retrospective organized by decade to show the prominent research focus within each period and the most salient findings. In the 1960s, research focused on the gross CNS malformations associated with exposure and the delineation of dose-response and stage-specific responses in rodent models. Relevant scientific events before and during the 1960s are also discussed to provide the zeitgeist in which the field of neurobehavioral teratology emerged in the 1970s. During this period, studies demonstrated that adverse effects on postnatal behavior could be produced in animals exposed to doses of vitamin A lower than those that were teratogenic or impacted growth. Work during the 1980s showed an overrepresentation of behavioral studies focused on the reliability of screening methods, while the marked effects of human exposure were illustrated in children born to women treated with isotretinoin during pregnancy. The human catastrophe invigorated research during the 1990s, a period when technological advances allowed more elegant examinations of the developing CNS, of biochemical, cellular, and molecular developmental events and regulatory actions, and of the effects of direct genetic manipulations. Likewise, research in the 1990s reflected a reinvigoration of research in neurobehavioral teratology evinced in studies that used animal models to try to better understand human vulnerability. These foci continued in the 2000-2010 period while examinations of the role of retinoids in brain development and lifelong functioning became increasingly sophisticated and broader in scope. This review of the work on retinoids also provides a lens on the more general ontogeny of the field of neurobehavioral teratology. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Retinoids for treatment of retinal diseases.

Knowledge about retinal photoreceptor signal transduction and the visual cycle required for normal eyesight has increased exponentially over the past decade. Substantial progress in human genetics has facilitated the identification of candidate genes and complex networks underlying inherited retinal diseases. Natural mutations in animal models that mimic human diseases have been characterized and advanced genetic manipulation can now be used to generate small mammalian models of human retinal diseases. Pharmacological repair of defective visual processes in animal models not only validates their involvement in vision, but also provides great promise for the development of improved therapies for millions who are progressing towards blindness or are almost completely robbed of their eyesight.

Two-photon fluorescence excitation microscopy to assess transscleral diffusional pathways in an isolated perfused bovine eye model.

PURPOSE: To assess the feasibility of using two-photon microscopy to study the pattern of diffusion through the sclera of a tracer (tazarotenic acid [TA]). METHODS: Polyvinyl alcohol films containing 1% tazarotenic acid (PVA-TA) were applied to the equatorial sclera of isolated perfused bovine eyes. Two-photon microscopy (TPM) was used to determine the lateral spread and depth of penetration of TA in the sclera over time. Protein and collagen binding were determined, and calibration standards were prepared by TPM imaging at 10 µm depth in scleral samples that had been immersed for 24 hours in solutions of TA of 0.7, 7.0, or 70 µg/mL. RESULTS: TA was weakly bound to collagen and sclera (<55%) but strongly bound to plasma protein (95%). In perfused eyes, 50 minutes after PVA-TA application, peak fluorescence in the sclera was detected at a 210-µm depth. By 85 minutes after application of the PVA-TA film, fluorescence had disappeared from surface layers of the sclera and was at maximum at 250 to 290 µm. Penetration of the tracer followed the track of scleral collagen bundles rather than that of the proteoglycan ground substance between collagen bundles. CONCLUSIONS: TPM can image in real time the progressive diffusion of TA from its source in a PVA-TA film applied to the equatorial sclera of the isolated perfused bovine eye and follow its subsequent penetration deeper into the sclera. The data suggest that lateral spread and deeper penetration of the test compound occurred along the course of scleral collagen bundles. Imaging was possible to a depth of 340 µm, the average thickness of the human equatorial sclera.

Alitretinoína y eczema crónico de manos / Allitretinoin and chronic eczema of hands

El eczema de manos (EM) es una dermatosis común que afecta a las manos. La exposición a irritantes, alergenos y factores endógenos desempeñanfunciones relacionadas entre sí en la etiología de esta enfermedad. Por ello cuesta tanto identificar los factores causales y eliminarlos por completo. Enun número considerable de pacientes, el eczema de manos se convierte en una enfermedad crónica, incluso cuando se evita el agente causal inicial. Engeneral, la dermatitis de manos se considera crónica si dura más de 6 meses en ausencia de factores causales externos. Los pacientes con Eczema Crónicode Manos (ECM) presentan grietas dolorosas, ampollas, picazón y sangrado, lo que puede limitar la destreza manual produciendo incapacidadlaboral. La condición de estos pacientes se puede perpetuar, siguiendo un curso crónicamente recidivante. Los casos leves de ECM se suelen manejarcon el uso cuidadoso de emolientes y corticoides tópicos, impidiendo el contacto con irritantes, pero ECM severo es debilitante si es resistente a estetratamiento estándar. El ECM severo causa una importante incapacidad laboral, funcional, social y psicológica, incluida la baja laboral indefinida porenfermedad y el desempleo, causando ansiedad, baja autoestima, y fobia social.En la actualidad los pacientes con ECM severo resistente a corticosteroides tópicos tiene limitadas las opciones de un tratamiento de uso crónico adecuado,y en este campo se han realizado pocos ensayos clínicos para estudiar nuevas terapias. Ninguna de las actuales opciones terapéuticas presentauna alternativa como Alitretinoína para el tratamiento del ECM refractario (AU)

Hand eczema is a common dermatosis affecting the hands. Exposure to irritants, allergens and endogenous factors play interrelated roles in the aetiologyof this disease. Consequently, it is rarely possible to identify all causative factors and remove them entirely.In a substantial number of patients, hand eczema develops into a chronic condition even when an initial causative agent is avoided. In general, handdermatitis is considered chronic if it lasts more than 6 months in the absence of external causal factors.Patients with CHE suffer from painful cracks, blisters, itching and bleeding, which can limit manual dexterity and prevent employment[1]. These typesof patients with CHE have a poor prognosis; it is a self perpetuating condition with a long-lasting and chronically relapsing course.Mild cases of CHE are usually managed with conscientious use of emollients and topical corticosteroids, and avoidance of irritants, but severe CHE isdebilitating if it is refractory to this standard regimen. Severe CHE causes substantial occupational, functional, social and psychological disability,including prolonged sick leave and unemployment, anxiety, low self-esteem, and social phobia.Currently patients with severe CHE refractory to topical corticosteroids have limited treatment options suited for chronic use, and few clinical trialshave investigated new therapies in this setting. None of the current treatment options present an alternative to Alitretinoin for the treatment of refractoryCHE (AU)