Tamibarotene targets heparin-binding protein for attenuating lung injury in sepsis

Background: Excessively active pulmonary inflammation is a hallmark of sepsis-induced lung damage. A synthetic retinoid drug called tamibarotene reduces inflammation in a variety of conditions, including acute promyelocytic leukemia (APL), renal fibrosis, and neuroinflammation. Its effect on sepsis-related lung injury, however, has not been explained. Purpose: The purpose of the study was to investigate how tamibarotene affected lung damage induced by cecal ligation and puncture (CLP) procedure. Methods: A CLP sepsis mouse model was developed, and tamibarotene was pretreated to determine whether it improved lung injury and survival. The degree of lung injury was evaluated using the Hematoxylin and eosin staining and lung injury score. In order to determine pulmonary vascular permeability, measurements were taken for total protein and cell content of bronchoalveolar lavage fluid (BALF), wet/dry ratio of the lung, and Evans blue stain. The BALF inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and IL-17A were discovered by enzyme-linked immunosorbent serologic assay (ELISA). Then, the levels of heparin-binding protein (HBP), and phospho-nuclear factor kappa-B (p-NF-κB) P65, and NF-κB P65 were determined using ELISA and Western blot analysis, respectively. Results: Tamibarotene considerably increases survival and lessens lung damage stimulated by sepsis. Specifically, tamibarotene significantly relieves pulmonary vascular permeability and inhibits inflammation response in sepsis. Moreover, we further confirmed that these ameliorating effects of tamibarotene on sepsis may be exerted by targeting HBP and regulating the activation of NF-κB signaling pathway. Conclusion: These findings demonstrated that tamibarotene lessens sepsis-induced lung injury, and the effect could be exerted by targeting HBP and thereby deregulating the NF-κB signaling pathway (AU)

Disfunción tiroidea y lipídica asociada a bexaroteno en el linfoma cutáneo de células T / Thyroid and lipidic dysfunction associated with bexarotene in cutaneous T-cell lymphoma

Fundamento y objetivo: El bexaroteno es un rexinoide sintético selectivo del receptor X aprobado para el tratamiento sistémico del linfoma cutáneo de células T. Durante el tratamiento es muy frecuente la aparición de hipotiroidismo e hiperlipidemia mixta grave, siendo ambos efectos adversos reversibles y dependientes de la dosis. La elevación del colesterol LDL y los triglicéridos (hasta unos niveles aumentados que incluso se han asociado a pancreatitis en algunos casos) está ampliamente descrita (al igual que sucede con otros retinoides), siendo el descenso del colesterol HDL menos conocido. Revisamos nuestra experiencia con el uso de bexaroteno. Material y métodos: Se presenta una serie de 3 casos de pacientes tratados con bexaroteno en los que, además de sufrir los efectos adversos bien conocidos, se observó un grave descenso del colesterol HDL. Resultados: Los 3 pacientes estudiados presentaron complicaciones metabólicas en forma de hipotiroidismo central e hiperlipidemia mixta grave, con especial énfasis en el marcado descenso que experimentaron nuestros pacientes (descenso medio > 83%) en las cifras de colesterol HDL. El tratamiento hipolipidemiante y hormonal sustitutivo con levotiroxina dio lugar a una mejoría de los parámetros, sin llegar a alcanzarse los objetivos. Conclusiones: El bexaroteno produce, como efectos secundarios predecibles, una hiperlipidemia mixta grave con descenso marcado de los niveles de colesterol HDL e hipotiroidismo central, los cuales son reversibles y dependientes de la dosis. Se incluye una reflexión sobre los posibles mecanismos etológicos e implicaciones de este fenómeno (AU)

Background and objective: Bexarotene is a synthetic selective X receptor rexinoide approved for the systemic treatment of cutaneous T-cell lymphoma. During treatment is very frequent the occurrence of hypothyroidism and severe mixed hyperlipidemia, both are reversibles and dose-dependent adverse events. Increase of triglycerides and LDL-cholesterol level (up to even higher levels have been associated with pancreatitis in some cases) is widely described (as is the case with other retinoids) but decrease in HDL-cholesterol is poored know. We review our experience with the use of bexarotene. Material and methods: We present a serie of 3 clinical report of patients treated with bexarotene in whose, in addition to these well-known adverse event, a serious lowering of HDL-cholesterol was observed. Results: The 3 patients studied had metabolic complications like central hypothyroidism and severe mixed hyperlipidemia; with special emphasis on the sharp fall (mean decrease > 83%) in the HDL-cholesterol level. Cholesterol lowering medication and substitutive hormonal replacement with levotiroxine resulted in an improvement of the biochimical parameters without reaching the correct goals. Conclusions: Bexarotene produce as predictable side effects severe mixed hyperlipidemia with marked decrease in HDL-cholesterol levels and central hypothyroidism, being the both reversible and dose-dependent. A reflection on the possible aetiological mechanisms and implications of this phenomenon are included (AU)

Papuloeritrodermia de Ofuji asociada a linfoma cutáneo de células T Cd3+, Cd4+, Cd8-y gammapatía monoclonal de significado incierto / Papuloerythroderma of Ofuji Associated With CD3, + CD4, + and CD8− Cutaneous T-Cell Lymphoma and Monoclonal Gammopathy of Undetermined Significance

No disponible

Hipotiroidismo central y dislipemia mixta secundarios a tratamiento con bexaroteno / Bexarotene-induced central hypothyroidism and mixed dyslipidemia

El bexaroteno es un análogo de retinoide sintético caracterizado por unirse selectivamente a un tipo de receptores retinoides (receptores X) que fue diseñado para el tratamiento, entre otros, de estadios avanzados de linfoma cutáneo de células T resistentes a tratamientos convencionales. Se ha descrito que hasta el 40% de los pacientes que reciben bexaroteno pueden desarrollar hipotiroidismo secundario y hasta el 70%, hiperlipemia mixta grave, efecto común a otros retinoides. Presentamos a 3 pacientes que desarrollaron hipotiroidismo central y dislipemia tras el inicio de tratamiento con bexaroteno; en uno de ellos pudimos observar que estas alteraciones remitían tras la supresión del tratamiento (AU)

Bexarotene is a synthetic retinoid analogue that joints selectively to retinoid X receptor and has been designed for treatment of advanced stages of cutaneous T- cell lymphoma. Up to a 40% of patients treated with bexarotene develop central hypothyroidism while severe mixed dyslipidemia may be present in up to 70%. We report 3 patients that developed central hypothyroidism and dyslipidemia after bexarotene treatment was initiated. In one of them, we observed normalization of the thyroid function when bexarotene treatment was stopped (AU)

Tratamiento de micosis fungoide con PUVA más bexaroteno / Treatment of mycosis fungoides with PUVA and bexarotene

Introducción. La utilización conjunta de bexaroteno y psoraleno y radiación ultravioleta A (PUVA) en la actualidad es un tratamiento en investigación. En el presente trabajo se presentan 6 pacientes tratados con esta combinación. Objetivos. Valorar eficacia y seguridad del tratamiento con PUVA más bexaroteno en pacientes con micosis fungoide. Pacientes, material y métodos. Seis pacientes diagnosticados de micosis fungoide en distintos estadios que han recibido PUVA, tres sesiones semanales (inicio 2,35 J/cm 2, con aumentos progresivos hasta llegar a un máximo de 23,5 J/cm 2) más bexaroteno (dosis inicial, 300 mg/m 2/día, disminuyendo a 200, 150 o 75 mg/m 2 si aparecía toxicidad). Todos los pacientes recibieron atorvastatina. Resultados. Al inicio de tratamiento, 2 pacientes se encontraban en estadio IIb, un paciente en Ib con afectación hemática B2, 2 pacientes en Ib y un paciente en estadio Ia. Cinco de los 6 pacientes respondieron al tratamiento (tres remisiones completas [RC], dos remisiones parciales [RP]). Un paciente no respondió. De los que obtuvieron RC, el tiempo hasta la respuesta fue de 10, 20 y 24 semanas, respectivamente. Todos los pacientes presentaron hipertrigliceridemia (máximo de 1.194 mg/dl). En cuatro de los pacientes fue necesario administrar suplementos de hormona tiroidea. Dos de ellos tuvieron alteraciones de la bioquímica hepática y dos más presentaron alteraciones analíticas del perfil muscular. Conclusión. La combinación de PUVA y bexaroteno es un tratamiento eficaz y seguro para la micosis fungoide. Habrá que esperar a los resultados de los ensayos clínicos en curso para ver si es mejor su uso combinado que el tratamiento con PUVA sola. El índice de respuesta fue del 86 % (3 RC y 2 RP de 6 pacientes)

Introduction. The combined use of bexarotene and PUVA is a treatment that is currently being investigated. In this paper, six patients treated with this combination are presented. Objectives. To assess the efficacy and safety of treatment with PUVA + bexarotene in patients with mycosis fungoides (MF). Patients, material and methods. Six patients diagnosed with MF in different stages, who received three sessions of PUVA treatment a week (initially 2.35 J/cm 2, with progressive increases to a maximum of 23.5 J/cm 2) + bexarotene (initial dose 300 mg/m 2/day, decreasing to 200, 150 or 75 mg/m 2 if signs of toxicity appeared). All received atorvastatin. Results. Stage at the start of treatment: two patients IIb, one patient Ib with B2 blood involvement, two patients Ib, one patient Ia. Five of the six patients responded to the treatment (three full remissions [FR], two partial remissions [PR]). One patient did not respond. In those in whom FR was achieved, the time required for the response was 10, 20 and 24 weeks. All presented with hypertriglyceridemia (maximum 1194 mg/ dL). It was necessary to administer thyroid hormone supplements to four of the patients. Two of them had alterations in the hepatic biochemistry values, and two others presented with alterations in the muscle profile analysis. Conclusion. The combination of PUVA and bexarotene is a safe and effective treatment for MF. It will be necessary to await the results of the clinical trials currently underway to see if their combined use is better than treatment with PUVA alone. The response rate (RR) was 86 % (three FR and two PR out of six patients)