RESUMEN
To establish real-world evidence about the safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma, we conducted a nationwide cohort study using data from post-marketing surveillance for bexarotene treatment. In total, 294 patients with cutaneous T-cell lymphoma were identified between June 2016 and June 2018. Of these, 267 patients were included as the safety analysis set. Of the 267 patients, 175 were included in the efficacy analysis set. Of these, 139 patients had mycosis fungoides, including 46 with early stage disease and 93 with advanced stage disease. Among the 139 patients with mycosis fungoides, the objective response rate was 46.8%. A significant difference in objective response rate was detected between patients who started with bexarotene at 300 mg/m2 (61.6%) and patients who started with bexarotene at less than 300 mg/m2 (22.6%, p < 0.001). Of the 139 patients with mycosis fungoides, 92 were treated with a combination of bexarotene plus photo(chemo)therapy. A significant difference in objective response rate was seen between bexarotene with a combination of photo(chemo)therapy (57.6%) and bexarotene without a combination of photo(chemo)therapy (25.5%, p < 0.001). Starting bexarotene at 300 mg/m2 and combination with photo(chemo)therapy were detected as independent factors influencing response. Common treatment-related adverse events included hypothyroidism (85.8%), hypertriglyceridemia (68.5%), hypercholesterolemia (43.8%), and neutropenia (21.3%). Hypertriglyceridemia, hypercholesterolemia, and neutropenia occurred more frequently in patients who started with bexarotene at 300 mg/m2 than patients who started with bexarotene at less than 300 mg/m2 (hypertriglyceridemia, 76.4% vs. 57.0%, p = 0.001; hypercholesterolemia, 49.0% vs. 36.4%, p = 0.045; neutropenia, 28.0% vs. 12.1%, p = 0.002; respectively). The present study indicates that starting bexarotene at 300 mg/m2 and combination of photo(chemo)therapy offer a promising efficacy for the treatment of patients with mycosis fungoides. Efficacy of low-dose bexarotene plus photo(chemo)therapy should be evaluated in future.
Asunto(s)
Linfoma Cutáneo de Células T , Micosis Fungoide , Neutropenia , Neoplasias Cutáneas , Bexaroteno , Estudios de Cohortes , Humanos , Japón/epidemiología , Linfoma Cutáneo de Células T/tratamiento farmacológico , Micosis Fungoide/tratamiento farmacológico , Vigilancia de Productos Comercializados , Resultado del TratamientoRESUMEN
AIMS: Glycyrrhizin has been widely used for the treatment of chronic hepatitis C. It decreases the serum levels of aminotransferases, and suppresses progression of liver fibrosis as well as subsequent occurrence of hepatocellular carcinoma. Although previous studies have shown that glycyrrhizin and its metabolite inhibit collagen gene expression, its underlying mechanisms are virtually unknown. This study was aimed to explore molecular mechanisms responsible for the inhibitory effect of glycyrrhizin on type I collagen gene transcription. MAIN METHODS: Effects of glycyrrhizin and its metabolite, glycyrrhetinic acid, on collagen promoter activity were examined by using transgenic reporter mice harboring alpha2(I) collagen gene (COL1A2) promoter. Their effects on the TGF-beta/Smad signaling pathway were studied by cell transfection assays and immunofluorescence studies using cultured hepatic stellate cells. KEY FINDINGS: Administration of glycyrrhizin or its metabolite, glycyrrhetinic acid, significantly suppressed COL1A2 promoter activation and progression of liver fibrosis induced by repeated carbon tetrachloride injections. In cultured hepatic stellate cells, glycyrrhetinic acid, but not glycyrrhizin, inhibited type I collagen synthesis mostly at the level of gene transcription. This inhibitory effect of glycyrrhetinic acid was abolished by a mutation introduced into a Smad3-binding region within the COL1A2 promoter. Glycyrrhetinic acid did not affect gene expression of TGF-beta receptors or Smad proteins, but inhibited nuclear accumulation of Smad3 in activated hepatic stellate cells. In addition to those direct inhibitory effects on COL1A2 transcription, glycyrrhetinic acid also suppressed activation of quiescent hepatic stellate cells in primary culture. SIGNIFICANCE: The results provide a molecular basis for the anti-fibrotic effect of glycyrrhizin treatment.
Asunto(s)
Antiinflamatorios/farmacología , Colágeno Tipo I/genética , Ácido Glicirrínico/farmacología , Cirrosis Hepática/prevención & control , Proteína smad3/antagonistas & inhibidores , Animales , Antiinflamatorios/metabolismo , Western Blotting , Intoxicación por Tetracloruro de Carbono/patología , Intoxicación por Tetracloruro de Carbono/prevención & control , Carcinoma Hepatocelular/prevención & control , Células Cultivadas , Técnica del Anticuerpo Fluorescente , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Ácido Glicirrínico/metabolismo , Humanos , Indicadores y Reactivos , Luciferasas/metabolismo , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Mutantes Quiméricas/metabolismo , Regiones Promotoras Genéticas/efectos de los fármacos , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transcripción GenéticaRESUMEN
1. We examined the effects of endogenous prostaglandin E(2) (PGE(2)) on the production of interleukin-6 (IL-6), macrophage colony stimulating factor (M-CSF), and vascular endothelial growth factor (VEGF) by interleukin-1beta (IL-1beta)-stimulated human synovial fibroblasts. 2. NS-398 (1 microM), a cyclo-oxygenase-2 (COX-2) inhibitor, inhibited IL-6 and VEGF production (35+/-4% and 26+/-2%, respectively) but enhanced M-CSF production (38+/-4%) by IL-1beta (1 ng ml(-1)) in synovial fibroblasts isolated from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Exogenous PGE(2) completely abolished the effects of NS-398 on the production of each mediator by OA fibroblasts stimulated with IL-1beta. 3. 8-Bromo cyclic AMP and dibutyryl cyclic AMP, cyclic AMP analogues, mimicked the effects of PGE(2) on IL-6, M-CSF, and VEGF production by OA fibroblasts. 4. The EP(2) selective receptor agonist ONO-AE1-259 (2 nM) and the EP(4) selective receptor agonist ONO-AE1-329 (2 or 20 nM), but not the EP(1) selective receptor agonist ONO-DI-004 (1 microM) and the EP(3) selective receptor agonist ONO-AE-248 (1 microM), replaced the effects of PGE(2) on IL-6, M-CSF, and VEGF production by OA and RA fibroblasts stimulated with IL-1beta in the presence of NS-398. 5. Both OA and RA fibroblasts expressed mRNA encoding EP(2) and EP(4) but not EP(1) receptors. In addition, up-regulation of EP(2) and EP(4) receptor mRNAs was observed at 3 h after IL-1beta treatment. 6. These results suggest that endogenous PGE(2) regulates the production of IL-6, M-CSF, and VEGF by IL-1beta-stimulated human synovial fibroblasts through the activation of EP(2) and EP(4) receptors with increase in cyclic AMP.
Asunto(s)
Dinoprostona/fisiología , Factores de Crecimiento Endotelial/biosíntesis , Fibroblastos/metabolismo , Interleucina-6/biosíntesis , Linfocinas/biosíntesis , Factor Estimulante de Colonias de Macrófagos/biosíntesis , Membrana Sinovial/metabolismo , Células Cultivadas , Dinoprostona/farmacología , Fibroblastos/fisiología , Humanos , Interleucina-1/farmacología , Receptores de Prostaglandina E/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E , Subtipo EP4 de Receptores de Prostaglandina E , Membrana Sinovial/citología , Membrana Sinovial/fisiología , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
The physiological interaction between glycyrrhizin (GL) and serum complement C3, and the inhibitory effects of GL, glycyrrhetinic acid (GA), and a GA derivative (oGA) on the phosphorylation of C3 by casein kinase 2 (CK-2), were investigated in vitro. C3 was found to be a GL-binding protein (gbP), because (i) of its high affinity for a GL-affinity HPLC column; and (ii) both GL and GA induce conformational changes in C3. At least four trypsin-resistant fragments (p30, p25, p18, and p15) were detected when the (32)P-labeled C3alpha was digested with trypsin in the presence of 100 micro M GA. Two of these (p25 and p15) were immuno-precipitated with anti-C3a serum. Furthermore, it was found that C3a contains GL-binding domains, because (i) C3a (anaphylatoxin) could be selectively purified from the synovial fluids of patients with rheumatoid arthritis by GL-affinity column chromatography (HPLC); and (ii) purified human C3a has a high affinity for a GL-affinity column. In addition, C3alpha (p115) of C3 was effectively phosphorylated by CK-2 in the presence of poly-Arg (a CK-2 activator) in vitro. This phosphorylation was completely inhibited by 10 micro M oGA, 30 micro M GA, or 100 micro M GL. Taken together, these results suggest that the GL-induced inhibition of the physiological activities of C3a and C3alpha may be involved in the anti-inflammatory effect of GL in vivo.
Asunto(s)
Complemento C3/metabolismo , Complemento C3a/metabolismo , Ácido Glicirretínico/farmacología , Ácido Glicirrínico/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Artritis , Sitios de Unión , Quinasa de la Caseína II , Complemento C3/análisis , Complemento C3/antagonistas & inhibidores , Complemento C3a/antagonistas & inhibidores , Glycyrrhiza/química , Ácido Glicirrínico/farmacología , Humanos , Fosforilación/efectos de los fármacos , Unión Proteica , Conformación Proteica/efectos de los fármacos , Líquido Sinovial/químicaRESUMEN
The purpose of this study was to examine the structure and activity relationships of glycyrrhetinic acid derivatives on the inhibition of hepatic and renal 11beta-hydroxysteroid dehydrogenases (HSDs) in rats. Furthermore, we explored whether inflammatory effect of the derivatives is involved in the inhibition of 11beta-HSD activity. 18beta-Glycyrrhetinic acid (Ia) potently inhibited 11beta-HSD activity of hepatic (IC50 (concentration giving 50% inhibition of cortisone production) = 0.09 microM) and renal (IC50 = 0.36 microM) homogenate. The inhibitory effect of 18beta-glycyrrhetol (Id) modified at the 30-position of glycyrrhetinic acid was weaker than that of glycyrrhetinic acid itself. 18beta-24-Hydroxyglycyrrhetinic acid (Ie), oxidized at the 24-position, remarkably reduced the inhibitory activity for both enzymes. 18beta-11-Deoxoglycyrrhetinic acid (IIc) showed the same inhibitory effect as glycyrrhetinic acid on hepatic 11beta-HSD activity, but less effect on renal 11beta-HSD activity. Furthermore, the inhibitory activity of 18beta-deoxoglycyrrhetol (IIa), modified at the 11- and 30-position, was markedly decreased. Dihemiphthalate derivatives (IIb, IIIb and IVb) of deoxoglycyrrhetol (IIa), 18beta-olean-9(11), 12-diene-3beta, 30-diol (IIIa) and olean-11, 13(18)-diene-3beta, 30-diol (IVa), which are anti-inflammatory agents, also showed weak inhibition against both hepatic and renal 11beta-HSDs. While glycyrrhetinic acid (200 mg kg(-1), p.o.) significantly inhibited 11beta-HSD activity in rat liver and kidney at 3 h after administration, compound IVb (100 mg kg(-1), p.o.) had no effect on either enzyme activity. In addition, the circulating corticosterone level was slightly increased by glycyrrhetinic acid but not by compound IVb. These results suggest that the anti-inflammatory effects of compound IVb, derived from glycyrrhetinic acid, are not due to accumulation of steroids induced by the inhibition of 11beta-HSD activity. Our data also showed that the 11-, 24- and 30-positions of glycyrrhetinic acid may play important roles in the differential inhibitory effects on 11beta-HSD isozyme activity.