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P-137 Long-Term Nintedanib Treatment in Idiopathic Pulmonary Fibrosis
( Jin Woo Song ),( Bruno Crestani ),( Manuel Quaresma ),( Mitchell Kaye ),( Wibke Stansen ),( Susanne Stowasser ),( Micheael Kreuter ) 대한결핵 및 호흡기학회 2017 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.124 No.-
Background: The efficacy and safety of nintedanib 150 mg twice daily in patients with IPF were assessed in the two Phase III INPULSIS trials. Patients who completed the 52-week treatment period and follow-up visit 4 weeks later in INPULSIS could receive open-label nintedanib in the extension trial INPULSIS-ON. Aim: To assess the long-term efficacy and safety of nintedanib based on an interim analysis of INPULSIS-ON Methods: Patients treated with placebo in INPULSIS initiated nintedanib in INPULSIS-ON; patients treated with nintedanib continued nintedanib. Results: 734 patients were treated in INPULSIS-ON (430 continuing nintedanib; 304 initiating nintedanib). At baseline of INPULSIS-ON, mean age was 67.2 years; 80.0% of patients were male, 58.7% were White, 29.3% were Asian. Mean FVC was 76.2% predicted. At this interim analysis, mean (SD) exposure in INPULSIS-ON was 27.7 (15.1) months. Mean (SD; minimum- maximum) total exposure for patients treated with nintedanib in INPULSIS and INPULSIS-ON was 40.7 (14.6; 11.9-63.1) months. In all patients treated in INPULSIS-ON, mean (SD) change in FVC from baseline of INPULSIS-ON to week 144 of INPULSIS-ON was -305 (365) mL; the annual rate (SE) of decline in FVC over 144 weeks was -131 (6) mL/year. The adverse event profile of nintedanib in INPULSIS-ON was consistent with that in INPULSIS. Conclusions: Data from INPULSIS-ON indicated that the effect of nintedanib on reducing disease progression is maintained over the long term. Nintedanib treatment (up to 63 months) had an acceptable safety and tolerability prof
Long-term nintedanib treatment in idiopathic pulmonary fibrosis (IPF) : final data from INPULSIS-ON
( Jin Woo Song ),( Bruno Crestani ),( Manuel Quaresma ),( Mitchell Kaye ),( Takashi Ogura ),( Wibke Stansen ),( Susanne Stowasser ),( Michael Kreuter ) 대한결핵 및 호흡기학회 2018 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.126 No.-
Background & Aims: The two 52-week Phase III INPULSIS trials investigated the efficacy and safety of nintedanib 150 mg bid vs placebo in patients with IPF. Patients who completed an INPULSIS trial could receive open-label nintedanib in the extension trial INPULSIS-ON. We assessed the long-term efficacy and safety of nintedanib based on final data from INPULSIS-ON. Methods: Placebo-treated patients in INPULSIS initiated nintedanib in INPULSIS-ON; patients treated with nintedanib in INPULSIS continued nintedanib in INPULSIS-ON. Results: 734 patients were treated in INPULSIS-ON (430 continuing nintedanib; 304 initiating nintedanib). Mean (SD) exposure in INPULSIS-ON was 29.0 (16.4) months; total exposure to nintedanib in both INPULSIS and INPULSIS-ON was 42.1 (16.0) months (max: 68.3 months). In INPULSIS, mean (SD) changes from baseline in FVC at week 52 were -89 (264) mL with nintedanib vs -203 (293) mL with placebo; annual rates (SE) of decline in FVC were -114 (11) mL/year and -224 (13) mL/year in these groups. In INPULSIS-ON, mean (SD) change from baseline in FVC at week 192 was -327 (385) mL; the annual rate (SE) of decline in FVC over 192 weeks was -135 (6) mL/year. The adverse event profile of nintedanib in INPULSIS-ON was consistent with that observed in INPULSIS. Conclusions: Final data from INPULSIS-ON indicate that the effect of nintedanib on reducing disease progression in patients with IPF is maintained over the long term. Nintedanib treatment, up to 68 months, had an acceptable safety and tolerability profile.
SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle
Koo, Young Do,Lee, Ji Seon,Lee, Seung-Ah,Quaresma, Paula G.F.,Bhat, Ratan,Haynes, William G.,Park, Young Joo,Kim, Young-Bum,Chung, Sung Soo,Park, Kyong Soo Elsevier 2019 clinical and experimental Vol.95 No.-
<P><B>Abstract</B></P> <P><B>Background and purpose</B></P> <P>In addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ. In this study, we examine whether SENP2 is involved in prolonged stimulation of FAO by leptin.</P> <P><B>Methods</B></P> <P>The Effect of leptin on expression of SENP2 and on SENP2-mediated FAO was investigated by using western blotting and real time qPCR of C2C12 myotubes, and of C2C12 myotubes in which expression of specific genes was knocked down using siRNAs. Additionally, muscle-specific SENP2 knockout mice were generated to test the involvement of SENP2 in leptin-induced FAO in vivo.</P> <P><B>Results</B></P> <P>We show that leptin treatment of C2C12 myotubes causes signal transducer and activator of transcription 3 (STAT3) to bind to the <I>Senp2</I> promoter, inducing SENP2 expression. We also show that leptin increases the binding of PPARδ and PPARγ to PPRE sites in the promoters of two FAO-associated genes: long-chain acyl-CoA synthetase 1 (<I>Acsl1</I>) or carnitine palmitoyl transferase 1b (<I>Cpt1b</I>). When SENP2 is knocked down in myotubes, leptin-induced expression of FAO-associated enzymes and prolonged increase of FAO are suppressed, but rapid increase of FAO is unaffected. In addition, leptin-induced expression of FAO-associated enzymes was not observed in muscle tissue of SENP2 knockout mice.</P> <P><B>Conclusions</B></P> <P>We demonstrate that the peripheral actions of leptin on FAO are mediated by two different pathways: AMPK causes a rapid increase in FAO, and SENP2 of the STAT3 pathway causes a slow, prolonged increase in FAO.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Leptin directly activates AMPK and STAT3 through leptin receptor in skeletal muscle. </LI> <LI> Leptin increases transcription of <I>Senp2</I> through STAT3 activation. </LI> <LI> Leptin increases expression of FAO-related genes through PPAR desumoylation by SENP2. </LI> <LI> Leptin increases FAO acutely by AMPK and later by the STAT3/SENP2 pathway. </LI> </UL> </P>