(Erythropoiesis stimulating agent, ESA) (erythropoietin, EPO) darbepoetin CERA EPO

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1 * *,** * ** (Erythropoiesis stimulating agent, ESA) (erythropoietin, ) darbepoetin CERA ESA ESA ( 70 ml/min 50 ml/min) 50% 12 g/dl 75% [1] Eschbach wctseng@vghtpe.gov.tw ; dctarng@vghtpe.gov.tw Lin 1985 [2] Eschbach [3] 90% (fibroblast-like interstitial cell)[4] 10% exons introns C arginine 165 N-linked O-linked 30,400D [5] Epoetin epoetin alfa beta

2 N-linked O-linked 14epoetin beta ( 1) U/kg/week ( ) U/kg/week ( ) 6000 U [6] 1 2 g/dl/mo 2 3 g/dl/mo Darbepoietin epoetin alfa N-linked darbepoetin alfa Da Macdougall darbepoetin epoetin alfa ( ) darbepoetin µg/kg/week 0.75 µg/kg/2weeks 1µg darbepoetin 200U epoetin CERA (Continuous erythropoiesis receptor activator; CERA) epoetin beta methoxypolyethylene glycol polymer 130 phase III CERA (0.6 µg/kg) darbepoetin (0.45 µg/kg) [7] CERA ( ) epoetin CERA epoetin [8]CERA hypoxia-inducible factor (HIF) HIF HIF-2α hypoxia responsive element (HRE) GATA-2 NF-κB [9] (R)R STAT5 R Ras/MAP kinase PI3-kinase/Akt Akt Bad Bcl-X L hematopoietic cell phosphatase BFU-E CFU-E R CFU-E 1. (Pharmacokinetics) [1] mean S.E.M ( ) Epoetin alfa Epoetin beta Darbepoetin alfa CERA

3 1000 R CFU-E [1] 1998 Besarab epoetin (42%) (30%) 1.3 ( ) Kt/V [10] CREATE (13 15 g/dl) ( g/dl) [11] CHOIR (13.5 g/dl)(11.3 g/dl) [12] ACCORD (13 15 g/dl) ( g/dl) [13] g/dl13 g/dl B12 (ferritin) 200 ng/ml 100 ng/ml 500 ng/ml (HO-1) PI3 kinase/akt HO-1 superoxide dismutase catalase glutathione peroxidase [14] NK-κB NMDA NO [15] 4-hydroxy-2- nonenal malondialdehyde Bcl-2 Bcl-X L bax bak [16] Gouva [17] ACCORD CREATE CHOIR [11-13] R

4 BEST epoetin alfa g/dl (70% 76%) ENHANCE epoetin beta g/dl ( 1.39) -CAN g/dl ( 1.84) 2007 [18] (PRCA) 20 30% ( 10 mmhg) ADMA NO endothelin norepinephrine PRCA Eprex (epoetin alfa) Eprex Tween-80 Eprex prednisolone (1 mg/kg/day) 50% cyclophosphamdie ( mg/day) 87% cyclosporine ( mg/day) IVIg plasmapheresis rituximab Hematide R Hematide mg/kg Hematide 2. (PRCA) ( /L) (transferrin saturation) ( 5% erythroblasts) 2 ( 10 )

5 PRCA [19] Prolyl Hydroxylase (HIF ) HIF HIF-α prolyl hydroxylase asparaginyl hydroxylase 2-oxoglutarate 2-oxoglutarate HIFHIF HIF prolyl hydroxylase [19] GATA GATA-2 mrna GATA-2 GATA-2 CFU-E [19] Hemopoietic cell phosphatase Hemopoietic cell phosphatase (HCP) HCP [19] R Receptor recycling P P P P HCP P P Proliferation Ras/MAP Pl3K/Akt Anti-apoptosis NFkB STAT5 SOCS/CIS 1. Ras/MAPK PI3K/Akt NF- B STAT5 HCP ( [20])

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