US20100160243A1 - Compounds and methods for enhancing erythropoiesis - Google Patents

Compounds and methods for enhancing erythropoiesis Download PDF

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US20100160243A1
US20100160243A1 US12/343,922 US34392208A US2010160243A1 US 20100160243 A1 US20100160243 A1 US 20100160243A1 US 34392208 A US34392208 A US 34392208A US 2010160243 A1 US2010160243 A1 US 2010160243A1
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compound
disease
subject
group
formula
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Rong-Tsun Wu
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National Yang Ming Chiao Tung University NYCU
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National Yang Ming University NYMU
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Assigned to NATIONAL YANG-MING UNIVERSITY reassignment NATIONAL YANG-MING UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WU, RONG-TSUN
Priority to EP14176172.6A priority patent/EP2893930B1/fr
Priority to EP19206081.2A priority patent/EP3628321B1/fr
Priority to JP2011543611A priority patent/JP5645845B2/ja
Priority to AU2009330200A priority patent/AU2009330200B2/en
Priority to CA2867277A priority patent/CA2867277C/fr
Priority to CN200980156609.5A priority patent/CN102316873B/zh
Priority to CA2747996A priority patent/CA2747996C/fr
Priority to KR1020117017126A priority patent/KR101448039B1/ko
Priority to EP09775516.9A priority patent/EP2381948B1/fr
Priority to CN201510171082.0A priority patent/CN104800232B/zh
Priority to PCT/US2009/068957 priority patent/WO2010075263A2/fr
Priority to TW098144640A priority patent/TWI386213B/zh
Publication of US20100160243A1 publication Critical patent/US20100160243A1/en
Priority to HK12101736.3A priority patent/HK1161543A1/zh
Priority to AU2013201714A priority patent/AU2013201714B2/en
Priority to US13/930,849 priority patent/US9248143B2/en
Priority to JP2014164524A priority patent/JP5856659B2/ja
Priority to US14/792,064 priority patent/US20160008386A1/en
Priority to HK15108651.6A priority patent/HK1209313A1/xx
Priority to US14/980,264 priority patent/US9980979B2/en
Priority to AU2017204887A priority patent/AU2017204887B2/en
Priority to AU2019236664A priority patent/AU2019236664A1/en
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Definitions

  • the present invention relates generally to erythropoiesis, and more specifically to enhancement of erythropoiesis.
  • CKD Chronic kidney disease
  • Anemia an early symptom of CKD, results from underproduction of endogenous erythropoietin (Epo) by kidney (Zarzecki el al., 2004).
  • Epo endogenous erythropoietin
  • anemia is also associated with other diseases, such as cancer, acute and chronic infections, autoimmune, inflammation and chronic rejection after solid-organ transplantation (Weiss and Goodnough, 2005).
  • Epo is a glycoprotein hormone mainly produced in adult kidney and fetal liver. Epo exerts its effect by binding to erythropoietin receptor (Epo receptor) on cell surface. When cells sense a relatively low oxygen level (such as the hypoxia), Epo is produced and released to regulate proliferation, differentiation, maturation, and survival in erythroid lineage cells (Moritz e al., 1997 and Fisher, 2003). Abnormal Epo levels in bloodstream may be an indicator for bone marrow and renal diseases. Relatively low Epo levels have been seen in patients with CKD, primary polycythemia rubra vera and chemotherapy-induced anemia. Relatively high Epo levels have been seen in secondary polycythemia and renal cancer patients (Eckardt and Kurtz, 2005 and Hodges el al., 2007).
  • Epo and its receptors have been found in non-erythroid tissues and organs, including brain, eye, heart, lung, gut, pancreas, muscle, uterus and gonads (Eckardt and Kurtz, 1992). Epo-Epo receptor signaling contributes to wound healing responses, angiogenesis and local tissue-protective functions, such as neuroprotections, cardiovascular protections and protections from tissue ischemia and ischemia/reperfusion injury (Pascilos el al., 2008 and Arcasoy, 2008). It has been reported that Epo has renoprotective effects by reducing the extent of renal dysfunction and facilitating the recovery from cisplatin-induced acute renal failure (Sepodes et al., 2006 and Arcasoy, 2008).
  • Erythropoiesis-stimulating agents are recommended by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines to treat anemia of CKD in patients with treatment-responsive anemia.
  • Recombinant human Epo rHuEpo
  • rHuEpo Recombinant human Epo
  • a novel erythropoiesis-stimulating protein (NESP), designed from Epo with a longer plasma half-life, has been approved for treating anemia in chronic renal failure (Fisher, 2003).
  • the invention is related to a method for enhancing erythropoietin formation in a subject in need thereof.
  • the method includes administering to the subject an effective amount of a compound of the formula:
  • R is a glycosyl group
  • the glycosyl group is at least one selected from the group consisting of dihydroxyacetone, glucose, galactose, glyceraldehydes, threose, xylose, mannose, ribose, ribulose, xylulose, tagatose, psicose (allulose), fructose, sorbose, rhamnose, erythrose, erythrulose, arabinose, lyxose, allose, altrose, gulose, idose and talose and any combinations thereof.
  • the invention is related to a method for treating a disease and/or disorder in a subject that would benefit from erythropoietin treatment.
  • the method includes administering to the subject an effective amount of the aforementioned compound of the formula (I).
  • the disease is at least one selected from anemia, a renal failure, and erythropoiesis deficiency-related diseases.
  • the disorder would benefit from an erythropoietin-related protective effect.
  • the erythropoietin-related protective effect is at least one selected from neuroprotection, cardiovascular protection, renoprotective effect, and protections from tissue ischemia and ischemia/reperfusion injury.
  • the invention is related to a method for enhancing erythropoiesis in a subject in need thereof.
  • the method includes administering to the subject an effective amount of the aforementioned compound of the formula (I).
  • the invention is related to a method for enhancing kidney function in a subject in need thereof.
  • the method includes administering to the subject an effective amount of the aforementioned compound of the formula (I).
  • the invention is related to a method for increasing the expression of hepatocyte growth factor in a subject in need thereof.
  • the method includes administering to the subject an effective amount of the aforementioned compound of the formula (I).
  • the invention is related to a method for treating a disease and/or disorder in a subject that would benefit from hepatocyte growth factor treatment.
  • the method includes administering to the subject an effective amount of the aforementioned compound of the formula (I).
  • the invention is related to a method for treating a disease and/or disorder via regulating the expression of hepatocyte growth factor in a subject in need thereof.
  • the method includes administering to the subject an effective amount of the aforementioned compound of the formula (I).
  • the disease and/or disorder is at least one selected from allergic inflammation, osteoarthritis, rheumatoid arthritis, muscular dystrophy, muscular atrophy, skin ulcer, burn, scleroderma,.crush syndrome, cerebrovascular diseases such as transient ischemic attack and stroke, neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease and, Parkinson's disease, spinal cord injury, diabetic retinopathy, peripheral neuropathy, spinal canal stenosis, deafness, acute hepatitis, liver cirrhosis, fulminant hepatitis, fatty liver, surgical treatments for liver transplantation, partial resection and ischemia, kidney fibrosis, acute renal failure, chronic renal failure such as nephritic syndrome and obstructive nephropathy, surgical treatments for renal transplantation and ischemia, diabetic nephropathy, acute pneumonia, pulmonary fibrosis, surgical treatments for lung transplantation, partial resection and ischemia, inflammation-mediated
  • FIG. 1 is a graph showing Compound A enhances hemoglobin levels in bone marrow cells.
  • FIG. 2 is a graph showing Compound A stimulates erythroid progenitor cell proliferation using burst-forming units-erythroid (BFU-E) assay on bone marrow cells.
  • BFU-E burst-forming units-erythroid
  • FIG. 3 is a graph showing Compound A increases the expression of erythropoietin (Epo) in kidney tissue.
  • FIG. 4 is a graph showing Compound A increases the expression of erythropoietin (Epo) in hepatocytes.
  • FIG. 5 is a graph showing Compound A increases the number of red blood cells in a cisplatin-induced acute renal failure animal model.
  • FIG. 6 is a graph showing Compound A decreases serum blood urea nitrogen levels in a cisplatin-induced acute renal failure animal model.
  • FIG. 7 is a graph showing Compound A increases the number of red blood cells in a cisplatin-induced acute renal failure animal model at day 23.
  • the horizontal arrow represents Compound A treatment (mg/Kg/day).
  • FIG. 8 is a graph showing Compound A decreases serum blood urea nitrogen levels in a cisplatin-induced acute renal failure animal model at day 23.
  • the horizontal arrow represents Compound A treatment (mg/Kg/day).
  • FIG. 9 is a graph showing Compound A increases the expression of erythropoietin (Epo) in liver tissue in a cisplatin-induced acute renal failure animal model.
  • the horizontal arrow represents Compound A treatment (mg/Kg/day).
  • FIG. 10 is a graph showing Compound A increases the expression of hepatocyte growth factor (HGF) in liver tissue in a cisplatin-induced acute renal failure animal model.
  • the horizontal arrow represents Compound A treatment (mg/Kg/day).
  • FIG. 11 is a graph showing Compound A stimulates erythroid progenitor cell proliferation using burst-forming units-erythroid (BFU-E) assay on bone marrow cells in a cisplatin-induced acute renal failure animal model.
  • the horizontal arrow represents Compound A treatment (mg/Kg/day).
  • “around”, “about” or “approximately” shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “around”, “about” or “approximately” can be inferred if not expressly stated.
  • Six EtOAc layers were pooled together, concentrated, and the concentrate was dried in Freeze Dryer (Kingniech, Taiwan) to obtain the EtOAc extract (called “PoMuEPe”).
  • R is a glucosyl group
  • mice C57BL/6JNar1 mice, 8-10 weeks of age, were purchased from the National Laboratory Animal Center (NLAC, Taiwan).
  • Acute hemolytic anemia was induced by a single intraperitoneal (i.p.) injection of phenylhydrazine hydrochloride (Sigma-Aldrich) at a dose of 100 mg/kg in a phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • bone marrow cells were isolated from mice and cultured according to the procedure described in Worthington el al., (I 985) and Rosenthal et al. (1987) with minor modifications.
  • the cell suspension was adjusted to a density of about 6 ⁇ 10 5 cells/ml in MEM alpha medium ( ⁇ -MEM, Gibco) containing 1% (v/v) bovine serum albumin (BSA, Sigma-Aldrich), 7.5 ⁇ M of 2-mercaptoethanol (Sigma-Aldrich), 1.4 mM of L-glutamine (Sigma-Aldrich), 10 ⁇ M of ferric chloride (FeCl 3 , Sigma-Aldrich) and 50 mU/ml of EPO (Recormon Epoetin, Roche).
  • the cells were plated at approximately 1.5 ⁇ 10 5 cells/well in 96-well plates (Costar), and cultured in a humidified 37° C. incubator containing 5% CO 2 -95% air.
  • burst-forming-units-erythroid (BFU-E) assay was conducted according to the procedures described in Corazza et al. (2004) and Jin el al. (2003) with modifications. Briefly, 6-week-old C57BL/6JNar1 mice were purchased from the National Laboratory Animal Center (NLAC, Taiwan).
  • Bone marrow cells were isolated from the mice, and the cell suspension was adjusted to about 8.3 ⁇ 10 4 cells/ml in a-MEM containing 15% (v/v) FBS (Gibco), 1% (v/v) BSA (Sigma-Aldrich), 0.8% (w/v) methylcellulose (Sigma-Aldrich), 10 ⁇ M 2-mercaptoethanol (Sigma-Aldrich), 2 U/ml Epo (Recormon Epoetin, Roche), and 10 ng/ml IL-3 (Sigma-Aldrich). Cells were plated at approximately 7.5 ⁇ 10 4 cells/well in 24-well plates (Falcon).
  • mice C57BL/6JNar1 mice, 8-10 weeks of age, were purchased from the National Laboratory Animal Center (NLAC, Taiwan). The kidney slices of mice were prepared as previously described with modifications (Parrish el al., 1995, Obatomi et al., 1998 and De Kanter et al., 1999).
  • mice were sacrificed by cervical dislocation and the kidneys were excised and immediately kept in gassed (95% O 2 and 5% CO 2 ) ice-cold sterile Krebs-HEPES buffer (pH 7.4) containing 20 mM HEPES (USB), 128 mM sodium chloride (Sigma-Aldrich), 2.5 mM potassium chloride (Sigma-Aldrich), 2.7 mM calcium chloride (Sigma-Aldrich), 1 mM magnesium chloride (Sigma-Aldrich) and 16 mM D-glucose (Sigma-Aldrich).
  • USB HEPES
  • 128 mM sodium chloride Sigma-Aldrich
  • 2.5 mM potassium chloride Sigma-Aldrich
  • 2.7 mM calcium chloride Sigma-Aldrich
  • 1 mM magnesium chloride Sigma-Aldrich
  • 16 mM D-glucose Sigma-Aldrich
  • Kidney slices (250 ⁇ m) were prepared in microslicer (D.S.K microslicer, DRK 1000, Dosaka EM Co) filled with gassed (95% O 2 : 5% CO 2 ) ice-cold sterile Krebs-HEPES buffer. Kidney slices were collected and stored on ice in gassed (95% O 2 , 5% CO 2 ) ice-cold sterile Krebs-HEPES buffer and used within 10 min of slice preparations.
  • D.S.K microslicer D.S.K microslicer, DRK 1000, Dosaka EM Co
  • Kidney slices were preincubated in a 24-well plate (Falcon) containing 1.0 ml/well of gassed (95% O 2 , 5% CO 2 ) fresh media (DMEM/F12 (Gibco/Invitrogen) containing 15 mM HEPES (USB), 20 mM sodium bicarbonate (Sigma-Aldrich)) and 5% (v/v) FBS (Gibco) for 90 ⁇ 120 min at 37° C. in a 95% O 2 : 5% CO 2 atmosphere chamber. Afterwards, kidney slices were incubated with different concentrations of Compound A (0, 0.6, 2.5, 10, 40 and 100 ⁇ g/ml), respectively, for 16 hr at 37° C.
  • Compound A 0., 0.6, 2.5, 10, 40 and 100 ⁇ g/ml
  • RNA Ribonucleic acids
  • RNA-Beel RNA isolation solvent Tel-test.
  • Total RNA 5 ⁇ g was used to prepare complementary deoxyribonucleic acid (cDNA) using MMLV reverse transcriptase (Promega).
  • the reverse-transcribed cDNA samples were analyzed by polymerase chain reaction (PCR) using ABI GeneAmpTM system 2700 (Applied Biosystems) with primers targeting toward mouse Mactin (SEQ ID NOs: 1 and 2) and erythropoietin (Epo) (SEQ ID NOs: 3 and 4) (Table 1). Results were compared with control group (0 ⁇ g/ml) and expressed as relative index. The results indicated that Compound A increased the expression of Epo in kidney tissue ( FIG. 3 ).
  • mice C57BL/6JNar1 mice, 8-10 weeks of age, were purchased from the National Laboratory Animal Center (NLAC, Taiwan).
  • the hepatocytes were isolated as previously described with modifications (Kreamer el al., 1986). Briefly, mice were anaesthetized with Avertin (2% (w/v) 2,2,2-tribromoethanol, i.p., 300 mg/Kg body weight). and the liver was perfused in situ through portal vein with a calcium-free Hank's balanced salt solution (HBSS) containing 0.5 mM Ethylene glycol-bis(2-aminoethylether)-N,N,N,N′-tetraacetic acid (EGTA; Sigma-Aldrich).
  • HBSS Hank's balanced salt solution
  • the flow rate was 1 ml/min with the perfusate exiting via the severed inferior vena cava.
  • HBSS containing 0.05% (w/v) collagenase (Type II; Worthington Biochemical Corporation) and 1 mM calcium chloride (Sigma-Aldrich) was introduced into the perfusion apparatus. The perfusion was continued for another 10 min at the same flow rate.
  • the partially digested liver was removed, placed in a 60-mm culture dish (BD Falcon) containing HBSS, and gently minced to open the liver capsula. The minced liver suspension was filtered through a nylon mesh (about 300 ⁇ m pore size), centrifugated at 50 ⁇ g for 3 min to obtain a cell pellet.
  • the percoll (GE Healthcare) medium of a density of 1.06 g/ml was prepared.
  • the cell pellet was suspended in DMEM medium (Gibco/Invitrogen), centrifuged with the percoll medium at 50 ⁇ g for 10 min at 4° C., washed once with DMEM medium and followed by centrifugation at 50 ⁇ g for 2 min to obtain hepatocytes.
  • the isolated hepatocytes were plated in 6-well plates (Costar) at approximately 6 ⁇ 10 5 cells/well in DMEM medium (Gibco/Invitrogen) containing 10% FBS (Gibco) in a humidified 37° C. incubator containing 5% CO 2 -95% air. After 3 hr, the medium was removed, and the cells were incubated with different concentrations of compound A (0, 0.1, 0.5, 2.5 and 12.5 ⁇ g/ml), respectively, for 24 hours.
  • the RNA of hepatocyte was extracted by RNA-BeeTM RNA isolation solvent (Tel-test) for reverse transcription, and the transcripts analyzed by PCR as previously described. The results indicated that Compound A enhanced the expression of Epo in hepatocytes ( FIG. 4 ).
  • mice C57BL/6JNar1 mice (8-week-old) were purchased from the National Laboratory Animal Center (NLAC, Taiwan). Cisplatin (Sigma-Aldrich) was dissolved in normal saline (0.9% (w/v) sodium chloride, Sigma-Aldrich) at a concentration of 1 mg/ml, and injected into mice intraperitoneally (i.p.) according to the following schedule: day 1, 7 mg/kg; day 5, 6 mg/kg; and day 9, 6 mg/kg. For cisplatin-untreated normal mice group, normal saline injections of corresponding volumes were given i.p. in parallel.
  • mice were injected with normal saline and followed by feeding with a standard diet
  • Control group Mice were injected with cisplatin and followed by feeding with a standard diet
  • Pomu 10 mg/kg/day group Mice were injected with cisplatin and followed by feeding with Compound A at the dose of 10 mg/kg/day
  • Pomu 30 mg/kg/day group Mice were injected with cisplatin and followed by Compound A at the dose of 30 mg/kg/day
  • (5) Pomu 90 mg/kg/day group Mice were injected with cisplatin and followed by Compound A treatment at the dose of 90 mg/kg/day.
  • Red blood cell (RBC) concentrations were determined by complete blood cell count using Sysmex Kx-2 I hematology analyzer.
  • Compound A Increases Liver Expressions of Epo and Hepatocyte Growth Factor in a Cisplatin-induced Acute Renal Failure Animal Model
  • mice were sacrificed, kidney and liver tissues were removed, and bone marrow cells were isolated.
  • RNA from tissues and bone marrow cells were extracted by RNA-BeeTM RNA isolation solvent (Tel-test). Total RNA (5 ⁇ g) was used to prepare cDNA using MMLV reverse transcriptase (Promega).
  • Compound A Activates Erythroid Progenitor Cells in a Cisplatin-Induced Acute Renal Failure Animal Model
  • Compound A has been found in several plants. According to the literatures, Compound A has the following pharmacological effects: stimulating melanogenesis by activating tyrosinase (Guan et al., 2008), inhibiting lipid peroxidation (Kimura et al., 1983), having a protective effect on colitis through alleviating oxygen and nitrogen free radicals level and down-regulating inducible nitric oxide synthase expression (Wang et al., 2008), having anti-atherosclerosis effect via its antagonistic effects on oxidation of lipoprotein, proliferation and decrease in nitric oxide content of coronary arterial smooth cells (Liu et al., 2007), having anti-inflammatory function that is related to the inhibition of cyclooxygenase-2 enzyme activity and expression (Zhang el al., 2007), and are beneficial for Alzheimer disease and cognitive impairment (Wang et
  • the Fleeceflower root contains numerous chemical components, such as eniodin, chrysophanol, physcion, rhein, chrysophanol anthrone, resveratrol, piceid, 2,3,5,4′-tetrahydrostilbene-2-O- ⁇ -D-glucopyranoside, 2,3,5,4′-tetrahydroxystilbene-2-O- ⁇ -D-gluco-pyranoside-2′-O-mo-nogalloyl ester, 2,3,5,4′-tetrahydroxystilbene-2-O- ⁇ -D-glucopyranosid-e-3′′-O-monogalloyl ester, gallic acid, catechin, epicatechin, 3-O-galloyl( ⁇ )-catechin, and 3-O-galloyl( ⁇ )epicatechin, 3-O-galloyl-procyanidin B-2,3,3′-di-O-galloyl-procyan
  • Compound A has been proved to be biologically active in increasing Epo production and enhancing erythropoiesis and kidney functions.
  • the glucosyl group in Compound A may be replaced by saccharides such as dihydroxyacetone, galactose, glyceraldehydes, threose, xylose, mannose, ribose, ribulose, xylulose, tagatose, psicose (allulose), fructose, sorbose, rhamnose, erythrose, erythrulose, arabinose, lyxose, allose, altrose, gulose, idose, talose, and any combinations thereof.
  • saccharides such as dihydroxyacetone, galactose, glyceraldehydes, threose, xylose, mannose, ribose, ribulose, xylulose, tagatose, p
  • Epo stimulates erythropoiesis, and that Epo is required for erythropoiesis (Moritz el al., 1997). It has also been reported that Epo has renoprotective effects (Sepodes el al., 2006 and Arcasoy, 2008). In addition to increasing Epo production, Compound A enhances erythropoiesis and kidney functions.
  • HGF is a multifunctional cytokine that is related to cell survival, growth, motility and morphogenesis, tissue regeneration, protection and repair. It has been reported that HGF activates signal transduction from Epo receptor (Iguchi et al., 1999 and Isobe et al., 2006).
  • HGF has been shown to have therapeutic potential for allergic inflammation (Ito et al., 2008), osteoarthritis, rheumatoid arthritis, muscular dystrophy, muscular atrophy, skin ulcer, burn, scleroderma, crush syndrome (Funakoshi and Nakamura, 2003), cerebrovascular diseases such as transient ischemic attack and stroke, neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease, spinal cord injury, diabetic retinopathy, peripheral neuropathy, spinal canal stenosis, deafness (Ftnakoshi and Nakamura, 2003 and Takeo et al., 2007), acute hepatitis, liver cirrhosis, fulminant hepatitis, fatty liver, surgical treatments for liver transplantation, partial resection and ischemia (Funakoshi and Nakamura, 2003 and Mizuno and Nakamura, 2007), kidney fibrosis, acute renal failure, chronic renal failure such as
  • Compound A has a structure based on 3,4′,5-trihydroxy-trans-stilbene, which is a natural compound possessing numerous biological activities, including renoprotection via nitric oxide dependent and/or antioxidant mechanisms (Sharma et al., 2006; Shankar et al., 2007; Do Amaral et al., 2008 and Orallo, 2008).
  • Compound A was found to be superior to 3,4′,5-trihydroxy-trans-stilbene in enhancing renal functions and improving anemia (data not shown).
  • rHuEpo and NESP have been used in intravenous (i.v.) or subcutaneous (s.c.) injection for treating anemia of CKD, anemia in cancer patients receiving chemotherapy, anemia in zidovudine-treated patients infected with human immunodeficiency virus (Fisher, 2003). It has been recommended that the administration be given more than once per week for maintenance therapy. The cost, the inconvenience due to frequent injections (parenteral administration) and development of anti-Epo antibodies due to inherent antigenicity of rHuEpo all point to a need for developing an improved therapeutic agent. Oral administration of Compound A, one of 3,4′,5-trihydroxy-trans-stilbene analogs, can increase Epo formation, enhances erythropoiesis and kidney functions, and reduces anemia.
  • the compound 3,4′,5-trihydroxy-trans-stilbene has been reported to have renoprotective effects via nitric oxide dependent and/or antioxidant mechanisms.
  • Compound A is superior to 3,4′,5-trihydroxy-trans-stilbene in enhancing erythropoiesis and kidney functions.
  • Compound A has the advantages that recombinant Epo does not have: An oral administration of Compound A does not pose inherent antigenicity, which recombinant Epo has.
  • the route of administration of rEPO is inconvenient because it requires frequent injections.
  • Compound A may be beneficial for disorder-associated anemia, such as CKD, cancer, acute and chronic infections, autoimmune, inflammation, chronic rejection after solid-organ transplantation, chemotherapy-induced anemia, and tissue ischemia.

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US12/343,922 US20100160243A1 (en) 2008-12-24 2008-12-24 Compounds and methods for enhancing erythropoiesis
PCT/US2009/068957 WO2010075263A2 (fr) 2008-12-24 2009-12-21 Composés et méthode d'amplification de l'érythropoïèse
EP09775516.9A EP2381948B1 (fr) 2008-12-24 2009-12-21 Composés pour l'amplification de l'érythropoïèse
CN201510171082.0A CN104800232B (zh) 2008-12-24 2009-12-21 促进红细胞生成的化合物用于制备治疗肾衰竭的药物的用途
EP19206081.2A EP3628321B1 (fr) 2008-12-24 2009-12-21 Composés pour l'amplification de l'érythropoïèse
JP2011543611A JP5645845B2 (ja) 2008-12-24 2009-12-21 赤血球生成の強化に係わる化合物とその方法
AU2009330200A AU2009330200B2 (en) 2008-12-24 2009-12-21 Compounds and methods for enhancing erythropoiesis
CA2867277A CA2867277C (fr) 2008-12-24 2009-12-21 Composes et methode d'amplification de l'erythropoiese
CN200980156609.5A CN102316873B (zh) 2008-12-24 2009-12-21 促进红细胞生成的化合物和方法
CA2747996A CA2747996C (fr) 2008-12-24 2009-12-21 Composes et methode d'amplification de l'erythropoiese
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EP14176172.6A EP2893930B1 (fr) 2008-12-24 2009-12-21 Composés pour l'amplification de l'érythropoïèse
TW098144640A TWI386213B (zh) 2008-12-24 2009-12-23 增進紅血球生成的化合物與方法
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AU2013201714A AU2013201714B2 (en) 2008-12-24 2013-03-20 Compounds and methods for enhancing erythropoiesis
US13/930,849 US9248143B2 (en) 2008-12-24 2013-06-28 Compounds and methods for enhancing erythropoiesis
JP2014164524A JP5856659B2 (ja) 2008-12-24 2014-08-12 赤血球生成の強化に係わる化合物とその方法
US14/792,064 US20160008386A1 (en) 2008-12-24 2015-07-06 Composition and method for inducing epo-mediated haemoglobin expression and mitochondrial biogenesis in nonhaematopoietic cell
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US14/980,264 US9980979B2 (en) 2008-12-24 2015-12-28 Compounds and methods for enhancing erythropoiesis
AU2017204887A AU2017204887B2 (en) 2008-12-24 2017-07-14 Compounds and methods for enhancing erythropoiesis
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WO2014158165A1 (fr) * 2013-03-28 2014-10-02 WU, Sophia, Shu Fen Composition et procédé pour induire l'expression d'hémoglobine médiée par l'epo et la biogénèse mitochondriale dans une cellule non hématopoïétique
WO2016201953A1 (fr) 2015-06-16 2016-12-22 Rong-Tsun Wu Méthode de traitement ou de prévention de la sécheresse oculaire
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WO2014080640A1 (fr) 2012-11-26 2014-05-30 国立大学法人東北大学 Promoteur d'expression de l'érythropoïétine
CN103087123B (zh) * 2013-02-05 2015-09-30 西安岳达植物科技有限公司 一种从何首乌中提取二苯乙烯苷的方法
CN107441182B (zh) * 2016-05-30 2021-08-10 中国人民解放军第三〇二医院 何首乌提取物的制备方法及其制剂和应用
JP6467762B2 (ja) * 2017-02-10 2019-02-13 香港友池有限公司 配糖化スチルベノイド化合物の製造方法
TWI671284B (zh) * 2018-08-03 2019-09-11 永勝藥品工業股份有限公司 治療大腸直腸癌的化合物
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US20130316967A1 (en) * 2008-12-24 2013-11-28 National Yang-Ming University Compounds and methods for enhancing erythropoiesis
US9248143B2 (en) * 2008-12-24 2016-02-02 National Yang-Ming University Compounds and methods for enhancing erythropoiesis
US9980979B2 (en) 2008-12-24 2018-05-29 National Yang-Ming University Compounds and methods for enhancing erythropoiesis
CN102718812A (zh) * 2012-05-22 2012-10-10 中国人民解放军第四军医大学 一种从珍珠菜中提纯二苯乙烯苷的方法
WO2014158165A1 (fr) * 2013-03-28 2014-10-02 WU, Sophia, Shu Fen Composition et procédé pour induire l'expression d'hémoglobine médiée par l'epo et la biogénèse mitochondriale dans une cellule non hématopoïétique
WO2016201953A1 (fr) 2015-06-16 2016-12-22 Rong-Tsun Wu Méthode de traitement ou de prévention de la sécheresse oculaire
US10383885B2 (en) 2015-06-16 2019-08-20 Rong-Tsun Wu Method for treating or preventing dry eyes
US10040813B2 (en) * 2015-07-23 2018-08-07 Acahealth Pharma & Biotech Co., Ltd. Compounds as positive allosteric modulators for erythropoietin and erythropoietin receptor to treat erythropoietin deficiency diseases

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