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Compounds and methods for enhancing erythropoiesis

a technology of erythropoiesis and compound, which is applied in the field of erythropoiesis, can solve the problems of unaddressed need in the art to address the above, and patients with ckd are at high risk of progression to the end stage renal diseas

Inactive Publication Date: 2010-06-24
NATIONAL YANG MING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The invention relates to a method for increasing the production of erythropoietin, a hormone that helps regulate red blood cell formation, in a subject in need thereof. The method involves administering a compound of the formula (I) to the subject. The invention also includes methods for treating diseases and disorders that would benefit from increased erythropoietin levels, such as anemia, renal failure, and cardiovascular diseases. The compound of formula (I) can also be used to enhance kidney function and increase the expression of hepatocyte growth factor. The patent text also describes the drawings and reference numbers used in the patent."

Problems solved by technology

Patients with CKD are at high risks for progression to the end stage renal disease and need the dialysis or kidney transplantation to maintain a long-term survival.
Moreover, ESAs pose safety risks in patients with higher hemoglobin levels and may cause complications such as hypertension, thromboembolism, iron deficiency and severe pure red-cell aplasia (Wish and Coyne, 2007).
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies, especially in connection with erythropoiesis and kidney functions.

Method used

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  • Compounds and methods for enhancing erythropoiesis
  • Compounds and methods for enhancing erythropoiesis
  • Compounds and methods for enhancing erythropoiesis

Examples

Experimental program
Comparison scheme
Effect test

example 1

Purification of Compound A

[0036]Two kilograms of dry Polygonum multiflorum were ground in a pulverizer and the ground material was immersed in 2 liters of 85% (v / v) ethanol overnight to form a reaction solution. The reaction solution was collected, and another 2 liters of 85% (v / v) ethanol were added to the ground Polygonum multiflorum residue for further extraction according to the aforementioned procedure. The ethanol extraction was repeated for additional three times. The collected solution was filtrated using a gas-extracting apparatus (with Whatman #1 filter papers), and followed by concentration in a rotavapor (Buchi) at 40° C. to a six-fold reduction in volume. The concentrated filtrates were pooled together and partitioned 5 times with n-hexane / H2O=1:1 (total 5 liters). The aqueous phase was collected and further partitioned 6 times with ethyl acetate water, EtOAc / H2O=1:1 (total 6.5 liters), to obtain EtOAc layer. Six EtOAc layers were pooled together, concentrated, and the ...

example 2

Compound A Enhances Hemoglobin Formation

[0038]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). Six days after the injection, 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 6×105 cells / ml in MEM alpha medium (α-MEM, Gibco) containing 1% (v / v) bovine serum albumin (BSA, Sigma-Aldrich), 7.5 μM of 2-mercaptoethanol (Sigma-Aldrich), 1.4 mM of L-glutamine (Sigma-Aldrich), 10 μM of ferric chloride (FeCl3, Sigma-Aldrich) and 50 mU / ml of EPO (Recormon Epoetin, Roche). The cells were plated at approximately 1.5×105 cells / well in 96-well plates (Costar), and cultu...

example 3

Compound A Activates Erythroid Progenitor Cells in Cell Culture

[0040]To investigate the effect of “Compound A” on erythroid progenitor cells, 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 8.3×104 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 μM 2-mercaptoethanol (Sigma-Aldrich), 2 U / ml Epo (Recormon Epoetin, Roche), and 10 ng / ml IL-3 (Sigma-Aldrich). Cells were plated at approximately 7.5×104 cells / well in 24-well plates (Falcon). They were incubated with different concentrations of Compound A (0, 0.1, 0.5, 2.5 and 12.5 μg / ml), respectively, for 9 days in a humidified 37° C. incubator ...

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Abstract

Compounds and methods for enhancing erythropoiesis. The compound contains a chemical structure of the formula (I) indicated below, in which R is a glucosyl group. In addition to having an erythropoiesis effect, the compound of the formula (1) is effective in enhancing erythropoietin formation, and increasing kidney function and expression of hepatocyte growth factor. The method includes the step of administering an effective amount of the compound of the formula (I) to a subject in need thereof and thereby results in an enhancement of erythropoiesis.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to erythropoiesis, and more specifically to enhancement of erythropoiesis.BACKGROUND OF THE INVENTION[0002]Chronic kidney disease (CKD) is a worldwide public health problem with adverse outcomes of kidney failure, cardiovascular disease and premature death (Levey, 2005). Patients with CKD are at high risks for progression to the end stage renal disease and need the dialysis or kidney transplantation to maintain a long-term survival. Anemia, an early symptom of CKD, results from underproduction of endogenous erythropoietin (Epo) by kidney (Zarzecki el al., 2004). In addition to CKD, 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).[0003]Epo is a glycoprotein hormone mainly produced in adult kidney and fetal liver. Epo exerts its effect by binding to erythropoietin re...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7004A61K31/085
CPCA61K31/7034C07H15/203A61P1/00A61P1/04A61P1/16A61P11/00A61P13/12A61P17/00A61P17/02A61P19/00A61P19/02A61P19/08A61P21/00A61P25/00A61P25/02A61P25/28A61P29/00A61P37/08A61P43/00A61P7/00A61P7/06A61P9/00A61P9/10A61P9/14A61P3/10
Inventor WU
Owner NATIONAL YANG MING UNIVERSITY
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