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Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist
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| Zeitschriftentitel: | Stem Cells |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , |
| In: | Stem Cells, 27, 2009, 2, S. 424-430 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Oxford University Press (OUP)
|
| Schlagwörter: |
| author_facet |
Erickson-Miller, Connie L. Delorme, Evelyne Tian, Shin-Shay Hopson, Christopher B. Landis, Amy J. Valoret, Elizabeth I. Sellers, Teresa S. Rosen, Jon Miller, Stephen G. Luengo, Juan I. Duffy, Kevin J. Jenkins, Julian M. Erickson-Miller, Connie L. Delorme, Evelyne Tian, Shin-Shay Hopson, Christopher B. Landis, Amy J. Valoret, Elizabeth I. Sellers, Teresa S. Rosen, Jon Miller, Stephen G. Luengo, Juan I. Duffy, Kevin J. Jenkins, Julian M. |
|---|---|
| author |
Erickson-Miller, Connie L. Delorme, Evelyne Tian, Shin-Shay Hopson, Christopher B. Landis, Amy J. Valoret, Elizabeth I. Sellers, Teresa S. Rosen, Jon Miller, Stephen G. Luengo, Juan I. Duffy, Kevin J. Jenkins, Julian M. |
| spellingShingle |
Erickson-Miller, Connie L. Delorme, Evelyne Tian, Shin-Shay Hopson, Christopher B. Landis, Amy J. Valoret, Elizabeth I. Sellers, Teresa S. Rosen, Jon Miller, Stephen G. Luengo, Juan I. Duffy, Kevin J. Jenkins, Julian M. Stem Cells Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist Cell Biology Developmental Biology Molecular Medicine |
| author_sort |
erickson-miller, connie l. |
| spelling |
Erickson-Miller, Connie L. Delorme, Evelyne Tian, Shin-Shay Hopson, Christopher B. Landis, Amy J. Valoret, Elizabeth I. Sellers, Teresa S. Rosen, Jon Miller, Stephen G. Luengo, Juan I. Duffy, Kevin J. Jenkins, Julian M. 1066-5099 1549-4918 Oxford University Press (OUP) Cell Biology Developmental Biology Molecular Medicine http://dx.doi.org/10.1634/stemcells.2008-0366 <jats:title>Abstract</jats:title> <jats:p>Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34+ bone marrow cells into CD41+ megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production.</jats:p> Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist Stem Cells |
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| title |
Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_unstemmed |
Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_full |
Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_fullStr |
Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_full_unstemmed |
Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_short |
Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_sort |
preclinical activity of eltrombopag (sb-497115), an oral, nonpeptide thrombopoietin receptor agonist |
| topic |
Cell Biology Developmental Biology Molecular Medicine |
| url |
http://dx.doi.org/10.1634/stemcells.2008-0366 |
| publishDate |
2009 |
| physical |
424-430 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34+ bone marrow cells into CD41+ megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production.</jats:p> |
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| author | Erickson-Miller, Connie L., Delorme, Evelyne, Tian, Shin-Shay, Hopson, Christopher B., Landis, Amy J., Valoret, Elizabeth I., Sellers, Teresa S., Rosen, Jon, Miller, Stephen G., Luengo, Juan I., Duffy, Kevin J., Jenkins, Julian M. |
| author_facet | Erickson-Miller, Connie L., Delorme, Evelyne, Tian, Shin-Shay, Hopson, Christopher B., Landis, Amy J., Valoret, Elizabeth I., Sellers, Teresa S., Rosen, Jon, Miller, Stephen G., Luengo, Juan I., Duffy, Kevin J., Jenkins, Julian M., Erickson-Miller, Connie L., Delorme, Evelyne, Tian, Shin-Shay, Hopson, Christopher B., Landis, Amy J., Valoret, Elizabeth I., Sellers, Teresa S., Rosen, Jon, Miller, Stephen G., Luengo, Juan I., Duffy, Kevin J., Jenkins, Julian M. |
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| description | <jats:title>Abstract</jats:title> <jats:p>Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34+ bone marrow cells into CD41+ megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production.</jats:p> |
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| institution | DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229 |
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| spelling | Erickson-Miller, Connie L. Delorme, Evelyne Tian, Shin-Shay Hopson, Christopher B. Landis, Amy J. Valoret, Elizabeth I. Sellers, Teresa S. Rosen, Jon Miller, Stephen G. Luengo, Juan I. Duffy, Kevin J. Jenkins, Julian M. 1066-5099 1549-4918 Oxford University Press (OUP) Cell Biology Developmental Biology Molecular Medicine http://dx.doi.org/10.1634/stemcells.2008-0366 <jats:title>Abstract</jats:title> <jats:p>Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34+ bone marrow cells into CD41+ megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production.</jats:p> Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist Stem Cells |
| spellingShingle | Erickson-Miller, Connie L., Delorme, Evelyne, Tian, Shin-Shay, Hopson, Christopher B., Landis, Amy J., Valoret, Elizabeth I., Sellers, Teresa S., Rosen, Jon, Miller, Stephen G., Luengo, Juan I., Duffy, Kevin J., Jenkins, Julian M., Stem Cells, Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist, Cell Biology, Developmental Biology, Molecular Medicine |
| title | Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_full | Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_fullStr | Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_full_unstemmed | Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_short | Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| title_sort | preclinical activity of eltrombopag (sb-497115), an oral, nonpeptide thrombopoietin receptor agonist |
| title_unstemmed | Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist |
| topic | Cell Biology, Developmental Biology, Molecular Medicine |
| url | http://dx.doi.org/10.1634/stemcells.2008-0366 |