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Connie L Ericksonmiller - One of the best experts on this subject based on the ideXlab platform.
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preclinical activity of eltrombopag sb 497115 an oral nonpeptide Thrombopoietin receptor agonist
Stem Cells, 2009Co-Authors: Connie L Ericksonmiller, Evelyne Delorme, Christopher B Hopson, Shinshay Tian, Amy Landis, Elizabeth I Valoret, Teresa S Sellers, Jon Rosen, Stephen G Miller, Juan I LuengoAbstract: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.
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phase 1 clinical study of eltrombopag an oral nonpeptide Thrombopoietin receptor agonist
Blood, 2007Co-Authors: Julian Jenkins, Daphne Williams, Yanli Deng, Valerie S Kitchen, David Collins, Connie L EricksonmillerAbstract:Eltrombopag (SB-497 115) is a first-in-class, oral, small-molecule, nonpeptide agonist of the Thrombopoietin receptor (TpoR), being developed as a treatment for thrombocytopenia of various etiologies. In this phase 1 placebo-controlled clinical trial in 73 healthy male subjects, eltrombopag was administered as once-daily oral capsules for 10 days at doses of 5, 10, 25, 30, 50, and 75 mg. The pharmacokinetics of eltrombopag were dose dependent and linear, and eltrombopag increased platelet counts in a dose-dependent manner. There were no apparent differences in the incidence or severity of adverse events in subjects receiving active or placebo study medication. These observations indicate that eltrombopag is a once-daily, oral TpoR agonist with demonstrated thrombopoietic activity in human subjects, encouraging further studies in patients with thrombocytopenia.
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hydrazinonaphthalene and azonaphthalene Thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis
Journal of Medicinal Chemistry, 2001Co-Authors: Kevin J Duffy, Michael G Darcy, Evelyne Delorme, Susan B Dillon, Daniel F Eppley, Connie L Ericksonmiller, Leslie Giampa, Christopher B Hopson, Yifang Huang, Richard M KeenanAbstract:High-throughput screening for the induction of a luciferase reporter gene in a Thrombopoietin (TPO)-responsive cell line resulted in the identification of 4-diazo-3-hydroxy-1-naphthalenesulfonic acids as TPO mimics. Modification of the core structure and adjustment of unwanted functionality resulted in the development of (5-oxo-1,5-dihydropyrazol-4-ylidene)hydrazines which exhibited efficacies equivalent to those of TPO in several cell-based assays designed to measure thrombopoietic activity. Furthermore, these compounds elicited biochemical responses in TPO-receptor-expressing cells similar to those in TPO itself, including kinase activation and protein phosphorylation. Potencies for the best compounds were high for such low molecular weight compounds (MW < 500) with EC50 values in the region of 1−20 nM.
James B. Bussel - One of the best experts on this subject based on the ideXlab platform.
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bone marrow fibrosis in 66 patients with immune thrombocytopenia treated with Thrombopoietin receptor agonists a single center long term follow up
Haematologica, 2014Co-Authors: Waleed Ghanima, Julia T Geyer, Christina Lee, Leonardo Boiocchi, Allison Imahiyerobo, Attilio Orazi, James B. BusselAbstract:Thrombopoietin-receptor agonists increase platelet counts by stimulating the Thrombopoietin receptor. Bone marrow fibrosis has been reported in patients receiving Thrombopoietin-receptor agonists. This study determined the extent of myelofibrosis, its clinical relevance, and incidence of phenotypic or karyotypic abnormalities in patients with immune thrombocytopenia treated with Thrombopoietin-receptor agonists. The grade of myelofibrosis was assessed before (n=15), during (n=117) and after (n=9) treatment in bone marrow biopsies from 66 patients. The proportion of bone marrow biopsies showing no fibrosis (myelofibrosis grade 0) decreased from 67% pre-treatment to 22% at last biopsy, of which 59% had grade 1 myelofibrosis and 18% had grade 2 myelofibrosis. The median duration of treatment with Thrombopoietin-receptor agonists to last bone marrow biopsies was 29 months; patients who had two or more biopsies significantly more frequently had myelofibrosis grades 2/3 in the last bone marrow biopsies as compared to the first. Older age was associated with higher grades of fibrosis. No differences in blood counts or lactate dehydrogenase levels were found between patients with myelofibrosis grades 0/1 and those with grade 2. No clonal karyotypic or immunophenotypic abnormalities emerged. This study found that Thrombopoietin-receptor agonists induce myelofibrosis grades 2/3 in approximately one-fifth of patients with immume thrombocytopenia, increasingly with >2 years of treatment with Thrombopoietin-receptor agonists. Annual/biannual follow-up with bone marrow biopsies is, therefore, recommended in patients being treated with Thrombopoietin-receptor agonists in order to enable prompt discontinuation of these drugs should grades 2/3 myelofibrosis develop. Discontinuation of Thrombopoietin-receptor agonists may prevent development of clinical manifestations by stopping progression of fibrosis in grade 2/3.
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a randomized double blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia
Blood, 2011Co-Authors: James B. Bussel, David J Gnarra, Lisa Bomgaars, Diane J Nugent, George R Buchanan, Victor S Blanchette, Yow Ming WangAbstract:Romiplostim, a Thrombopoietin-mimetic peptibody, increases and maintains platelet counts in adults with immune thrombocytopenia (ITP). In this first study of a thrombopoietic agent in children, patients with ITP of > 6 months’ duration were stratified by age 1:2:2 (12 months 50 109/Lfor 2 consecutive weeks was achieved by 15/17 (88%) patients in the romiplostim group and no patients in the placebo group (P .0008). Platelet counts > 50 109/L were maintained for a median of 7 (range, 0-11) weeks in romiplostim patients and 0 (0-0) weeks in placebo patients (P .0019). The median weekly dose of romiplostim at 12 weeks was 5 g/kg. Fourteen responders received romiplostim for 4 additional weeks for assessment of pharmacokinetics. No patients discontinued the study. There were no treatment-related, serious adverse events. The most commonly reported adverse events in children, as in adults, were headache and epistaxis. In this short-term study, romiplostim increased platelet counts in 88% of children with ITP and was well-tolerated and apparently safe. The trial was registered with http:// www.clinicaltrials.gov as NCT00515203. (Blood. 2011;118(1):28-36)
Kenneth Kaushansky - One of the best experts on this subject based on the ideXlab platform.
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Thrombopoietin and Hematopoietic Stem Cell Development
Annals of the New York Academy of Sciences, 1999Co-Authors: Kenneth KaushanskyAbstract:: Thrombopoietin, the long sought primary regulator of thrombopoiesis, was cloned four years ago. In addition to its fulfilling most, if not all, of the expected biological activities relating to megakaryocyte and platelet development, the availability of the recombinant hormone and reagents to characterize its receptor have allowed detailed investigation of additional biological activities. In cultures of purified populations of candidate stem cells, Thrombopoietin supports the survival, and aubments the proliferation of hematopoietic stem cells when present together with interleukin-3 or steel factor. The progeny of such cultures are not skewed in their developmental potential; colony-forming cells of all lineages arise from thrombopoietion-stimulated stem cells. Evidence for an important effect of Thrombopoietin on stem cell physiology in vivo are equally compelling. Genetic elimination of Thrombopoietin or its receptor leads to a profound reduction not only of megakaryocytes and platelets, but also of committed myeloid progenitors of all types, primitive progenitors and hematopoietic stem cells. When administered to animals, Thrombopoietin profoundly stimulates thrombopoiesis and enhances the number of hematopoietic progenitor cells of all lineages, and when used in most animal models of myelosuppressive therapy, accelerates the recovery of platelet, erythrocyte and leukocyte production. Thus, Thrombopoietin appears to be more than a lineage-restricted growth factor.
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THE ENIGMATIC MEGAKARYOCYTE GRADUALLY REVEALS ITS SECRETS
BioEssays, 1999Co-Authors: Kenneth KaushanskyAbstract:The recent cloning of Thrombopoietin has brought many insights into the cellular and molecular mechanisms of megakaryocyte and platelet development. Thrombopoietin was cloned based on its binding to the product of the proto-oncogene c-mpl and was found to affect all aspects of thrombopoiesis. Many of the molecular pathways that mediate Thrombopoietin action have been discerned. Upon hormone binding, the megakaryocyte Thrombopoietin receptor homodimerizes, activating members of the JAK family of kinases, which, in turn, phosphorylate the receptor, generating docking sites for second messengers that affect multiple signalling pathways. Ultimately, cellular proliferative and anti-apoptotic mechanisms are initiated, increasing megakaryocyte numbers, as are processes that uncouple DNA synthesis from nuclear and cytoplasmic division, generating polyploid cells. As the net result of Thrombopoietin action is an expansion of cells that give rise to mature platelets, the availability of the recombinant hormone has provided new opportunities to manipulate blood cell development for therapeutic benefit.
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Biology of Thrombopoietin.
Current Opinion in Pediatrics, 1998Co-Authors: Virginia C. Broudy, Kenneth KaushanskyAbstract:Thrombopoietin is a hematopoietic growth factor that stimulates megakaryopoiesis. Recent results indicate that Thrombopoietin has multilineage hematopoietic effects both in vitro and in vivo. Clinical studies of Thrombopoietin have begun, and are reviewed.
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the c mpl ligand Thrombopoietin stimulates tyrosine phosphorylation of jak2 shc and c mpl
Journal of Biological Chemistry, 1995Co-Authors: Jonathan G Drachman, James D Griffin, Kenneth KaushanskyAbstract:Abstract c-Mpl is a member of the cytokine receptor superfamily, expressed primarily on hematopoietic cells. Recently, the c-Mpl ligand was cloned and found to have thrombopoietic activity. In this paper we report that ligand binding induced tyrosine phosphorylation in BaF3 cells engineered to express the murine Mpl receptor (BaF3/mMpl). Phosphorylation occurred within 1 min at cytokine concentrations sufficient for proliferation of receptor-bearing cells. Using specific antibodies for immunoprecipitation and Western blotting, several of these phosphorylated proteins were identified. Shc and Jak2, known cytokine signaling molecules, and the c-Mpl receptor were shown to be major substrates for tyrosine phosphorylation. In contrast, phospholipase C-γ and phosphatidylinositol 3-kinase displayed little and no tyrosine phosphorylation, respectively, after Thrombopoietin stimulation. Co-immunoprecipitation studies demonstrated that Jak2 became physically associated with c-Mpl relatively late in the observed time course (20-60 min), significantly later than tyrosine phosphorylation of Jak2 (1-5 min). These results suggest that c-Mpl induces signal transduction pathways similar to those of other known cytokines. Additionally, in light of its late physical association with c-Mpl following ligand binding, Jak2 may not be the initiating tyrosine kinase in the Thrombopoietin-induced signaling cascade.
David J. Kuter - One of the best experts on this subject based on the ideXlab platform.
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Thrombopoietins and Thrombopoiesis: A Clinical Perspective
Vox Sanguinis, 1998Co-Authors: David J. KuterAbstract:Since the discovery of Thrombopoietin four years ago there has been much interest in the clinical use of this growth factor and its impact on platelet transfusions. Two recombinant Thrombopoietin molecules are currently under intense clinical investigation. One is a full-length, glycosylated Thrombopoietin (rHuTPO) and the other is a non-glycosylated, truncated Thrombopoietin coupled to polyethylene glycol (PEG-rHuMGDF). Both bind to the Thrombopoietin receptor, c-mpl, and stimulate megakaryocyte growth and platelet production in vitro and in vivo. In early clinical studies these Mpl ligands have been effective in reducing thrombocytopenia after non-myeloablative but not after myeloablative chemotherapy. In transfusion medicine, they may serve to increase the yield of stem cell harvests, expand progenitor cells ex vivo and stimulate platelet apheresis donors. Their impact on platelet usage is still unclear but may be less than initially estimated.
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Thrombopoiesis and Thrombopoietins Molecular, Cellular, Preclinical, and Clinical Biology
1997Co-Authors: David J. Kuter, Pamela Hunt, William P. Sheridan, Dorothea Zucker-franklinAbstract:I: Introduction -- 1 Megakaryocyte Biology -- 2 Platelet Structure and Function -- 3 The Evolution of Mammalian Platelets -- 4 Potential Clinical Applications of Thrombopoietic Growth Factors -- II: The Search for the Physiologic Regulator of Platelet Production -- 5 Historical Perspective and Overview -- 6 The Murine Myeloproliferative Leukemia Virus MPLV, v-mpl Oncogene, and c-mpl -- 7 Mpl Expression and Functional Role in Human Megakaryocytopoiesis -- 8 The Purification and Cloning of Human Thrombopoietin -- 9 The Purification of Thrombopoietin from Thrombocytopenic Plasma -- 10 The Role of Other Hemopoietic Growth Factors and the Marrow Microenvironment in Megakaryocytopoiesis -- III: Molecular Biology -- 11 Structure of Thrombopoietin and the Thrombopoietin Gene -- 12 Transcription Factors in Megakaryocyte Differentiation and Gene Expression -- 13 The Biological Significance of Truncated and Full-Length Forms of Mpl Ligands -- IV: Cellular Biology -- 14 In Vitro Effects of Mpl Ligand on Human Hemopoietic Progenitor Cells -- 15 Effect of Cytokines on the Development of Megakaryocytes and Platelets: An Ultrastructural Analysis -- 16 The Thrombopoietin Receptor, Mpl, and Signal Transduction -- 17 Regulation of Proplatelet and Platelet Formation In Vitro -- 18 In Vitro Effects of Mpl Ligands on Platelet Function -- V: Preclinical Biology -- 19 In Vivo Dose—Response Effects of Mpl Ligands on Platelet Production and Function -- 20 Efficacy of Mpl Ligands and other Thrombopoietic Cytokines in Animal Models -- 21 Genetic Manipulation of Mpl Ligand and Thrombopoietin In Vivo -- VI: Clinical Biology -- 22 Serum Levels of Thrombopoietin in Health and Disease -- 23 The Regulation of Platelet Production In Vivo.
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Thrombopoietin: Biology, clinical applications, role in the donor setting
Journal of Clinical Apheresis, 1996Co-Authors: David J. KuterAbstract:Thrombopoietin (c-Mpl ligand) is the hematopoietic growth factor that is responsible for regulating the production of platelets from bone marrow megakaryocytes. This approximately 90 kd protein has recently been isolated and is comprised of an erythropoietin domain that is approximately 50% homologous to erythropoietin and a carbohydrate domain that is highly glycosylated and appears to stabilize the protein in the circulation. Thrombopoietin is produced in the liver and blood levels are determined by the mass of circulating platelets. However, there is no platelet "sensor." Rather platelets contain high affinity Thrombopoietin receptors that bind and remove Thrombopoietin from the circulation and thereby directly determine circulating levels. In vitro Thrombopoietin stimulates both early and late megakaryocyte precursors as well as some erythroid and multipotential progenitor cells. When administered to normal animals, it stimulates platelet production up to six-fold without affecting other lineages. However, when given to animals following chemotherapy or irradiation, it stimulates erythroid and myeloid as well as platelet recovery. Several different recombinant Thrombopoietin proteins are now entering clinical trials in humans and all preliminary reports confirm a potent thrombopoietic stimulus and apparent lack of toxicity. Thrombopoietin shows great promise in preventing the thrombocytopenia associated with chemotherapy, bone marrow transplantation, and other acute or chronic thrombocytopenic disorders. In transfusion medicine, Thrombopoietin may help mobilize peripheral blood progenitor cells, stimulate donors for plateletpheresis, and enhance platelet survival and function during storage, Many studies are currently underway in all these areas and should soon establish the role of Thrombopoietin in clinical medicine.
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Thrombopoietin: Biology and Clinical Applications
The Oncologist, 1996Co-Authors: David J. KuterAbstract:Thrombopoietin (also called c-Mpl ligand, megakaryocyte growth and development factor, megapoietin) has recently been purified and cloned. This molecule is indeed the long-sought-after hematopoietic factor that controls platelet production. Thrombopoietin levels increase within 24 h after the onset of thrombocytopenia and are inversely and exponentially proportional to the platelet count. Injection of Thrombopoietin into animals stimulates the number, size and ploidy of bone marrow megakaryocytes and increases the platelet count up to ten-fold. Although human studies with several different forms of recombinant Thrombopoietin have just begun, animal studies suggest a wide range of potential clinical applications. In animals, recombinant Thrombopoietin reduced radiation- and chemotherapy-induced thrombocytopenia, enhanced platelet recovery after bone marrow transplantation and increased the number of megakaryocyte precursor cells in stem cell harvests. Active at very low concentrations, Thrombopoietin appears to have few adverse effects in animals. At very high doses, reversible marrow fibrosis has occasionally been seen, but despite platelet counts up to ten times normal, there is no evidence that it increased the risk of thrombosis. There is little likelihood that Thrombopoietin will stimulate tumor growth since receptors for Thrombopoietin have not been detected on solid tumors. Therefore, Thrombopoietin promises to be a specific and effective stimulator of platelet production and will soon join erythropoietin and G/GM-CSF in the clinical armamentarium. Although thrombocytopenia is uncommon in most chemotherapy protocols, ongoing clinical studies will determine the role of Thrombopoietin in the prevention and treatment of thrombocytopenia in oncology
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the reciprocal relationship of Thrombopoietin c mpl ligand to changes in the platelet mass during busulfan induced thrombocytopenia in the rabbit
Blood, 1995Co-Authors: David J. Kuter, Robert D RosenbergAbstract:Thrombopoietin (c-Mpl ligand) has recently been purified and is considered to be the humoral regulator of platelet production. To see whether this molecule possessed the physiologic characteristics necessary to mediate the feed-back loop between blood platelets and the bone marrow megakaryocytes, we determined the relationship between blood levels of Thrombopoietin and changes in the circulating platelet mass. We developed a model of nonimmune thrombocytopenia in rabbits by the subcutaneous administration of busulfan. Compared with pretreatment plasma, plasma taken from all thrombocytopenic rabbits at their platelet nadir contained increased amounts of Thrombopoietin. All of this activity was neutralized by soluble c-Mpl receptor. We subsequently measured the level of Thrombopoietin in the circulation over the entire time course after the administration of busulfan. As the platelet mass declined, levels of Thrombopoietin increased inversely and proportionally and peaked during the platelet nadir. With return of the platelet mass toward normal, Thrombopoietin levels decreased accordingly. When platelets were transfused into thrombocytopenic rabbits near the time of their platelet count nadir, the elevated levels of Thrombopoietin decreased. In addition, platelets were observed to remove Thrombopoietin from thrombocytopenic plasma in vitro. These results confirm that Thrombopoietin is the humoral mediator of megakaryocytopoiesis and suggest that the platelet mass may directly play a role in regulating the circulating levels of this factor.
Richard M Keenan - One of the best experts on this subject based on the ideXlab platform.
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hydrazinonaphthalene and azonaphthalene Thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis
Journal of Medicinal Chemistry, 2001Co-Authors: Kevin J Duffy, Michael G Darcy, Evelyne Delorme, Susan B Dillon, Daniel F Eppley, Connie L Ericksonmiller, Leslie Giampa, Christopher B Hopson, Yifang Huang, Richard M KeenanAbstract:High-throughput screening for the induction of a luciferase reporter gene in a Thrombopoietin (TPO)-responsive cell line resulted in the identification of 4-diazo-3-hydroxy-1-naphthalenesulfonic acids as TPO mimics. Modification of the core structure and adjustment of unwanted functionality resulted in the development of (5-oxo-1,5-dihydropyrazol-4-ylidene)hydrazines which exhibited efficacies equivalent to those of TPO in several cell-based assays designed to measure thrombopoietic activity. Furthermore, these compounds elicited biochemical responses in TPO-receptor-expressing cells similar to those in TPO itself, including kinase activation and protein phosphorylation. Potencies for the best compounds were high for such low molecular weight compounds (MW < 500) with EC50 values in the region of 1−20 nM.
