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James B. Bussel - One of the best experts on this subject based on the ideXlab platform.

  • Mechanisms and therapeutic prospects of thrombopoietin receptor agonists.
    Seminars in Hematology, 2019
    Co-Authors: James B. Bussel, Austin G. Kulasekararaj, Nichola Cooper, Amit Verma, Ulrich Steidl, John W. Semple, Britta Will
    Abstract:

    The second-generation thrombopoietin (TPO) receptor agonists Eltrombopag and romiplostim are potent activators of megakaryopoiesis and represent a growing treatment option for patients with thrombocytopenic hematological disorders. Both TPO receptor agonists have been approved worldwide for the treatment of children and adults with chronic immune thrombocytopenia. In the EU and USA, Eltrombopag is approved for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy and in the USA for the first-line treatment of severe aplastic anemia in combination with immunosuppressive therapy. Eltrombopag has also shown efficacy in several other disease settings, for example, chemotherapy-induced thrombocytopenia, selected inherited thrombocytopenias, and myelodysplastic syndromes. While both TPO receptor agonists stimulate TPO receptor signaling and enhance megakaryopoiesis, their vastly different biochemical structures bestow upon them markedly different molecular and functional properties. Here, we review and discuss results from preclinical and clinical studies on the functional and molecular mechanisms of action of this new class of drug.

  • safety and efficacy of long term treatment of chronic persistent itp with Eltrombopag final results of the extend study
    Blood, 2017
    Co-Authors: Raymond Sm Wong, Mansoor N Saleh, Maria Socorro O Portella, Paul Burgess, Abderrahim Khelif, Abdulgabar Salama, James B. Bussel
    Abstract:

    In phase 2/3 trials, Eltrombopag treatment of 6 months or less in patients with chronic/persistent immune thrombocytopenia (ITP) increased platelet counts and reduced bleeding. The open-label EXTEND study evaluated long-term safety and efficacy of Eltrombopag in adults with ITP who had completed a previous Eltrombopag study. For the 302 patients enrolled, median duration of Eltrombopag treatment was 2.37 years (2 days-8.76 years). Median platelet counts increased to 50 × 109/L or more by week 2 and were sustained throughout the treatment period. Overall, 259 patients (85.8%) achieved a response (platelet count ≥50 × 109/L at least once in the absence of rescue), and 133 (52%) of 257 patients achieved a continuous response of 25 weeks or longer. Responses in patients with platelet counts lower than 15 × 109/L, more previous therapies, and/or splenectomy were somewhat lower. Thirty-four (34%) of 101 patients receiving concomitant ITP medication discontinued 1 or more medication. In patients with assessments, bleeding symptoms (World Health Organization grades 1-4) decreased from 57% at baseline to 16% at 1 year. Forty-one patients (14%) withdrew because of adverse events. Hepatobiliary adverse events (n = 7), cataracts (n = 4), deep vein thrombosis (n = 3), cerebral infarction (n = 2), headache (n = 2), and myelofibrosis (n = 2) occurred in more than 1 patient; the remaining adverse events occurred only once. Rates of thromboembolic events (6%) and hepatobiliary adverse events (15%) did not increase with treatment duration past 1 year. EXTEND demonstrated that long-term use of Eltrombopag was effective in maintaining platelet counts of 50 × 109/L or more and reducing bleeding in most patients with ITP of more than 6 months' duration. Important adverse events (eg, thrombosis, hepatobiliary, and bone marrow fibrosis) were infrequent. (ClinicalTrials.gov:NCT00351468).

  • efficacy of Eltrombopag in adult east asian and non east asian patients with chronic immune thrombocytopenia citp results from the extend study
    Blood, 2016
    Co-Authors: Raymond Sm Wong, James B. Bussel, Mansoor N Saleh, Abderrahim Khelif, B Meddeb, Ali Elali, Erhard Quebefehling, Abdulgabar Salama
    Abstract:

    Abstract Introduction: Eltrombopag is an oral thrombopoietin receptor agonist, approved for the treatment of patients with cITP (persisting >12 months) aged ≥1 year, who are refractory to other treatments (eg corticosteroids, immunoglobulins). Pharmacokinetic studies of Eltrombopag have demonstrated that patients of East Asian origin (eg Japanese, Chinese, Taiwanese and Korean) experience increased plasma exposure to Eltrombopag compared to non-East Asian patients (predominantly Caucasian). As such, the recommended starting dose is 25 mg/day for East Asian patients, compared with 50 mg/day in non-East Asians. In the EXTEND (Eltrombopag eXTENded Dosing) study, all patients, irrespective of ancestry, received 50 mg/day starting dose that was subsequently adjusted to the platelet response. Unpublished anecdotal reports of platelet responses in East Asian patients from EXTEND describe lower doses of Eltrombopag. Here, we examine the responses to Eltrombopag in East Asian and non-East Asian patients who completed the EXTEND study. Methods: Adult patients (≥18 years old) diagnosed with cITP who had completed a previous ITP study of Eltrombopag were enrolled in EXTEND. All patients received Eltrombopag starting at 50 mg/day, titrated to 25-75 mg/day or less often as required, based on individual platelet count responses (range ≥50-200x109/L). Maintenance dosing continued after minimization of concomitant ITP medication and optimization of Eltrombopag dosing. Patients who received 2 years of treatment and transitioned off due to commercial availability of Eltrombopag were considered to have completed the study. Patients could remain on study beyond 2 years until Eltrombopag became commercially available. Here we describe the efficacy and durability of response in East Asian and non-East Asian patients. Analyses were conducted using the safety population, defined as all patients who had taken at least one dose of the study medication. Results: Of 302 patients enrolled and exposed to treatment (median duration 2.4 years [range, 2 days to 8.8 years]), 41 (14%) were of East Asian origin. Mean average Eltrombopag dose in East Asian and non-East Asian patients was 48.9 (range 4.2-74.9) mg/day and 50.4 (range 1.0-74.6) mg/day, respectively. Maintenance of platelet counts ≥30×109/L for at least 25 weeks was seen in 25/35 (71%) East Asian and 158/222 (71%) non-East Asian patients. In total, 13/35 (37%) East Asian patients and 120/222 (54%) non-East Asian patients maintained continuous platelet counts ≥50×109/L for at least 25 weeks, without rescue therapy (Figure). At the start of response, mean daily dose in East Asian and non-East Asian patients was 45.2 and 45.4 mg/day, respectively. The number of patients receiving dose adjustments according to platelet response was similar in East Asian and non-East Asian patients (Table). Conclusions: Treatment with Eltrombopag in East Asian and non-East Asian patients resulted in sustained platelet responses ≥30×109/L for at least 25 weeks in a similar proportion of patients. However, a higher proportion of non-East Asian patients achieved continuous platelet counts ≥50×109/L. Direct comparisons should be interpreted with caution because: a) of limited patient numbers in the East Asian group; b) the possible selection bias of patients entering the EXTEND study following completion of earlier Eltrombopag studies, eg, primarily responders; and c) the absence of PK data from these patient groups. All patients received similar doses of Eltrombopag irrespective of racial background, and dose modifications according to platelet responses were similar. Further investigations are ongoing to determine whether there were any differences in terms of safety and tolerability outcomes in East Asian and non-East Asian patients. Download : Download high-res image (84KB) Download : Download full-size image Download : Download high-res image (105KB) Download : Download full-size image Disclosures Wong: Bayer, Biogen-Idec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, and Roche: Research Funding; Biogen-Idec and Novartis: Membership on an entity’s Board of Directors or advisory committees; Bayer, Biogen-Idec and Novartis: Consultancy. Bussel: Amgen, Novartis & GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Boehringer Ingleheim, Prophylix Pharma, Protalex, Rigel Pharmaceuticals: Research Funding; Momenta Pharmaceuticals, Novartis, Prophylix Pharma, Protalex, Rigel Pharmaceutical: Membership on an entity’s Board of Directors or advisory committees; UptoDate: Patents & Royalties; Physicians Education Resource: Speakers Bureau. Saleh: GSK: Consultancy, Research Funding, Speakers Bureau. El-Ali: Novartis: Employment. Quebe-Fehling: Novartis: Employment.

  • effects of Eltrombopag on thrombocytopenia platelet function and bleeding in patients with wiskott aldrich syndrome x linked thrombocytopenia
    Blood, 2013
    Co-Authors: Emily Leven, Andrew L Frelinger, Michelle A Bernylang, Beau W Mitchell, Shoshana Revelvilk, Hannah Tamary, Sabrina L Carmichael, Alan D Michelson, James B. Bussel
    Abstract:

    Introduction Patients with Wiskott-Aldrich syndrome (WAS) including X-linked thrombocytopenia (XLT) have microthrombocytopenia, and hemorrhage is a major problem. Current management options in WAS/XLT patients include splenectomy, human stem cell transplant (HSCT) and gene therapy. In this study, we asked whether Eltrombopag, a thrombopoietin mimetic, would increase platelet counts, improve platelet function, and/or reduce bleeding in WAS/XLT patients. Methods In 9 WAS/XLT patients and 8 age-matched healthy control subjects, flow cytometry was used to assess platelet function by surface expression of activated GPIIb-IIIa (reported by PAC1) and P-selectin in whole blood after stimulation with low and high concentrations of ADP or thrombin receptor activating peptide (TRAP), and by annexin V binding (a measure of surface phosphatidylserine) in platelet-rich plasma after stimulation with convulxin. Eltrombopag was administered to 5 WAS and 3 XLT patients (50 mg in 2 adults, and 1 mg/kg in 6 children up to 75 mg/day) with a goal platelet count ≥50k. Results High concentration ADP- or TRAP-induced PAC1 mean fluorescence intensity (MFI) was significantly reduced in WAS/XLT patients compared to healthy controls ([Figure][1]). Platelet surface P-selectin MFI in response to TRAP was also significantly reduced. In contrast, annexin V binding to platelets was not different between WAS/XLT and controls. As expected, platelet size of WAS/XLT patients was smaller than controls. WAS protein (which is deficient in WAS/XLT), is important for cytoskeletal movement and could therefore be involved in trafficking of surface proteins. However, surface expression of activated GPIIb-IIIa and P-selectin were no longer different in WAS/XLT patients vs. controls when corrected for size by platelet surface CD41 MFI. In 3 WAS/XLT patients whose platelet count improved on Eltrombopag, platelet function did not improve. The table summarizes the results of Eltrombopag treatment in 5 responders (2 WAS, 3 XLT patients) and 3 non-responders (3 WAS patients). Comparison of baseline, peak and change in immature platelet fraction in 5 WAS/XLT responders to Eltrombopag vs. 7 pediatric chronic immune thrombocytopenia (ITP) patients responding to Eltrombopag showed a significant decrease in all three measures, suggesting that platelet production in WAS/XLT patients is more difficult to increase than in ITP patients. Long term Eltrombopag use in WAS/XLT patients showed no tachyphylaxis, transaminitis or induction of malignancy. ![Figure][2] Conclusions 1) Baseline platelet function in WAS/XLT is reduced compared to healthy age-matched controls, as measured by agonist-induced platelet surface activated GPIIb-IIIa and P-selectin. 2) This reduction is proportional to the reduced platelet size in WAS/XLT compared to controls. 3) In contrast, annexin V binding (a measure of platelet procoagulant activity) showed no differences between WAS/XLT and controls. 4) Eltrombopag has beneficial effects on the thrombocytopenia and bleeding, but not platelet function, in the majority of WAS/XLT patients. 5) This Eltrombopag-induced reduction in bleeding is presumably primarily the result of the increased platelet count, but it was also observed in 2 Eltrombopag “non-responders” (i.e. patients whose platelet counts did not increase after Eltrombopag). 6) The production of new platelets with Eltrombopag is less in WAS/XLT than in ITP. View this table: Table Disclosures: Off Label Use: Eltrombopag was given to WAS/XLT patients for treatment of thrombocytopenia. Michelson: Sysmex: Honoraria. Bussel: GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees. [1]: #F1 [2]: pending:yes

  • repeated short term use of Eltrombopag in patients with chronic immune thrombocytopenia itp
    British Journal of Haematology, 2013
    Co-Authors: James B. Bussel, Mansoor N Saleh, Bhabita Mayer, Sandra Y Vasey, Michael Arning, Nicole L Stone
    Abstract:

    Eltrombopag is a thrombopoietin-receptor agonist that stimulates platelet production and increases platelet counts in patients with chronic immune thrombocytopenia (ITP). This open-label, single-arm study evaluated consistency of response and safety following repeated intermittent dosing of Eltrombopag 50 mg daily over 3 cycles (1 cycle = up to 6 weeks on therapy followed by up to 4 weeks off therapy). The primary endpoint was proportion of patients with a response (platelet count ≥50 × 10(9) /l and ≥2× baseline) in Cycle 1 who subsequently responded in Cycle 2 or 3. Fifty-two of 65 evaluable patients (80%) responded in Cycle 1; these responding patients comprised the primary analysis population. Of these, 45/52 (87%) responded in Cycle 2 or 3 [95% confidence interval (CI), 74-94%] and 34/48 (71%; 95% CI, 56-83%) responded in both Cycles 2 and 3. Time to response was consistent, with >50% of responders responding by Day 8 in each cycle. Bleeding rates relative to baseline decreased by approximately 50% during each treatment cycle. The frequency or severity of adverse events, most commonly headache, did not increase over successive cycles. If a chronic ITP patient not requiring consistent therapy responds to short-term Eltrombopag, then subsequent courses of Eltrombopag, as needed, are likely to be safe and effective.

Nicole L Stone - One of the best experts on this subject based on the ideXlab platform.

  • repeated short term use of Eltrombopag in patients with chronic immune thrombocytopenia itp
    British Journal of Haematology, 2013
    Co-Authors: James B. Bussel, Mansoor N Saleh, Bhabita Mayer, Sandra Y Vasey, Michael Arning, Nicole L Stone
    Abstract:

    Eltrombopag is a thrombopoietin-receptor agonist that stimulates platelet production and increases platelet counts in patients with chronic immune thrombocytopenia (ITP). This open-label, single-arm study evaluated consistency of response and safety following repeated intermittent dosing of Eltrombopag 50 mg daily over 3 cycles (1 cycle = up to 6 weeks on therapy followed by up to 4 weeks off therapy). The primary endpoint was proportion of patients with a response (platelet count ≥50 × 10(9) /l and ≥2× baseline) in Cycle 1 who subsequently responded in Cycle 2 or 3. Fifty-two of 65 evaluable patients (80%) responded in Cycle 1; these responding patients comprised the primary analysis population. Of these, 45/52 (87%) responded in Cycle 2 or 3 [95% confidence interval (CI), 74-94%] and 34/48 (71%; 95% CI, 56-83%) responded in both Cycles 2 and 3. Time to response was consistent, with >50% of responders responding by Day 8 in each cycle. Bleeding rates relative to baseline decreased by approximately 50% during each treatment cycle. The frequency or severity of adverse events, most commonly headache, did not increase over successive cycles. If a chronic ITP patient not requiring consistent therapy responds to short-term Eltrombopag, then subsequent courses of Eltrombopag, as needed, are likely to be safe and effective.

  • oral Eltrombopag for the long term treatment of patients with chronic idiopathic thrombocytopenic purpura results of a phase iii double blind placebo controlled study raise
    Blood, 2008
    Co-Authors: Gregory Cheng, James B. Bussel, Mansoor N Saleh, Bhabita Mayer, Manuel Aivado, Claus Werenberg Marcher, Sandra Y Vasey, Michael Arning, Nicole L Stone
    Abstract:

    INTRODUCTION: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline, Collegeville, PA, USA) is a first-in-class, oral, small molecule, non-peptide, thrombopoietin receptor agonist being studied for the treatment of thrombocytopenia related to a variety of conditions. METHODS: RAISE was a 6-month, randomized, double-blind, placebo-controlled, phase III study that evaluated the efficacy and safety of Eltrombopag in previously treated adults with chronic idiopathic thrombocytopenic purpura (ITP) with platelet counts RESULTS: One hundred ninety-seven patients (Eltrombopag, 135; placebo, 62) were enrolled in RAISE, and baseline characteristics were balanced: in both arms ~50% of patients had platelet counts □15,000/μL, ~50% were receiving concomitant ITP therapies, ~35% were splenectomized, and >15% had received at least 3 prior ITP medications. Patients who received Eltrombopag were 8 times more likely to achieve platelet counts 50,000 to 400,000/μL during the 6-month treatment period compared with patients on placebo (OR [95% CI] = 8.2 [4.32, 15.38]; P DISCUSSION: Long-term Eltrombopag therapy significantly increased platelet counts, decreased bleeding symptoms, allowed for a reduction or discontinuation of baseline ITP therapies, and reduced the use of rescue ITP medications compared with placebo. Eltrombopag was well-tolerated, with a similar safety profile to placebo, and is an important new treatment option for patients with chronic ITP.

  • Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura
    The New England Journal of Medicine, 2007
    Co-Authors: James B. Bussel, Gregory Cheng, Mansoor N Saleh, Bethan Psaila, Lidia Kovaleva, Balkis Meddeb, Janusz Kloczko, Habib Hassani, Bhabita Mayer, Nicole L Stone
    Abstract:

    Background The pathogenesis of chronic idiopathic thrombocytopenic purpura (ITP) involves antibody-mediated platelet destruction and reduced platelet production. Stimulation of platelet production may be an effective treatment for this disorder. Methods We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one standard treatment for ITP were randomly assigned to receive the oral thrombopoietin-receptor agonist Eltrombopag (30, 50, or 75 mg daily) or placebo. The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43. Results In the Eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81% of patients, respectively. In the placebo group, the end point was achieved in 11% of patients. The median platelet counts on day 43 for the groups receiving 30, 50, and 75 mg of Eltrombopag were 26,0...

Yuhchyau Chen - One of the best experts on this subject based on the ideXlab platform.

  • Eltrombopag a thrombopoietin receptor agonist enhances human umbilical cord blood hematopoietic stem primitive progenitor cell expansion and promotes multi lineage hematopoiesis
    Stem Cell Research, 2012
    Co-Authors: Hongliang Sun, Ying Tsai, Irena Nowak, Jane L Liesveld, Yuhchyau Chen
    Abstract:

    Umbilical cord blood (UCB) transplantation has emerged as a promising therapy, but it is challenged by scarcity of stem cells. Eltrombopag is a non-peptide, thrombopoietin (TPO) receptor agonist, which selectively activates c-Mpl in humans and chimpanzees. We investigated Eltrombopag's effects on human UCB hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) expansion, and its effects on hematopoiesis in vivo. Eltrombopag selectively augmented the expansion of human CD45+, CD34+, and CD41+ cells in bone marrow compartment without effects on mouse bone marrow cells in the NOD/SCID mice xenotransplant model. Consequently, Eltrombopag increased peripheral human platelets and white blood cells. We further examined effects in the STAT and AKT signaling pathways in serum-free cultures. Eltrombopag expanded human CD34+ CD38-, CD34+, and CD41+ cells. Both Eltrombopag and recombinant human TPO (rhTPO) induced phosphorylation of STAT5 of CD34+ CD41-, CD34- CD41+, and CD34- CD41- cells. rhTPO preferentially induced pSTAT3, pAKT, and more pSTAT5 in CD34- C41+ cells, while Eltrombopag had no effects on pSTAT3. In conclusion, Eltrombopag enhanced expansion of HSCs/HPCs of human UCB in vivo and in vitro, and promoted multi-lineage hematopoiesis through the expansion of bone marrow HSCs/HPCs of human UCB in vivo. Eltrombopag differed somewhat from rhTPO in the signal transduction pathways by favoring earlier HSC/HPC populations.

Connie L Ericksonmiller - One of the best experts on this subject based on the ideXlab platform.

  • reduced proliferation of non megakaryocytic acute myelogenous leukemia and other leukemia and lymphoma cell lines in response to Eltrombopag
    Leukemia Research, 2010
    Co-Authors: Connie L Ericksonmiller, Manuel Aivado, Jennifer Kirchner, Richard D May, Parrish Payne, Antony Chadderton
    Abstract:

    Abstract Leukemia cell lines were treated with Eltrombopag or thrombopoietin and their proliferative response was determined. Eltrombopag did not increase proliferation of cell lines that did not express high levels of megakaryocyte markers. Instead, treatment with Eltrombopag alone inhibited proliferation of many cell lines (IC 50 range = 0.56–21 μg/mL). The addition of other cytokines, such as G-CSF, Epo or Tpo, did not affect the decrease in proliferation. The decrease in proliferation appears to be through a TpoR-independent, nonapoptotic mechanism. These findings suggest that Eltrombopag does not enhance, but rather inhibits, proliferation of leukemia cell lines in vitro.

  • effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome
    Blood, 2009
    Co-Authors: Britta Will, Amit Verma, Connie L Ericksonmiller, Masahiro Kawahara, Julia P Luciano, Ingmar Bruns, Samir Parekh, Manuel Aivado, Ulrich Steidl
    Abstract:

    Thrombocytopenia is a frequent symptom and clinical challenge in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Eltrombopag is a small molecule thrombopoietin receptor agonist that might be a new option to treat thrombocytopenia in these diseases, provided that it does not stimulate malignant hematopoiesis. In this work, we studied the effects of Eltrombopag on proliferation, apoptosis, differentiation, colony formation, and malignant self-renewal of bone marrow mononuclear cells of patients with AML and MDS. Malignant bone marrow mononuclear cells did not show increased proliferation, or increased clonogenic capacity at concentrations of Eltrombopag ranging from 0.1 to 30 μg/mL. On the contrary, we observed a moderate, statistically nonsignificant (P = .18), decrease of numbers of malignant cells (mean, 56%; SD, 28%). Eltrombopag neither led to increased 5-bromo-2-deoxyuridine incorporation, decreased apoptosis, an increase of malignant self-renewal, nor enhanced in vivo engraftment in xenotransplantations. Furthermore, we found that Eltrombopag was capable of increasing megakaryocytic differentiation and formation of normal megakaryocytic colonies in patients with AML and MDS. These results provide a preclinical rationale for further testing of Eltrombopag for treatment of thrombocytopenia in AML and MDS.

  • comparative analyses of the small molecule thrombopoietin receptor agonist Eltrombopag and thrombopoietin on in vitro platelet function
    Experimental Hematology, 2009
    Co-Authors: Joseph A Erhardt, Connie L Ericksonmiller, Manuel Aivado, Melanie Abboud, Kodandaram Pillarisetti, John R Toomey
    Abstract:

    Objective The thrombopoietin receptor (TPOR) is a therapeutic target for treatment of thrombocytopenia because stimulation of this receptor results in enhanced megakaryocyte proliferation, differentiation, and ultimately platelet production. In addition to effects on megakaryocytes, TPOR stimulation also impacts platelet function. The present study examined platelet function following stimulation with the small molecule TPOR agonist Eltrombopag. Materials and Methods Platelets were obtained from healthy volunteers, and signal transduction pathway activation was examined in washed platelet preparations. Platelet aggregation was examined in both washed platelet preparations and platelet-rich plasma. Platelet α-granule release was determined via fluorescein-activated cell sorting measurement of CD62P. Results In signal transduction studies of washed human platelets, Eltrombopag induced the phosphorylation signal transducers and activators of transcription (STAT) proteins with no phosphorylation of Akt, whereas recombinant human TPO (rhTPO) induced the phosphorylation of Akt as well as STAT-1, -3, and -5. In studies conducted at subthreshold/submaximal concentrations of adenosine diphosphate (ADP) or collagen, Eltrombopag pretreatment did not result in platelet aggregation. In contrast, rhTPO acted in synergy with submaximal concentrations of ADP or collagen to induce maximal aggregation under all conditions examined. Similarly, platelet activation as examined via surface expression of CD62P was not enhanced by Eltrombopag pretreatment as compared to rhTPO. Conclusions These results demonstrate that the nonpeptidyl TPOR agonist Eltrombopag stimulates platelet signal transduction with little or no effect on overall platelet function, in contrast to TPO, which significantly primes platelet activation. These data demonstrate that effects of TPOR ligands on platelet function can vary depending on the specific mechanism utilized to stimulate the TPOR.

  • preclinical activity of Eltrombopag sb 497115 an oral nonpeptide thrombopoietin receptor agonist
    Stem Cells, 2009
    Co-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 Luengo
    Abstract:

    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.

  • phase 1 clinical study of Eltrombopag an oral nonpeptide thrombopoietin receptor agonist
    Blood, 2007
    Co-Authors: Julian Jenkins, Daphne Williams, Yanli Deng, Valerie S Kitchen, David Collins, Connie L Ericksonmiller
    Abstract:

    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.

Díaz Amaya, Diego Orlando - One of the best experts on this subject based on the ideXlab platform.

  • Agonistas de trombopoyetina en el manejo de trombocitopenia inmune primaria, descripción de la experiencia en un centro de cuarto nivel en Bogotá
    'Anales de la Facultad de Medicina', 2018
    Co-Authors: Espinosa Redondo, Daniel Lorenzo, Díaz Amaya, Diego Orlando
    Abstract:

    20 p.El manejo de la trombocitopenia inmune primaria (TPI) disminuye la destrucción plaquetaria, mediante inmunosupresión y/o esplenectomía. Romiplostim y Eltrombopag aumentan la producción plaquetaria y cuentan con estudios clínicos que prueban su seguridad y eficacia, no obstante, en Colombia faltan estudios que las describan en la práctica clínica diaria. Describimos características clínicas, respuesta y efectos secundarios de dichos medicamentos en pacientes adultos con TPI primaria tratados en el Hospital San José de Bogotá entre 2014 y 2017. Se incluyeron 46 pacientes, se utilizó estadística descriptiva, medidas de tendencia central y dispersión para variables cuantitativas y proporciones para variables cualitativas. La mediana de edad fue 55 años [Q1-Q3 37-67], 63% fueron mujeres, en 80% de los casos el primer agonista usado fue Eltrombopag, en 20% Romiplostim y 15% de los casos requirieron uso secuencial. La mediana de uso de agonista fue 46 semanas [Q1-Q3, 16-44], lograron respuesta plaquetaria el 85% de los pacientes con Eltrombopag y el 100% con Romiplostim, se obtuvo respuesta durable en 75% con Eltrombopag y en 86% con Romiplostim; 91% de los pacientes lograron reducción de terapia concomitante. El 28% de pacientes con Eltrombopag y el 37% con Romiplostim presentaron eventos adversos, la más frecuente trombosis (15%). Romiplostim y Eltrombopag son efectivos y seguros en el manejo de la TPI en nuestro grupo de pacientes, es necesario realizar más estudios para definir factores de riesgo relacionados con el desarrollo de trombosis, entre ellos la presencia de anticuerpos anti fosfolípidos, e implementar estrategias para su prevención.EspecializaciónEspecialista En Hematologí

  • Agonistas de trombopoyetina en el manejo de trombocitopenia inmune primaria, descripción de la experiencia en un centro de cuarto nivel en Bogotá
    Subespecialidad de Hematología, 2018
    Co-Authors: Espinosa Redondo, Daniel Lorenzo, Díaz Amaya, Diego Orlando
    Abstract:

    20 p.El manejo de la trombocitopenia inmune primaria (TPI) disminuye la destrucción plaquetaria, mediante inmunosupresión y/o esplenectomía. Romiplostim y Eltrombopag aumentan la producción plaquetaria y cuentan con estudios clínicos que prueban su seguridad y eficacia, no obstante, en Colombia faltan estudios que las describan en la práctica clínica diaria. Describimos características clínicas, respuesta y efectos secundarios de dichos medicamentos en pacientes adultos con TPI primaria tratados en el Hospital San José de Bogotá entre 2014 y 2017. Se incluyeron 46 pacientes, se utilizó estadística descriptiva, medidas de tendencia central y dispersión para variables cuantitativas y proporciones para variables cualitativas. La mediana de edad fue 55 años [Q1-Q3 37-67], 63% fueron mujeres, en 80% de los casos el primer agonista usado fue Eltrombopag, en 20% Romiplostim y 15% de los casos requirieron uso secuencial. La mediana de uso de agonista fue 46 semanas [Q1-Q3, 16-44], lograron respuesta plaquetaria el 85% de los pacientes con Eltrombopag y el 100% con Romiplostim, se obtuvo respuesta durable en 75% con Eltrombopag y en 86% con Romiplostim; 91% de los pacientes lograron reducción de terapia concomitante. El 28% de pacientes con Eltrombopag y el 37% con Romiplostim presentaron eventos adversos, la más frecuente trombosis (15%). Romiplostim y Eltrombopag son efectivos y seguros en el manejo de la TPI en nuestro grupo de pacientes, es necesario realizar más estudios para definir factores de riesgo relacionados con el desarrollo de trombosis, entre ellos la presencia de anticuerpos anti fosfolípidos, e implementar estrategias para su prevención