After removal of the lysed red cells, 2.5105 cells of the bone marrow cell suspension were stained with fluorescence-labelled CD11b, CD34, Sca1, c-kit, CD25 and a lineage cocktail involving biotin conjugated-CD8a, CD45R/B220, CD4, Ly6G (Gr-1), TER119, CD11c and NK1.1. Mouthon MA, et al. Haematopoietic progenitor cell counts (total number of CFU-GM, CFU-Mix and BFU-E) in the bone marrow of irradiated mice were insufficiently restored by RP treatment, as were mononuclear cells, whose numbers remained almost identical (Table1). Watch the video to learn more about Prussian Blue (Radiogardase) and its use in the treatment of acute radiation exposure. I.K. designed the study; M.Y., T.H., K.Y., A.N. Surgery. Herein, we present the results of an analysis in mice of romiplostim as a medical countermeasure to improve survival and PLT recovery following acute radiation.Materials and methods: Male and female C57BL/6J mice (11 - 12 weeks of age, n = 21/sex/group) were total body irradiated (TBI) with 6.8 Gy X-rays that reduces 30-day survival to 30% . In the case of a radiological or nuclear public health emergency, many thousands of people could experience severe injuries from radiation exposure, resulting in immunosuppression and infection, hemorrhage, major morbidities, and even death. Correspondence to Use the Previous and Next buttons to navigate three slides at a time, or the slide dot buttons at the end to jump three slides at a time. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Stem Cells. INDICATIONSNplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in adult patients with immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Nenot, J. C. & Thierry, D. Clinical approaches to treatment of radiation-induced haematopoietic injury (ed. T. 53BP1: pro choice in DNA repair. Romiplostim (Nplate. Specific antibodies against cytokeratin 18 is used for determination of early apoptotic events in cells and/or tissues by detection of specific cytokeratin 18 fragments containing the aspartic acid residue 396 neo-epitope, which is exposed after cleavage of cytokeratin 18 by caspases. and I.K. Romiplostim is a fusion protein thrombopoietin (TPO) peptide analog that increases platelet counts by binding to and activating the human TPO receptor. Each dosage was fixed at 50g/kg/day (n=8 in each group). The TPO receptor c-mpl is constantly expressed on the surface of haematopoietic stem/progenitor cells27 and not only promotes megakaryocytic differentiation but also regulates their self-renewal activity and pluripotency28,29. Mesenchymal stromal cell-derived extracellular vesicles provide long-term survival after total body irradiation without additional hematopoietic stem cell support. In our previous study involving mice lethally irradiated with 7Gy of -rays, we successfully optimized a protocol with multiple approved drugs: romiplostim (RP), erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and nandrolone (ND; 19-nortestosterone)9. The National Institute of Allergy and Infectious Diseases(NIAID)/National Institute of Healths (NIH) Radiation and Nuclear Countermeasures Program (RNCP) announced on January 28, 2021, that the FDA approved application by Amgen for Nplate (Romiplostim) to add the following indication to the package insert: Patients with Hematopoietic Syndrome of Acute Radiation Syndrome (HS-ARS):Nplate is indicated to increase survival in adults and pediatric patients (including term neonates) acutely exposed to myelosuppressive doses of radiation.. This work was supported by a KAKENHI Grant-in-Aid for Scientific Research (B) (No. 1996-2022 Amgen Inc. All Rights Reserved. For more information, follow us on www.twitter.com/amgenoncology. Sections of duodenum tissues (approximately 1cm in thickness) were embedded in paraffin. CAS The irradiated mice were administered the human thrombopoietin-mimetic c-mpl agonist RP (Romiplate; Kyowa Hakko Kirin, Co., Ltd., Tokyo, Japan) within 2h after -irradiation. (B) The villus length and (C) villus width were measured. romiplostim injection is used to increase the number of platelets (cells that help the blood to clot) in order to decrease the risk of bleeding in adults who have immune thrombocytopenia (itp; idiopathic thrombocytopenic purpura; an ongoing condition that may cause easy bruising or bleeding due to an abnormally low number of platelets in the With the January 28, 2021 approval of Nplate for hematopoietic acute radiation syndrome (H-ARS), the FDA has now granted approvals for four products to treat H-ARS, three of which relied on NIAID-supported preclinical data. (D) Radiomitigative effects of RP were shown against large doses of -irradiation (7Gy+RP, 8Gy+RP, 9Gy+RP, and 10Gy+RP, n=8 in all the groups) compared with each radiation control. On the primary endpoint, the median number of months with platelet response ( 50 x 109/L) was 11 months during the 12-month treatment period (95% CI: 10, 11), with a median time to first platelet response of 2.1 weeks (95% CI: 1.1, 3.0). 4C,D). It may be given to you for other reasons. Signals emanating from the membrane proximal region of the thrombopoietin receptor (mpl) support hematopoietic stem cell self-renewal. Do not use to . B cells (CD45R/B220+NK1.1) (M), NK cells (NK1.1+) (N) and B/NK cells (O) were isolated from non-T lineage cells. 45, 175188 (2009). Further, some raw materials, medical devices and component parts for our products are supplied by sole third-party suppliers. 140, 10371051 (2004). Similarly, the non-irradiated mice were also administered RP and used as controls. Patients receive romiplostim subcutaneously (SC) once weekly for up to 6 weeks. PE-Cy7-conjugated anti-mouse CD34 was purchased from Santa Cruz Biotechnology (Dallas, TX, USA). "The addition of this new data will help physicians and patients communicate and weigh the benefits and risks of treatment to find an appropriate treatment choice.". DNA double-strand breakage and DNA repair response in nuclei of bone marrow cells from the femurs of surviving mice. In addition, thrombopoietin receptor agonists, such as TPO and eltrombopag, protect against cell death/apoptosis in cardiac myocytes via the down-regulation of caspase-3 activity, which is downstream of JAK/Src tyrosine kinase36, and Tronik-Le et al. PubMed 2. Body weight of surviving mice through day 30. 1C). Romiplostim is available under the following different brand names: Nplate What Are Dosages of Romiplostim? Additionally, 93% (70) of patients achieved one or more platelet responses during the 12-month treatment period. Whole-body exposure to high doses of radiation can injure multiple tissues and organs, but the rapidly dividing cells of the bone marrow are among the most sensitive to radiation damage. Mitigative efficacy of the clinical dosage administration of granulocyte colony-stimulating factor and romiplostim in mice with severe acute radiation syndrome. Hirouchi, T. et al. Fluorescein isothiocyanate (FITC)-conjugated anti-mouse Sca-1 monoclonal antibodies (mAbs), allophycocyanin-cianin-7-forochrome (APC-Cy7)-conjugated anti-mouse CD11b mAbs, Texas Red-conjugated anti-mouse CD45/B220 mAbs, phycoerythrin-cyanin-7-forochrome (PE-Cy7)-conjugated anti-mouse CD4 mAbs, APC-Cy7-conjugated anti-mouse CD8a mAbs, phycoerythrin (PE)-conjugated anti-mouse CD8b mAbs, phycoerythrin (PE)-conjugated anti-mouse CD25 mAbs, FITC-conjugated anti-mouse Gr-1 mAbs, allophycocyanin (APC)-conjugated anti-mouse TER119 mAbs, biotin-conjugated anti-mouse TER119 mAbs, PE-Texas Red-conjugated streptavidin and 7-AAD were purchased from Becton Dickinson. The data are expressed as the meansSD (n=3 independent experiments). 1A). The FDA's decision was based largely on NIAID-supported studies showing that romiplostim greatly increases survival in an animal model of radiation exposure. 5-HT3 receptor antagonist. Following a second wash with PBS (), the cells were adhered to microscope glass slides (Matsunami Glass Ind., Osaka, Japan) using a StatSpin CytoFuge 2 (Iris Sample Processing, Inc., Westwood, MA, USA) and mounted using Vectashield Mounting Medium with DAPI (Vector Laboratories, Inc., Burlingame, CA, USA). The cell numbers of 15 populations in the bone marrow of surviving mice. In children, fever, mouth /throat pain, diarrhea, easy. Radiat Res. The Food and Drug Administration (FDA) approved Nplate in January 2021 as an agent that increases platelet counts, helping to reduce radiation-induced bleeding. 5AD) and mature cell populations (Fig. The drug can be used to treat adults and children." [7] References [ edit] ^ a b Waknine, Yael (4 September 2008). Hematology Am Soc Hematol Educ Program. Approval Letter(s) (PDF) Summary Review (PDF) Officer/Employee List (PDF) Office Director Memo(PDF) Cross Discipline Team Leader Review(PDF) The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. Xue, J. et al. TPO has been shown to exhibit important selective DNA repair promoting activity for NHEJ but not homologous recombination. Animal models for medical countermeasures to radiation exposure. Vishnu P, Aboulafia DM. (C) Effect of administration delay. The bone marrow cells were collected at days 0, 1, 4, and 14, washed with PBS (), and fixed with ice-cold 75% ethanol for 10min at room temperature. 2. Kuo LJ, Yang LX. In a clinical trial, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate therapy. In addition, RP treatment for 3 days after irradiation improved intestinal integrity and morphology, indicating the restoration of the intestinal mucosa (Fig. 25293256 IK) and Scientific Research (A) (No. Regarding common lymphoid progenitors (Linc-kitSca-1+CD34+), similar levels were found between RP-untreated irradiated and RP-treated irradiated mice, and there were no significant differences on day 20 (Fig. In most radiation accidents, drug therapy is chosen as the most suitable treatment; the chosen drug should already be approved domestically, stably supplied and regularly stockpiled. Histology of the small intestine of surviving mice. Internet Explorer). M. Yamaguchi, Marino Suzuki, Moeri Funaba, Akane Chiba, I. Kashiwakura To obtain Safety reports series No. Following a second wash with PBS (), the cells were adhered to microscope glass slides using a StatSpin CytoFuge 2 and mounted using Vectashield Mounting Medium with DAPI. Radiat Res. Conclusion: A single injection of romiplostim administered 24 h after TBI is a promising radiation medical countermeasure that dramatically increased survival, with or without pegfilgrastim, and hastened PLT recovery in mice. 1A). 2.2 Patients with Hematopoietic Syndrome of Acute Radiation Syndrome For Adult and Pediatric Patients (including term neonates) The recommended dose of Nplate is 10 mcg/kg administered once as a subcutaneous injection. Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-B pathways and their target, IEX-1. 3AC). However, the small intestines of the RP-treated mice regained their morphological integrity. If material is not included in the articles Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. From these results, we decided in the present study to analyse the radiomitigative effects of RP in 7 Gy-irradiated mice treated with a suitable regimen for that radiation dose. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. At Amgen, we are driven by our commitment to transform the lives of cancer patients and keep them at the center of everything we do. In addition, a quantitative analysis was performed using a flow cytometer (Cytomics FC500; Beckman-Coulter, Fullerton, CA, USA). Romiplostim is approved by the FDA for the treatment of thrombocytopaenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy 7.. Xue J, et al. The effectiveness of romiplostim for this use was only studied in animals, because it could not be studied in people. OShea, J. J., Pesu, M., Borie, D. C. & Changelian, P. S. A new modality for immunosuppression: targeting the JAK/STAT pathwa. However, there was a difference in the response to irradiation among peripheral blood cells: white blood cells behaved similarly to bone marrow cells (Fig. It should not be used to treat thrombocytopenia caused by other conditions and may worsen pre . Our results may be affected by our ability to successfully market both new and existing products domestically and internationally, clinical and regulatory developments involving current and future products, sales growth of recently launched products, competition from other products including biosimilars, difficulties or delays in manufacturing our products and global economic conditions. In contrast to myelosuppression, which did not fully recover until day 30, the expression of several bone marrow cell surface antigens recovered sooner, and DNA repair concurrently increased in haematopoietic cells, speeding the resolution of double strand breaks and reducing the rates of apoptosis. Prussian Blue is an ingestable capsule that helps remove radioactive cesium and thallium from the body. The median time from ITP diagnosis to study enrollment was 2.2 months. PubMed Carousel with three slides shown at a time. Thrombopoietin receptor agonists protect cardiac myocytes from injury by activation of cell survival pathways. The nucleated bone marrow cells in the femurs of the non-irradiated and irradiated groups with or without RP were classified into 15 populations according to their cell surface antigen profiles. 1323 (IAEA, 1998). Nplate is indicated for the treatment of thrombocytopenia in pediatric patients 1 year of age and older with ITP for at least 6 months who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. In Vivo. The period of RP administration was varied to 1, 3 and 5 consecutive days (IR+RP-1d, 3d and 5d,n=1220 in each group) at identical dosage (50g/kg of body weight/day). Statistical significance was determined by a comparison among (a) the non-irradiated groups with and without RP, (b) the irradiated groups with and without RP, (c) the non-irradiated and irradiated groups, and (d) the RP-treated groups with and without irradiation (P<0.05). Long-term safety and efficacy of romiplostim for treatment of immune thrombocytopenia. The priority for ARS is achieving the reconstitution and restoration of haematopoiesis, as radiation-induced bone marrow death frequently results in infections due to a decreased number of white blood cells, bleeding due to a lack of platelets, and anaemia due to a dearth of red blood cells in the circulation3,4 within 60 days after irradiation. Side effects of RP were not shown, since all non-irradiated mice that received RP administration survived with no malignancy until 200 days. Health Conditions Patients received single weekly SC injections of Nplate over a 12-month treatment period, with individual dose adjustments to maintain platelet counts (50 x 109/L to 200 x 109/L). Questo studio di fase II studia l'efficacia di romiplostim nell'aumentare la bassa conta piastrinica in pazienti con mieloma multiplo sottoposti a . Region of the clinical dosage administration of granulocyte colony-stimulating factor and romiplostim in mice with severe radiation! 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For up to 6 weeks RP were not shown, since all non-irradiated were.

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