Diverse functions of the thrombopoietin receptor agonist romiplostim rescue individuals exposed to lethal radiation

Yamaguchi, Masaru; Hirouchi, Tokuhisa; Yoshioka, Haruhiko; Watanabe, Jun; Kashiwakura, Ikuo

doi:10.1016/j.freeradbiomed.2019.03.023

Cited by 18 publications

(39 citation statements)

References 52 publications

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“…We previously reported that treatment with the combination of domestically approved pharmaceutical drugs (e.g. G-CSF and RP) enhances the survival of mice exposed to lethal TBI [8][9][10].…”

Section: Discussionmentioning

confidence: 99%

“…The post-radiation treatment was performed within 2 h after TBI, and the TBI and non-TBI mice were administered different types of medications ( Table 1). The four types of medications were delivered in combinations of the following two commercially available drugs based on our previous reports [8][9][10]: recombinant human G-CSF Neutrogin® (Chugai Pharmaceutical, Tokyo, Japan) and human TPOR agonist RP (Romiplate®; Kyowa Hakko Kirin, Tokyo, Japan). G-CSF or RP was intraperitoneally administered once-daily for 3 or 4 times or once a week for up to 4 times, respectively.…”

Section: Drug Administrationmentioning

confidence: 99%

“…The approval of cytokine use varies by country, and GM-CSFs, interleukin-3, and thrombopoietin (TPO), which are recommended as the principal therapeutic cytokines corresponding to ARS severity by the International Atomic Energy Agency [7], are not approved in Japan. We recently found that treatment with a combination of domestically approved drugs, such as a G-CSF (Neutrogin®) and the TPO receptor (TPOR) agonist romiplostim (RP; Romiplate®), rescues mice from lethal TBI [8][9][10]. Although the effectiveness of these drugs as a medical treatment for emergency radiation exposure has been reported, the necessary dosages reported were much higher than the clinically used dosages.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mitigative Efficacy of the Clinical Dosage Administration of Granulocyte Colony-stimulating Factor and Romiplostim in Mice With Severe Acute Radiation Syndrome

Yamaguchi

Suzuki

Funaba

et al. 2020

Preprint

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Background:It has been reported that the high-dosage administration of domestically approved pharmaceutical drugs, especially granulocyte colony-stimulating factor (G-CSF) and romiplostim (RP), is a rapid and appropriate medical treatment for preventing severe acute radiation syndrome (ARS) of victims exposed to lethal total-body irradiation (TBI). However, it remains unclear whether or not the clinical dosage administration of these drugs can ameliorate TBI-induced ARS and related high mortality in order to find various drug treatment options and less toxic optimum protocol depending on the situation surrounding the radiological accidents.Methods:We assessed the clinical dosageadministration in combination with G-CSF and RP as intraperitoneal injection in C57BL/6J mice exposed to more than 7-Gy lethal dose of X-ray TBI for the survival studyevaluated by the log-rank test. Bone marrow and splenic cellswere collected on the 21st day, when1 week have passed from last administration, to detect the level of cell apoptosis, intracellular reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related anti-oxidative gene expressions, and enzyme-linked immune sorbent assayusing serawas performed for cell senescence and inflammationstatusanalyzed with one-way ANOVA and Tukey-Kramer or Bonferroni/Dunn multiple comparison tests.Results: The combined once-daily administration of 10 μg/kg G-CSF for 4 times and 10 μg/kgRP once a week for 3 times improve the 30-day survival rate of lethal TBI mice compared with untreated TBI mice, accompanied by a gradual increase in the body weight and hematopoietic cell numbers. The radio-mitigative effect is probably attributed to the scavenging of ROS and the reduction in cell apoptosis. These changes were associated with the upregulation of Nrf2 and its downstream anti-oxidative targets in TBI mice. Furthermore, this combination modulated TBI-induced cell senescence and inflammation markers. Conclusions:This study suggested that the clinical dosage administration in combination with G-CSF and RP may also have radio-mitigative effects on mice exposed to lethal TBI and may be a potent therapeutic agent for mitigating radiation-induced severe ARS.

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Section: Discussionmentioning

confidence: 99%

Section: Drug Administrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitigative Efficacy of the Clinical Dosage Administration of Granulocyte Colony-stimulating Factor and Romiplostim in Mice With Severe Acute Radiation Syndrome

Yamaguchi

Suzuki

Funaba

et al. 2020

Preprint

Self Cite

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“…In a recent study, Romiplostim administration to lethally irradiated mice increased survival, promoted hematopoiesis in multiple organs, and reduced injury to tissues. Furthermore, Romiplostim suppressed the expression of several microRNAs known to be associated with radiation-induced leukemogenesis [71]. In another study, the maximal survival enhancement of ∼40% was achieved after a single 30 µg/kg dose of Romiplostim [72].…”

Section: Biologicsmentioning

confidence: 97%

Pharmacological management of ionizing radiation injuries: current and prospective agents and targeted organ systems

Singh

Seed²

2020

Expert Opinion on Pharmacotherapy

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Introduction: There is a limited array of currently available medicinals that are useful for either the prevention, mitigation or treatment of bodily injuries arising from ionizing radiation exposure. Area covered: In this brief article, the authors review those pharmacologic agents that either are currently being used to counter the injurious effects of radiation exposure, or those that show promise and are currently under development. Expert opinion: Although significant, but limited progress has been made in the development and fielding of safe and effective pharmacotherapeutics for select types of acute radiation-associated injuries, additional effort is needed to broaden the scope of drug development so that overall health risks associated with both short-and long-term injuries in various organ systems can be reduced and effectively managed. There are several promising radiation countermeasures that may gain regulatory approval from the government in the near future for use in clinical settings and in the aftermath of nuclear/radiological exposure contingencies. ARTICLE HISTORY

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“…G-CSF or RP was intraperitoneally administered once-daily for 3 or 4 times or once a week for up to 4 times, respectively. The dose of G-CSF and RP was 10 µg/kg of body weight/day, which was the same as the clinically used dose [11][12][13]. Mice treated with TBI only and control mice alternatively received injections of normal saline solution as the vehicle (Otsuka Pharmaceutical, Tokyo, Japan) used to prepare the drugs.…”

Section: Drug Administrationmentioning

confidence: 99%

Mitigative efficacy of the clinical dosage administration of granulocyte colony-stimulating factor and romiplostim in mice with severe acute radiation syndrome

Yamaguchi

Suzuki

Funaba

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: It has been reported that the high-dosage administration of domestically approved pharmaceutical drugs, especially granulocyte colony-stimulating factor (G-CSF) and romiplostim (RP), is a rapid and appropriate medical treatment for preventing severe acute radiation syndrome (ARS) of victims exposed to lethal total-body irradiation (TBI). However, it remains unclear whether or not the clinical dosage administration of these drugs can ameliorate TBI-induced ARS and related high mortality in order to find various drug treatment options and less toxic optimum protocol depending on the situation surrounding the radiological accidents.Methods: We assessed the clinical dosage administration in combination with G-CSF and RP as intraperitoneal injection in C57BL/6J mice exposed to more than 7-Gy lethal dose of X-ray TBI for the survival study evaluated by the log-rank test. Bone marrow and splenic cells were collected on the 21st day, when 1 week have passed from last administration, to detect the level of cell apoptosis, intracellular reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related anti-oxidative gene expressions, and enzyme-linked immune sorbent assay using sera was performed for cell senescence and inflammation status analyzed with one-way ANOVA and Tukey-Kramer or Bonferroni/Dunn multiple comparison tests.Results: The combined once-daily administration of 10 μg/kg G-CSF for 4 times and 10 μg/kg RP once a week for 3 times improve the 30-day survival rate of lethal TBI mice compared with untreated TBI mice, accompanied by a gradual increase in the body weight and hematopoietic cell numbers. The radio-mitigative effect is probably attributed to the scavenging of ROS and the reduction in cell apoptosis. These changes were associated with the upregulation of Nrf2 and its downstream anti-oxidative targets in TBI mice. Furthermore, this combination modulated TBI-induced cell senescence and inflammation markers. Conclusions: This study suggested that the clinical dosage administration in combination with G-CSF and RP may also have radio-mitigative effects on mice exposed to lethal TBI and may be a potent therapeutic agent for mitigating radiation-induced severe ARS.

show abstract

Diverse functions of the thrombopoietin receptor agonist romiplostim rescue individuals exposed to lethal radiation

Cited by 18 publications

References 52 publications

Mitigative Efficacy of the Clinical Dosage Administration of Granulocyte Colony-stimulating Factor and Romiplostim in Mice With Severe Acute Radiation Syndrome

Mitigative Efficacy of the Clinical Dosage Administration of Granulocyte Colony-stimulating Factor and Romiplostim in Mice With Severe Acute Radiation Syndrome

Pharmacological management of ionizing radiation injuries: current and prospective agents and targeted organ systems

Mitigative efficacy of the clinical dosage administration of granulocyte colony-stimulating factor and romiplostim in mice with severe acute radiation syndrome

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