Role of drugs in the prevention and amelioration of radiation induced toxic effects

Patyar, Rakesh Raman; Patyar, Sazal

doi:10.1016/j.ejphar.2017.12.011

Cited by 32 publications

(22 citation statements)

References 121 publications

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“…However, exposure to radiation induces apoptotic cell death of both tumor cells and healthy tissue cells by causing excessive production of free radicals (e.g., reactive oxygen species and reactive nitrogen species) over the antioxidant system potency in cells or tissues. Thus, damage to surrounding healthy tissues, particularly the spleen, bone marrow and gastrointestinal tract, has been suggested as a limitation for the clinical application of radiation therapy (Patyar & Patyar, ; Yahyapour et al, ), and much research focuses on developing agents to prevent or treat radiation injury (Rosen, Day, & Singh, ).…”

Section: Introductionmentioning

confidence: 99%

Repeated injection of KMRC011, a medical countermeasure for radiation, can cause adverse health effects in cynomolgus monkeys

Lee

Park

Cho

et al. 2018

J of Applied Toxicology

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High‐dose radiation‐induced tissue damage is a major limiting factor in the medical application of nuclear technology. Herein, we tested 28‐day repeated‐dose toxicity of KMRC011, an agonist of toll‐like receptor (TLR) 5, which is being developed as a medical countermeasure for radiation, using cynomolgus monkeys. KMRC011 (0.01, 0.02 or 0.04 mg/kg/day) was intramuscularly injected once daily for 4 weeks, and each two monkeys in both control and 0.04 mg/kg/day group were observed for an additional 2‐week recovery period. There were no dose‐related toxicological changes in mortality, clinical observations, body weight, food consumption, ophthalmological findings, electrocardiographs, coagulation, serum chemistry, organ weights, or urinalysis and urine chemistry. Although treatment‐related changes, such as increased white blood cells, increased absolute and relative neutrophils, decreased relative lymphocytes and inflammatory lesions, were noted in the maximum dose group, these findings were not observed after the 2‐week recovery period. Further, we considered that the kidneys and heart may be target organs of TLR5 agonists, as well as the spleen, and that autophagic signals can be triggered in tissue damage and the repair process. Importantly, accumulation of p62 protein, an indicator of autophagy, and a decrease of caveolin‐1 protein, a regulator of TLR5 protein half‐life, were found in both tissues from the highest dose group. Therefore, we conclude that the no‐observed‐adverse‐effect level for KMRC011 may be greater than 0.04 mg/kg/day in male and female monkeys. Additionally, we propose that further studies are needed to identify the molecular signals, which are related to KMRC011‐induced adverse effects.

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Section: Introductionmentioning

confidence: 99%

Repeated injection of KMRC011, a medical countermeasure for radiation, can cause adverse health effects in cynomolgus monkeys

Lee

Park

Cho

et al. 2018

J of Applied Toxicology

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“…However, its application is limited because of its serious side effects, short halflife, nonoral nature, and other disadvantages [28,29]. The search for a radioprotective agent with a long half-life, oral administration, and no obvious side effects on the human body has always been an important issue in the field of radiation medicine [30,31]. We previously used the structure of amifostine to design and synthesize a small molecule compound containing a sulfhydryl group, HL-003, for which we have 100% independent intellectual property rights.…”

Section: Pk Parametermentioning

confidence: 99%

Preclinical Evaluation of Safety, Pharmacokinetics, Efficacy, and Mechanism of Radioprotective Agent HL‐003

Liu

Miao

Tian

2021

Oxidative Medicine and Cellular Longevity

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Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the increasing risk of exposure to radiation, the development of new radioprotective agents is critical. We previously synthesized a new amifostine derivative, the small molecule compound HL-003. In this study, we focused on evaluating the radioprotective properties of HL-003. Using the in vitro 2,2-diphenyl-1-picrylhydrazyl assay, we initially confirmed HL-003 as a strong antioxidant and demonstrated that its free radical scavenging activity was stronger than that of amifostine. Then, we performed an acute toxicity test, a 28-day toxicity test, a 30-day survival rate test, and a pharmacokinetic study, all of which provided aggregate evidence that HL-003 functioned as a small molecule radioprotector with high efficacy, a favorable safety profile, a long half-life, and oral administration. The intestinal radioprotective mechanism of HL-003 was explored in male C57 mice after abdominal irradiation by analyzing intestinal tissue samples with hematoxylin-eosin staining, immunohistochemistry, TUNEL staining, and immunofluorescence detection. The results showed that HL-003 protected intestinal DNA from radiation damage and suppressed the expression of phosphorylated histone H2AX, phosphorylated p53, and the apoptosis-related proteins caspase-8 and caspase-9, which contributed to maintaining the normal morphology of the small intestine and provided insights into the mechanism of radioprotection. Thus, HL-003 is a small molecule radioprotector with a potential application in radiation medicine.

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“…Встановлена L. Gray ще у 1953 р. здатність молекулярного кисню посилювати біологічні ефекти іонізуючого опромінення («кисневе посилення»), надихнула дослідників до пошуку радіопротекторів, здатних викликати гіпоксію. Результатом чисельних досліджень став поділ всіх радіопротекторів на індуктори гіпоксії («оксидомодулятори») та лікарські засоби з негіпоксичним механізмом дії [77,18,51,25,34,42,26,49].…”

Section: результати дослідженняunclassified

Pharmacoprophylactic and Pharmacotherapeutic Approaches to Mitigating the Damaging Effects of Ionizing Radiation: Review of Information Sources

Hladkykh

2018

PoS

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Анотація. Метою статті є узагальнення наукових точок зору щодо сучасних підходів до фармакологічної корекції ушкоджень радіаційного генезу. Проведення лікувальних заходів, спрямованих на усунення негативних наслідків впливу іонізуючого опромінення та прискорення відновлювальних процесів в опроміненому організмі потребує обов'язкового застосування протипроменевих засобів. На сьогоднішній день є обґрунтованим поділ всіх протипроменевих препаратів на фармакопрофілактичні та фармакотерапевтичні лікарські засоби. До засобів профілактики радіаційних уражень належать три класи препаратіврадіопротектори, радіомодулятори та радіомодифікатори. Окреме місце посідають препарати ранньої патогенетичної терапії (радомітігатори) та засоби терапії відтермінованих наслідків дії радіаційного чинника. Зважаючи на доволі широкий спектр медикаментозних засобів з протипроменевими ефектами, що значно ускладнює цілісне сприйняття їх компартменталізації із врахуванням їх практичної значущості за конкретних сценаріїв радіаційного ураження, складено їх сучасну класифікацію.Ключові слова: іонізуюче опромінення; протипроменеві лікарські засоби; радіопротектори; радіомодулятори; радіомодифікатори; радіомітігатори.Abstract. The purpose of the article is to synthesize the scientific points of view on modern approaches to pharmacological correction of radiation damage. Conducting medical treatment, aimed at eliminating the negative effects of exposure to ionizing radiation and accelerating the recovery processes in an irradiated organism requires the mandatory use of anti-radiation agents. Today there is a reasonable division of all anti-radiation drugs into pharmacoprophylactic and pharmacotherapeutic. The means of preventing radiation damage include three classes of drugs -radioprotectors, radio modulators and radio modifiers. Special attention is paid to preparations of early pathogenetic therapy (radiomitigators) and the means of therapy of delayed effects of the radiation factor. The modern classification of the rather wide range of medicines with anti-radiation effects, which greatly complicates the holistic perception of their compartmentalization, taking into account their practical significance in specific scenarios of radiation damage, is compiled. ВСТУПШироке впровадження використання ефектів іонізуючого опромінення (ІО) у всіх сферах життєдіяльності людини супроводжується невпинним зростанням числа контактів з джерелами радіації, зокрема з медичним опроміненням (МО), на долю якого припадає 15-20 % сумарного пулу променевого навантаження [44,56,62]. Заслуговує уваги й тен-

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Role of drugs in the prevention and amelioration of radiation induced toxic effects

Cited by 32 publications

References 121 publications

Repeated injection of KMRC011, a medical countermeasure for radiation, can cause adverse health effects in cynomolgus monkeys

Repeated injection of KMRC011, a medical countermeasure for radiation, can cause adverse health effects in cynomolgus monkeys

Preclinical Evaluation of Safety, Pharmacokinetics, Efficacy, and Mechanism of Radioprotective Agent HL‐003

Pharmacoprophylactic and Pharmacotherapeutic Approaches to Mitigating the Damaging Effects of Ionizing Radiation: Review of Information Sources

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