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International Journal of Molecular... Mar 2024E0703, a new steroidal compound optimized from estradiol, significantly increased cell proliferation and the survival rate of KM mice and beagles after ionizing...
Prediction of Human Pharmacokinetics of E0703, a Novel Radioprotective Agent, Using Physiologically Based Pharmacokinetic Modeling and an Interspecies Extrapolation Approach.
E0703, a new steroidal compound optimized from estradiol, significantly increased cell proliferation and the survival rate of KM mice and beagles after ionizing radiation. In this study, we characterize its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. The preclinical PK of E0703 was studied in mice and Rhesus monkeys. Asian human clearance (CL) values for E0703 were predicted from various allometric methods. The human PK profiles of E0703 (30 mg) were predicted by the PBPK model in Gastro Plus software 9.8 (SimulationsPlus, Lancaster, CA, USA). Furthermore, tissue distribution and the human PK profiles of different administration dosages and forms were predicted. The 0.002 L/h of CL and 0.005 L of V in mice were calculated and optimized from observed PK data. The plasma exposure of E0703 was availably predicted by the CL using the simple allometry (SA) method. The plasma concentration-time profiles of other dosages (20 and 40 mg) and two oral administrations (30 mg) were well-fitted to the observed values. In addition, the PK profile of target organs for E0703 exhibited a higher peak concentration (C) and AUC than plasma. The developed E0703-PBPK model, which is precisely applicable to multiple species, benefits from further clinical development to predict PK in humans.
Topics: Mice; Humans; Animals; Dogs; Radiation-Protective Agents; Models, Biological; Administration, Oral; Tissue Distribution; Pharmacokinetics
PubMed: 38474292
DOI: 10.3390/ijms25053047 -
Biomedicine & Pharmacotherapy =... Jul 2017Radiation damage can occur in nuclear power plant workers when physical protections fail, which results in nuclear leakage through the protective layers. Alternatively,... (Review)
Review
Radiation damage can occur in nuclear power plant workers when physical protections fail, which results in nuclear leakage through the protective layers. Alternatively, workers may be unable to use physical protection in time (in the case of a sudden nuclear weapons attack). In addition, patients who receive local radiotherapy and are not allowed to adopt local physical protection may experience radiation damage. Thus, protection against chemical radiation has become indispensable. In view of the side effects caused by synthetic radioprotective agents (such as amisfostine), searching for radioprotective agents from plant sources is an alternative strategy. Radiation damage can cause multiple signalling pathway disturbances, leading to multiple organ injuries. Changes in these signalling pathways can lead to apoptosis, necrosis, and autophagy, as well as organ fibrosis, atrophy, and inflammation. Through literature searches, we determined that most targets for treating radiation injury are mechanistically opposite those of anti-tumour agents. This is likely attributable to the idea that anti-tumour agents promote cell necrosis or apoptosis, whereas the goal of anti-radiation agents is to promote cell survival or autophagy. This observation has important theoretical and practical significance when searching and developing new radioprotective agents derived from plant extracts. Further, it has important guiding value for meeting military needs and serving the public.
Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Plant Extracts; Radiation-Protective Agents; Signal Transduction
PubMed: 28531942
DOI: 10.1016/j.biopha.2017.05.001 -
Haematologica Nov 1999Amifostine is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[(3-aminopropyl)amino]dihydrogen phosphate. It is a pro-drug of... (Review)
Review
BACKGROUND AND OBJECTIVE
Amifostine is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[(3-aminopropyl)amino]dihydrogen phosphate. It is a pro-drug of free thiol that may act as a scavenger of free radicals generated in tissues exposed to cytotoxic drugs, and binds to reactive metabolites of such drugs. Amifostine was originally developed as a radioprotective agent in a classified nuclear warfare project. Following declassification of the project it was evaluated as a cytoprotective agent against toxicity of the alkylating drugs and cisplatin. In fact, pretreatment with amifostine was well tolerated and reduced the cumulative hematologic, renal and neurological toxicity associated with cisplatin, cyclophosphamide and vinblastine therapy of advanced and metastatic solid tumors. The objective of this review is to focus the importance of amifostine as a myeloprotective and cytoprotective drug during treatment with chemotherapeutics, presenting the most recent results, and to discuss the application of amifostine in the therapy of myelodysplastic syndromes.
EVIDENCE AND INFORMATION SOURCES
The material analyzed in this study includes data published or under publication by the authors as full papers or clinical protocols. Articles and abstracts published in Journals covered by Medline constitute the other source of information.
STATE OF THE ART AND PERSPECTIVES
Amifostine, formerly known as WR-2721, is an organic thiophosphate that was developed to protect normal tissues selectively against the toxicities of chemotherapy and radiation. Amifostine is a pro-drug that is dephosphorylated at the tissue site to its active metabolite by alkaline phosphatase. Differences in the alkaline phosphatase concentrations of normal versus tumor tissues can result in greater conversion of amifostine in normal tissues. Once inside the cell the free thiol provides an alternative target to DNA and RNA for the reactive molecules of alkylating or platinum agents and acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation and some chemotherapies. Preclinical animal studies demonstrated that the administration of amifostine protected against a variety of chemotherapy-related toxicities including cisplatin-induced nephrotoxicity, cisplatin-induced neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity, and the cytotoxicities (including cardiotoxicity) induced by doxorubicin and related chemotherapeutic agents. Amifostine was shown to protect a variety of animal species from lethal doses of radiation. Studies in tumor-bearing animals demonstrated that the administration of amifostine results in cytoprotection without loss of antitumor activity. Multiple phase I studies were carried out with amifostine in combination with chemotherapy for various neoplasms. Appropriate doses of amifostine resulted to be 740-910 mg/m(2) in a single dose regimen, and 340 mg/m(2) in a multiple dose regimen. Amifostine afforded not only hematologic protection, but also other organ protection from cytotoxic agents such as nephrotoxicity, mucositis and peripheral neuropathy from cisplatin. Many studies have been performed to investigate cytoprotective efficacy of amifostine. In brief, amifostine gives hematologic protection from cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and peripheral nerve protection from cisplatin; mucosa, skin, and salivary gland from radiotherapy. In phase I/II studies these properties have been confirmed, together with a generally good tolerability of the drug, hypotension being the most common side effect. It has been observed that amifostine possibly enhances the anti-tumor effect of carboplatin, nitrogen mustard, melphalan, and cisplatin combined with 5-FU or vinblastine. For all these characteristics, amifostine is at present broadly used as supportive treatment during chemotherapy, in lymphomas and solid tumors, and its spec
Topics: Amifostine; Animals; Antineoplastic Agents; Hematologic Neoplasms; Humans; Neutropenia; Radiation-Protective Agents; Thrombocytopenia
PubMed: 10553165
DOI: No ID Found -
Advances in Experimental Medicine and... 2007This chapter gives an overview of the radioprotective and radiosensitizing effect of curcumin. Ionizing radiations interact with biological molecules inducing radiolytic... (Review)
Review
This chapter gives an overview of the radioprotective and radiosensitizing effect of curcumin. Ionizing radiations interact with biological molecules inducing radiolytic products like e(aq), *OH, *H, -OH, +H, O2, and peroxides. These free radicals damage important biomolecules and subsequently inflict deleterious effects in the organism. Whole-body exposure to ionizing radiations results in central nervous system, gastrointestinal tract, and bone marrow syndromes, whereas chronic irradiation causes cancer, birth anomalies, erythema, and dysfunctions to almost all organ of the body depending on the total dose and site of irradiation. Curcumin (diferuloyl methane), a yellow pigment present in the rhizomes of turmeric, has been used in Southeast Asia to give yellow color and flavor to curries. Turmeric has been used to treat various ailments in the Ayurvedic system of medicine in India. Recently, it has been evaluated for its radioprotective and radiosensitizing activities. Curcumin has been found to exert a dual mode of action after irradiation depending on its dose. It has been reported to protect various study systems against the deleterious effects induced by ionizing radiation and to enhance the effect of radiation. Therefore, curcumin can be very useful during radiotherapy of cancer. Administration of curcumin in patients will be able to kill the tumor cells effectively by enhancing the effect of radiation and, at the same time, protect normal cells against the harmful effects of radiation. The available information on curcumin suggests that the radioprotective effect might be mainly due to its ability to reduce oxidative stress and inhibit transcription of genes related to oxidative stress and inflammatory responses, whereas the radiosensitive activity might be due the upregulation of genes responsible for cell death.
Topics: Animals; Curcumin; Dose-Response Relationship, Radiation; Humans; Models, Biological; Radiation Tolerance; Radiation, Ionizing; Radiation-Protective Agents; Radiation-Sensitizing Agents
PubMed: 17569217
DOI: 10.1007/978-0-387-46401-5_13 -
Journal of Clinical Pharmacology Apr 1996Amifostine, a chemo- and radioprotective agent developed as adjunctive therapy for malignancies, induces hypotension after approximately 20% of patient administrations....
Amifostine, a chemo- and radioprotective agent developed as adjunctive therapy for malignancies, induces hypotension after approximately 20% of patient administrations. This study examines the molecular mechanisms underlying hypotension induced by amifostine. Amifostine and its metabolite, WR-1065, induced dose-dependent hypotension in anesthetized rats that was not blocked by N(G)-methyl L arginine (L-NAME), an NO synthase inhibitor. WR-1065 but not amifostine induced concentration-dependent relaxation of isolated rat aortic rings in an endothelium-independent fashion. Relaxation was not associated with increases in cGMP or cAMP and could not be blocked by L-NAME or indomethacin. Similarly, neither amifostine or WR-1065 activated adenylyl, particulate guanylyl, or soluble guanylyl cyclases. WR-1065 relaxed rat aortic rings precontracted with norepinepherine, suggesting alpha-adrenergic blocking activity. However, neither amifostine nor WR-1065 altered the ability of prazosin or phentolamine to bind to alpha-adrenergic receptors. Further, WR-1065 had no effect on receptor-mediated increases in intracellular calcium in BAL 17 murine B lymphocytes in vitro. Thus, hypotension after administration of amifostine is mediated by WR-1065 and appears to result from direct relaxation of vascular smooth muscle. Smooth muscle relaxation induced by WR-1065 is not related to production of nitric oxide, prostaglandins, or cyclic nucleotides; alpha-adrenergic receptor antagonism; or interference with receptor-dependent increases in intracellular calcium. Administration of ephedrine, an efficacious adrenergic agonist, attenuated hypotension induced by amifostine in anesthetized rats and may be useful in alleviating hypotension associated with amifostine administration in patients.
Topics: Adrenergic Agents; Amifostine; Animals; Aorta, Thoracic; Arginine; Blood Pressure; Calcium; Cyclic AMP; Cyclic GMP; Ephedrine; Hypotension; In Vitro Techniques; Ligands; Male; Mercaptoethylamines; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Radiation-Protective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha
PubMed: 8728352
DOI: 10.1002/j.1552-4604.1996.tb04214.x -
Brazilian Dental Journal 2013The aim of this study was to evaluate the radioprotective effect of vitamin E on rat parotid glands by morphometric analysis. Sixty male rats were divided into 5 groups... (Comparative Study)
Comparative Study
The aim of this study was to evaluate the radioprotective effect of vitamin E on rat parotid glands by morphometric analysis. Sixty male rats were divided into 5 groups (n=6): control, in which animals received olive oil solution; olive oil/irradiated, in which animals received olive oil and were irradiated with a dose of 15 Gy of gamma radiation; irradiated, in which animals were irradiated with a dose of 15 Gy gamma radiation; vitamin E, which received α-tocopherol acetate solution; vitamin E/irradiated, which received α-tocopherol acetate solution before irradiation with a dose of 15 Gy gamma rays. Half of the animals were euthanized at 8 h, and the remaining at 30 days after irradiation. Both parotid glands were surgically removed and morphometric analysis of acinar cells was performed. Data were subjected to two-way ANOVA and Tukey's test (α=0.05). Morphometric analysis showed a significant reduction in the number of parotid acinar cells at 30 days in olive oil/irradiated and irradiated groups. In groups evaluated over time a significant reduction was shown at 30 days in olive oil/irradiated and irradiated groups, indicating that ionizing radiation caused tissue damage. The vitamin E/irradiated group presented more acinar cells than the irradiated group, but no statistically significant difference was observed (p>0.05). In conclusion, vitamin E seems to have failed as a radioprotective agent on acinar cells in rat parotid glands.
Topics: Animals; Antioxidants; Atrophy; Gamma Rays; Male; Organ Size; Parotid Gland; Radiation Dosage; Radiation-Protective Agents; Random Allocation; Rats; Rats, Wistar; Salivary Ducts; Time Factors; Vitamin E
PubMed: 23969903
DOI: 10.1590/0103-6440201301781 -
Journal of Photochemistry and... Jan 2018Free radicals and reactive oxygen species (ROS) are generated using various endogenous systems or from external sources such as exposure to different physiochemicals....
Free radicals and reactive oxygen species (ROS) are generated using various endogenous systems or from external sources such as exposure to different physiochemicals. Ionizing radiation damage to the cell can be caused by the direct or indirect effects of radiotherapy processes. Silymarin (SM), a flavanolignan compound, has been identified as a natural potent antioxidant with cytoprotection activities due to scavenging free radicals. The aim of the present study was to evaluate the radioprotective effect of SM on sperm parameters of mice induced by γ-rays. A total number of 40 adult, male NMRI mice were randomly divided into four equal groups. The control group was neither treated with SM nor irradiated by γ-rays. The second group was only irradiated with 2Gy of γ-rays. The third group was firstly treated with 50mg/kg of SM for 7 consecutive days, and one day later, last injections were irradiated by 2Gy of γ-rays. The fourth groups received only 50mg/kg of SM for 7 consecutive days. All the animals were treated intraperitoneally. Histopathological and morphometrical examinations were performed. The data were analyzed using ANOVA and Tukey post hoc test. A value of p<0.05 was considered significant. The results showed that in the radiation-only group when compared with those treated with SM and irradiated, a significant different was observed in testicular parameters and DNA damage (p<0.05). In conclusion, SM can be considered as a promising herbal radioprotective agent in complementary medicine which may play an important role to protect normal spermatocytes against possible effects of γ-radiation-induced cellular damage.
Topics: Animals; DNA Damage; Gamma Rays; Histones; Male; Mice; Protamines; Radiation-Protective Agents; Reactive Oxygen Species; Silymarin; Sperm Motility; Spermatozoa; Testis
PubMed: 29232573
DOI: 10.1016/j.jphotobiol.2017.12.004 -
Bioorganic & Medicinal Chemistry Aug 2014In radiation therapy, adverse side effects are often induced due to the excessive cell death that occurs in radiosensitive normal cells. The radiation-induced cell death...
In radiation therapy, adverse side effects are often induced due to the excessive cell death that occurs in radiosensitive normal cells. The radiation-induced cell death of normal cells is caused, at least in part, by apoptosis, which undergoes via activation of p53 and increase in the p53 protein, a zinc-containing transcriptional factor, in response to cellular damage. Therefore, radioprotective drugs that can protect normal cells from radiation and thus suppress adverse side effects would be highly desirable. We report herein on the radioprotective activity of 8-hydroxyquinoline (8HQ) derivatives that were initially designed so as to interact with the Zn(2+) in p53. Indeed, the 5,7-bis(methylaminosulfonyl)-8HQ and 8-methoxyquinoline derivatives considerably protected MOLT-4 cells against γ-ray radiation (10 Gy), accompanied by a low cytotoxicity. However, mechanistic studies revealed that the interaction of these drugs with p53 is weak and the mechanism for inhibiting apoptosis appears to be different from that of previously reported radioprotectors such as bispicen, which inhibits apoptosis via the denaturation of p53 as well as by blocking both transcription-dependent and -independent apoptotic pathways.
Topics: Apoptosis; Cell Line, Tumor; Drug Design; Electrophoretic Mobility Shift Assay; Gamma Rays; Humans; Oxyquinoline; Radiation-Protective Agents; Tumor Suppressor Protein p53; Zinc
PubMed: 25002230
DOI: 10.1016/j.bmc.2014.06.017 -
Molecular Interventions Dec 2008Adverse effects of ionizing radiation are mediated through reactive oxygen and nitrogen species. Mitochondria are the principal source of these species in the cell and... (Review)
Review
Adverse effects of ionizing radiation are mediated through reactive oxygen and nitrogen species. Mitochondria are the principal source of these species in the cell and play an important role in irradiation-induced apoptosis. The use of free radical scavengers and nitric oxide synthase inhibitors has proven to protect normal tissues and, in some cases, to sensitize tumor tissues to radiation damage. Dual molecules that combine radical-scavenging and NOS-inhibitory functions may be particularly effective. Drugging strategies that target mitochondria can enhance the effectiveness of such agents, in comparison to systemic administration, and circumvent side effects.
Topics: Animals; Drug Delivery Systems; Humans; Mitochondria; Neoplasms; Radiation-Protective Agents; Radiation-Sensitizing Agents
PubMed: 19144902
DOI: 10.1124/mi.8.6.7 -
European Journal of Medicinal Chemistry Feb 2020The goal of this study was to develop novel radioprotective agents targeting the intrinsic apoptotic pathway and thus decreasing the radiation-induced damage. For that...
The goal of this study was to develop novel radioprotective agents targeting the intrinsic apoptotic pathway and thus decreasing the radiation-induced damage. For that purpose, we designed, synthesized and analyzed ten new compounds based on the 1-(4-(2-hydroxyethyl)piperazin-1-yl)-3-phenoxypropan-2-ol leading structure. The cytotoxicity of the newly synthesized substances was tested in vitro on cell lines derived from different progenitor cells by WST-1 proliferation assay. MTT test was utilized to assess half-maximal inhibitory concentrations and maximum tolerated concentrations of novel compounds in A-549 cells. Screening for radioprotective properties was performed using flow-cytometry in MOLT-4 cells exposed to Co ionizing gamma radiation. Selected candidates underwent in vivo testing in C57Bl/6 J mice having a positive impact on their immunological status. In summary, we report here promising compounds with radioprotective effect in vivo.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Propanols; Radiation-Protective Agents; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 31901334
DOI: 10.1016/j.ejmech.2019.111606