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1.
Int Immunopharmacol ; 15(2): 348-56, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23328620

ABSTRACT

The hematopoietic system is sensitive to radiation injury, and mortality can occur due to blood cell deficiency and stem cell loss. Genistein and the angiotensin converting enzyme (ACE) inhibitor captopril are two agents shown to protect the hematopoietic system from radiation injury. In this study we examined the combination of genistein with captopril for reduction of radiation-induced mortality from hematopoietic damage and the mechanisms of radiation protection. C57BL/6J mice were exposed to 8.25Gy (60)Co total body irradiation (TBI) to evaluate the effects of genistein and captopril alone and in combination on survival, blood cell recovery, hematopoietic progenitor cell recovery, DNA damage, and erythropoietin production. 8.25Gy TBI resulted in 0% survival after 30days in untreated mice. A single subcutaneous injection of genistein administered 24h before TBI resulted in 72% survival. Administration of captopril in the drinking water, from 1h through 30days postirradiation, increased survival to 55%. Genistein plus captopril increased survival to 95%. Enhanced survival was reflected in a reduction of radiation-induced anemia, improved recovery of nucleated bone marrow cells, splenocytes and circulating red blood cells. The drug combination enhanced early recovery of marrow progenitors: erythroid (CFU-E and BFU-E), and myeloid (CFU-GEMM, CFU-GM and CFU-M). Genistein alone and genistein plus captopril protected hematopoietic progenitor cells from radiation-induced micronuclei, while captopril had no effect. Captopril alone and genistein plus captopril, but not genistein alone, suppressed radiation-induced erythropoietin production. These data suggest that genistein and captopril protect the hematopoietic system from radiation injury via independent mechanisms.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Captopril/administration & dosage , Erythrocytes/drug effects , Genistein/administration & dosage , Hematopoiesis/drug effects , Hematopoietic Stem Cells/drug effects , Radiation Injuries, Experimental/prevention & control , Radiation-Protective Agents/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Animals , Captopril/adverse effects , Cell Survival/drug effects , Cell Survival/radiation effects , Cells, Cultured , Drug Therapy, Combination , Erythrocytes/pathology , Erythrocytes/radiation effects , Erythropoietin/metabolism , Female , Genistein/adverse effects , Hematopoiesis/radiation effects , Hematopoietic Stem Cells/pathology , Hematopoietic Stem Cells/radiation effects , Humans , Mice , Mice, Inbred C57BL , Radiation-Protective Agents/adverse effects , Whole-Body Irradiation
2.
Int J Radiat Biol ; 78(6): 535-43, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12065057

ABSTRACT

PURPOSE: We evaluated the use of a subcutaneously (s.c.) implantable, biodegradable pellet as a drug delivery system for the radioprotector amifostine. MATERIALS AND METHODS: Mice were implanted s.c. with either the custom-made biodegradable amifostine drug pellet or the placebo pellet without amifostine, exposed to cobalt-60 gamma-radiation (bilateral, 1 Gy min(-1), 7-16 Gy), and the 30-day survival rate was monitored. The non-irradiated mouse was used for pharmacokinetic and behavioural tests. RESULTS: Significant radioprotection (85-95% survival) at 10 Gy was observed in the three-amifostine pellet implanted group 3-5 h after implantation. LD50/30 was 7.97, 8.74 and 16.64 Gy for the control, three-placebo pellet (dose reduction factor, DRF=1.10, p<0.01), and three-amifostine pellet (DRF=1.79, p<0.01) groups respectively in mouse exposed to radiation 2h after implantation. Radioprotection at 12 Gy was observed up to 4h after s.c. amifostine administration and up to 3h after implantation. Pharmacokinetic data revealed that the three-amifostine pellet group had sustained blood WR-1065 levels at 2 h after implantation, in contrast to the reported sharp peak at 30 min for s.c. administration. Although locomotor activity was significantly reduced (p<0.01) in the amifostine pellet group, the onset of the locomotor decrement was delayed as compared with groups that received 400 and 750 mg kg(-1) s.c. amifostine. CONCLUSIONS: Amifostine in biodegradable implant was effective. The radioprotection observed was comparable between conventional s.c. administration of the drug and implantation. Pharmacokinetic data and locomotor activity suggest that the implantation was beneficial though radioprotection data warrants formulation improvements in implants.


Subject(s)
Amifostine/administration & dosage , Motor Activity/drug effects , Motor Activity/radiation effects , Radiation-Protective Agents/administration & dosage , Amifostine/pharmacokinetics , Animals , Drug Implants , Injections, Subcutaneous , Male , Mice , Radiation-Protective Agents/pharmacokinetics
4.
J Appl Toxicol ; 21(1): 25-31, 2001.
Article in English | MEDLINE | ID: mdl-11180277

ABSTRACT

The effect of combining a radiation-protective phosphorothioate with another agent was investigated in an attempt to increase radioprotection and reduce toxicity. The calcium channel blocker nimodipine (NIMO) was administered alone (1 or 10 mg kg-1) or in combination with 200 mg kg-1 of the phosphorothioate radioprotector WR-151327 (WR) (S-3-(3-methylaminopropylamino)propylphosphorothioic acid). Radioprotection as measured (30-day survival) of mice treated i.p. 30 min before (60)Co irradiation at a dose rate of 1 Gy min-1 was evaluated in CD2F1 male mice. The effects of nimodipine and WR-151327 on locomotor activity were investigated also in a separate group of non-irradiated mice. The LD(50/30) for the Emulphor vehicle control group was 8.56. For nimodipine alone (1 or 10 mg kg-1) the LD(50/30)was 8.39 and 10.21 Gy, respectively, yielding dose modification factors (DMFs) of 0.98 and 1.19, respectively. When WR-151327 was given alone, the

Subject(s)
Calcium Channel Blockers/pharmacology , Motor Activity/drug effects , Nimodipine/pharmacology , Organothiophosphorus Compounds/pharmacology , Radiation Injuries, Experimental/prevention & control , Radiation-Protective Agents/pharmacology , Animals , Calcium Channel Blockers/administration & dosage , Dose-Response Relationship, Drug , Drug Combinations , Lethal Dose 50 , Male , Mice , Mice, Inbred Strains , Nimodipine/administration & dosage , Organothiophosphorus Compounds/administration & dosage , Radiation Injuries, Experimental/mortality , Radiation-Protective Agents/administration & dosage , Survival Rate , Time Factors
5.
Mil Med ; 166(12 Suppl): 69-70, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11778443

ABSTRACT

During the Persian Gulf War, soldiers may have inhaled, ingested, and/or experienced wound contamination by depleted uranium (DU), which is used in military projectiles and armor. DU is produced by depleting natural uranium of 234U and 235U during the uranium-enrichment process. Although the long-term effects of significant DU exposures require investigation, many veterans express fears about its impact on health. An assay by which DU exposure can be assessed would not only be a useful research tool, but the information could help mitigate the concerns of exposed individuals. In this study, urine samples from individuals enrolled in the Depleted Uranium Follow-Up Program at the Baltimore Veterans Administration Medical Center were examined for uranium content. Isotopic composition of urine uranium was determined by measuring the 235U/238U ratio, using an inductively coupled plasma mass spectrometer. Using this method, natural and depleted uranium could be readily differentiated. By demonstrating the absence of DU in soldiers who suspect exposure by inhalation or ingestion, the assay should reduce psychological stress in these individuals.


Subject(s)
Environmental Exposure/analysis , Uranium/urine , Wounds, Penetrating/urine , Biomarkers/urine , Humans , Inhalation Exposure , Middle East , Warfare
6.
Mil Med ; 166(12 Suppl): 71-3, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11778444

ABSTRACT

Ionizing radiation could increase morbidity from common bacterial infections in military personnel on the modern battlefield. The combined effects of a sublethal dose of ionizing radiation and the bacterial diarrheal agent Shigella sonnei on body weight and forelimb grip strength in mice were assessed over a 30-day period. Individually housed B6D2F1 female mice were divided into four groups: control, sham irradiation + gavage with saline vehicle; 3 Gy 60Co gamma radiation at 0.4 Gy/min radiation + saline gavage; sham irradiation + 1.3 x 10(8) colony-forming units (CFUs) S. sonnei via gavage, administered 4 days postirradiation; and the combination of 3 Gy 60Co gamma radiation + 1.3 x 10(8) CFUs S. sonnei. Behavioral tests were conducted 3 days preirradiation and on days 9, 14, and 22 postirradiation. Body weight was significantly reduced in the radiation + Shigella group on days 5 to 10 postirradiation. Forelimb grip strength was reduced for mice in the radiation + Shigella group on days 9 and 14 postirradiation. These data demonstrate that an exposure to gamma radiation in combination with the bacterial agent S. sonnei can lead to a synergistic loss of body weight and degradation in performance.


Subject(s)
Dysentery, Bacillary/complications , Gamma Rays/adverse effects , Shigella sonnei/pathogenicity , Weight Loss , Animals , Body Weight/radiation effects , Extremities/physiopathology , Extremities/radiation effects , Female , Hand Strength/physiology , Mice
7.
Ann N Y Acad Sci ; 899: 44-60, 2000.
Article in English | MEDLINE | ID: mdl-10863528

ABSTRACT

The role of reactive oxygen species in ionizing radiation injury and the potential of antioxidants to reduce these deleterious effects have been studied in animal models for more than 50 years. This review focuses on the radioprotective efficacy and the toxicity in mice of phosphorothioates such as WR-2721 and WR-151327, other thiols, and examples of radioprotective antioxidants from other classes of agents. Naturally occurring antioxidants, such as vitamin E and selenium, are less effective radioprotectors than synthetic thiols but may provide a longer window of protection against lethality and other effects of low dose, low-dose rate exposures. Many natural antioxidants have antimutagenic properties that need further examination with respect to long-term radiation effects. Modulation of endogenous antioxidants, such as superoxide dismutase, may be useful in specific radiotherapy protocols. Other drugs, such as nimodipine, propranolol, and methylxanthines, have antioxidant properties in addition to their primary pharmacological activity and may have utility as radioprotectors when administered alone or in combination with phosphorothioates.


Subject(s)
Antioxidants/pharmacology , Radiation-Protective Agents/pharmacology , Animals , Antioxidants/adverse effects , Humans , Mice , Organophosphorus Compounds/adverse effects , Organophosphorus Compounds/pharmacology , Radiation-Protective Agents/adverse effects , Sulfhydryl Compounds/adverse effects , Sulfhydryl Compounds/pharmacology
8.
Int J Radiat Biol ; 76(2): 261-71, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10716647

ABSTRACT

PURPOSE: To determine the efficacy of WR-151327 (WR) [S-3-(3-methylaminopropylamino) propylphosphorothioic acid; (CH3-HN-(CH2)3-NH-(CH2)3-S-PO3H2)] in increasing resistance to bacterial infection after a sublethal dose of gamma-photons or mixed-field neutrons plus gamma-photons. MATERIALS AND METHODS: B6D2F1/J female mice received 200 mg/kg WR i.p. or saline vehicle 20-30 min before or after sham (0 Gy) or 7.0 Gy 60Co gamma-photon irradiation. WR or saline vehicle was given only before 3.5 Gy TRIGA-reactor-produced mixed-field [n/(n+y) = 0.67] irradiation. Four days after drug treatment or drug treatment and irradiation, graded doses of Klebsiella pneumoniae were injected s.c. into mice, and 30-day survival was recorded. To assess haemopoietic changes other unirradiated and irradiated mice not injected with bacteria were given WR or saline. Peripheral blood (PB) and femoral bone marrow (BM) cells were measured 1, 3 or 4, 7, 10 and 14 or 15 days later. RESULTS: WR pretreatment increased resistance to infection in irradiated but not in unirradiated mice. Bacterial CFU-LD50/30 values for 0 Gy saline-treated mice were 1.20x10(6); for 0 Gy WR-treated mice 1.16x10(6); for gamma-photon-irradiated saline-treated mice 3.02x10(1); for gamma-photon-irradiated WR-treated mice 1.24x10(4); for mixed-field-irradiated saline-treated mice 1.94x10(2); and for mixed-field-irradiated WR-treated mice 6.13x10(3). WR-induced resistance to infection paralleled increased numbers of PB white cells, neutrophils, platelets, femoral BM cells and granulocyte macrophage colony-forming cells (GM-CFC) in irradiated mice not given bacteria. CONCLUSIONS: These studies quantify the resistance to bacterial infection in mice treated with WR before sublethal irradiation. The findings suggest that WR treatment increases resistance to infection in immunocompromised hosts.


Subject(s)
Immunity, Innate/radiation effects , Klebsiella Infections/immunology , Klebsiella pneumoniae , Organothiophosphorus Compounds/pharmacology , Radiation-Protective Agents/pharmacology , Animals , Blood Cell Count , Bone Marrow Cells/drug effects , Bone Marrow Cells/radiation effects , Female , Gamma Rays , Immunity, Innate/drug effects , Klebsiella Infections/mortality , Mice , Relative Biological Effectiveness
9.
Int J Immunopharmacol ; 22(1): 1-14, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10684984

ABSTRACT

The ionizing radiation-induced hemopoietic syndrome is characterized by defects in immune function and increased mortality due to infections and hemorrhage. Since the steroid 5-androstene-3beta, 17beta-diol (5-androstenediol, AED) modulates cytokine expression and increases resistance to bacterial and viral infections in rodents, we tested its ability to promote survival after whole-body ionizing radiation in mice. In unirradiated female B6D2F1 mice, sc AED elevated numbers of circulating neutrophils and platelets and induced proliferation of neutrophil progenitors in bone marrow. In mice exposed to whole-body (60)Co gamma-radiation (3 Gy), AED injected 1 h later ameliorated radiation-induced decreases in circulating neutrophils and platelets and marrow granulocyte-macrophage colony-forming cells, but had no effect on total numbers of circulating lymphocytes or erythrocytes. In mice irradiated (0, 1 or 3 Gy) and inoculated four days later with Klebsiella pneumoniae, AED injected 2 h after irradiation enhanced 30-d survival. Injecting AED 24 h before irradiation or 2 h after irradiation increased survival to approximately the same extent. In K. pneumoniae-inoculated mice (irradiated at 3-7 Gy) and uninoculated mice (irradiated at 8-12 Gy), AED (160 mg/kg) injected 24 h before irradiation significantly promoted survival with dose reduction factors (DRFs) of 1.18 and 1.26, respectively. 5-Androstene-3beta-ol-17-one (dehydroepiandrosterone, DHEA) was markedly less efficacious than AED in augmenting survival, indicating specificity. These results demonstrate for the first time that a DHEA-related steroid stimulates myelopoiesis, and ameliorates neutropenia and thrombocytopenia and enhances resistance to infection after exposure of animals to ionizing radiation.


Subject(s)
Androstenediol/pharmacology , Bacterial Infections/immunology , Hematopoiesis/drug effects , Radiation-Protective Agents/pharmacology , Animals , Blood Platelets/drug effects , Female , Gamma Rays , Mice , Neutrophils/drug effects
10.
Toxicol Sci ; 49(1): 29-39, 1999 May.
Article in English | MEDLINE | ID: mdl-10367339

ABSTRACT

During the Persian Gulf War, soldiers were injured with depleted uranium (DU) fragments. To assess the potential health risks associated with chronic exposure to DU, Sprague Dawley rats were surgically implanted with DU pellets at 3 dose levels (low, medium and high). Biologically inert tantalum (Ta) pellets were used as controls. At 1 day and 6, 12, and 18 months after implantation, the rats were euthanized and tissue samples collected. Using kinetic phosphorimetry, uranium levels were measured. As early as 1 day after pellet implantation and at all subsequent sample times, the greatest concentrations of uranium were in the kidney and tibia. At all time points, uranium concentrations in kidney and bone (tibia and skull) were significantly greater in the high-dose rats than in the Ta-control group. By 18 months post-implantation, the uranium concentration in kidney and bone of low-dose animals was significantly different from that in the Ta controls. Significant concentrations of uranium were excreted in the urine throughout the 18 months of the study (224 +/- 32 ng U/ml urine in low-dose rats and 1010 +/- 87 ng U/ml urine in high-dose rats at 12 months). Many other tissues (muscle, spleen, liver, heart, lung, brain, lymph nodes, and testicles) contained significant concentrations of uranium in the implanted animals. From these results, we conclude that kidney and bone are the primary reservoirs for uranium redistributed from intramuscularly embedded fragments. The accumulations in brain, lymph nodes, and testicles suggest the potential for unanticipated physiological consequences of exposure to uranium through this route.


Subject(s)
Bone and Bones/metabolism , Kidney/metabolism , Tantalum/metabolism , Uranium/pharmacokinetics , Animals , Brain/metabolism , Rats , Rats, Sprague-Dawley , Risk Assessment , Tablets , Time Factors , Tissue Distribution , Uranium/blood , Uranium/urine
11.
J Radiat Res ; 38(1): 45-54, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9164080

ABSTRACT

This study evaluated synthetic trehalose dicorynomycolate (S-TDCM), an immunomodulator, for its survival enhancing capacity and behavioral toxicity in B6D2F1 female mice. In survival experiments, mice were administered S-TDCM (25-400 micrograms/mouse i.p.) 20-24 hr before 5.6 Gy mixed-field fission-neutron irradiation (n) and gamma-photon irradiation. The 30-day survival rates for mice treated with 100-400 micrograms/mouse S-TDCM were significantly enhanced compared to controls. Toxicity of S-TDCM was measured in nonirradiated mice by locomotor activity, food intake, water consumption, and alterations in body weight. A dose-dependent decrease was noted in all behavioral measures in mice treated with S-TDCM. Doses of 100 and 200 micrograms/mouse S-TDCM significantly reduced motor activity beginning 12 hr postinjection with recovery by 24 hr. A dose of 400 micrograms/mouse significantly decreased activity within the first 4 hr after administration and returned to control levels by 32 hr following injection. Food and water intake were significantly depressed at doses of 200 and 400 micrograms/mouse on the day following drug administration, and were recovered in 24 hr. Body weight was significantly decreased in the 200 micrograms/mouse group for 2 days and in the 400 micrograms/mouse group for 4 days following injection. A dose of 100 micrograms/mouse effectively enhanced survival after fission-neutron irradiation with no adverse effect on food consumption, water intake, or body weight and a minimal, short-term effect on locomotor activity.


Subject(s)
Adjuvants, Immunologic/pharmacology , Behavior, Animal/drug effects , Behavior, Animal/radiation effects , Cord Factors/pharmacology , Radiation-Protective Agents/pharmacology , Adjuvants, Immunologic/toxicity , Animals , Cord Factors/toxicity , Drinking/drug effects , Drinking/radiation effects , Eating/drug effects , Eating/radiation effects , Female , Mice , Motor Activity/drug effects , Motor Activity/radiation effects , Radiation-Protective Agents/toxicity
15.
J Radiat Res ; 37(3): 209-15, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8996979

ABSTRACT

Exposure of rats to 5-10 Gy of ionizing radiation produces hyperthermia and reduces motor activity. Previous studies suggested that radiation-induced hyperthermia results from a relatively direct action on the brain and is mediated by prostaglandins. To test the hypothesis that hypoactivity may be, in part, a thermoregulatory response to this elevation in body temperature, adult male rats were given indomethacin (0.0, 0.5, 1.0, and 3.0 mg/kg, intraperitoneally), a blocker of prostaglandin synthesis, and were either irradiated (LINAC 18.6 MeV (nominal) high-energy electrons, 10 Gy at 10 Gy/min, 2.8 microseconds pulses at 2 Hz) or sham-irradiated. The locomotor activity of all rats was then measured for 30 min in a photocell monitor for distance traveled and number of vertical movements. Rectal temperatures of irradiated rats administered vehicle only were elevated by 0.9 +/- 0.2 degree C at the beginning and the end of the activity session. Although indomethacin, at the two higher doses tested, attenuated the hyperthermia in irradiated rats by 52-75%, it did not attenuate radiation-induced reductions in motor activity. These results indicate that motor hypoactivity after exposure to 10 Gy of high-energy electrons is not due to elevated body temperature or to the increased synthesis of prostaglandins.


Subject(s)
Cyclooxygenase Inhibitors/pharmacology , Fever/etiology , Fever/prevention & control , Indomethacin/pharmacology , Motor Activity/drug effects , Motor Activity/radiation effects , Animals , Body Temperature Regulation/drug effects , Body Temperature Regulation/radiation effects , Male , Prostaglandins/biosynthesis , Rats , Rats, Sprague-Dawley
16.
Pharmacol Biochem Behav ; 50(4): 521-6, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7617697

ABSTRACT

Experimental drugs and compounds that do not easily dissolve in water or saline are frequently combined with vehicles like solvents, detergents, or vegetable oils. Yet very little has been reported on the behavioral effects of vehicles. In this study, we assessed the effects of a vegetable oil (emulphor-620), two detergents (Tween-20 and Tween-80), and two solvents [dimethyl sulphoxide (DMSO) and ethanol] on the locomotor activity in CD2F1 male mice. Locomotor activity was monitored for 12 h after vehicle administration (IP). The concentrations for each vehicle were expressed as percent of vehicle in saline (v/v). Emulphor-620 did not affect locomotor activity at any concentration tested (2%, 4%, 8%, 16%, and 32%). Tween-20 significantly decreased locomotor activity at a concentration of 16% and Tween-80 at 32%. DMSO significantly decreased locomotor activity at concentrations of 32% and 64%. In contrast, ethanol produced a biphasic behavioral response: increased activity at a concentration of 16% and decreased activity at a concentration of 32%. These results will facilitate the selection and concentration of vehicles to be used in combination with experimental drugs or test agents.


Subject(s)
Motor Activity/drug effects , Pharmaceutical Vehicles/pharmacology , Animals , Dimethyl Sulfoxide/pharmacology , Ethanol/pharmacology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Plant Oils/pharmacology , Polysorbates/pharmacology , Solvents/pharmacology
17.
Adv Space Res ; 14(10): 583-6, 1994 Oct.
Article in English | MEDLINE | ID: mdl-11539995

ABSTRACT

Spaceflight personnel need treatment options that would enhance survival from radiation and would not disrupt task performance. Doses of prophylactic or therapeutic agents known to induce significant short-term (30-day) survival with minimal behavioral (locomotor) changes were used for 180-day survival studies. In protection studies, groups of mice were treated with the phosphorothioate WR-151327 (200 mg/kg, 25% of the LD(10)) or the immunomodulator, synthetic trehalose dicorynomycolate (S-TDCM; 8 mg/kg), before lethal irradiation with reactor-generated fission neutrons and gamma-rays (n/gamma=1) or 60Co gamma-rays. In therapy studies, groups of mice received either S-TDCM, the antimicrobial ofloxacin, or S-TDCM plus ofloxacin after irradiation. For WR-151327 treated-mice, survival at 180 days for n/gamma=1 and gamma-irradiated mice was 90% and 92%, respectively; for S-TDCM (protection), 57% and 78%, respectively; for S-TDCM (therapy), 20% and 25%, respectively; for ofloxacin, 38% and 5%, respectively; for S-TDCM combined with ofloxacin, 30% and 30%, respectively; and for saline, 8% and 5%, respectively. Ofloxacin or combined ofloxacin and S-TDCM increased survival from the gram-negative bacterial sepsis that predominated in n/gamma=1 irradiated mice. The efficacies of the treatments depended on radiation quality, treatment agent and its mode of use, and microflora of the host.


Subject(s)
Anti-Infective Agents/therapeutic use , Gamma Rays , Neutrons , Ofloxacin/therapeutic use , Organothiophosphorus Compounds/therapeutic use , Radiation Injuries, Experimental/mortality , Radiation Tolerance/drug effects , Radiation-Protective Agents/therapeutic use , Adjuvants, Immunologic/therapeutic use , Animals , Ceftriaxone/therapeutic use , Cephalosporins/therapeutic use , Cord Factors/therapeutic use , Female , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/etiology , Liver/immunology , Liver/microbiology , Mice , Mice, Inbred Strains , Radiation Injuries, Experimental/drug therapy , Radiation Injuries, Experimental/prevention & control , Survival Rate
18.
Adv Space Res ; 12(2-3): 223-31, 1992.
Article in English | MEDLINE | ID: mdl-11537012

ABSTRACT

The need exists for compounds that will protect individuals from high-dose acute radiation exposure in space and the agents that might be less protective but less toxic and longer acting. Metals and metal derivatives provide a small degree of radioprotection (dose reduction factor < or = 1.2 for animal survival after whole-body irradiation). Emphasis is placed here on the radioprotective potential of selenium (Se). Both the inorganic salt, sodium selenite, and the organic Se compound, selenomethionine, enhance the survival of irradiated mice (60Co, 0.2 Gy/min) when injected IP either before (-24 hr and -1 hr) or shortly after (+15 min) radiation exposure. When administered at equitoxic doses (one-fourth LD10; selenomethionine = 4.0 mg/kg Se, sodium selenite = 0.8 mg/kg Se), both drugs enhanced the 30-day survival of mice irradiated at 9 Gy. Survival after 10-Gy exposure was significantly increased only after selenomethionine treatment. An advantage of selenomethionine is lower lethal and behavioral toxicity (locomotor activity depression) compared to sodium selenite, when they are administered at equivalent doses of Se. Sodium selenite administered in combination with WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid, enhances the radioprotective effect and reduces the lethal toxicity, but not the behavioral toxicity, of WR-2721. Other studies on radioprotection and protection against chemical carcinogens by different forms of Se are reviewed. As additional animal data and results from human chemoprevention trials become available, consideration also can be given to prolonged administration of Se compounds for protection against long-term radiation effects in space.


Subject(s)
Radiation-Protective Agents/administration & dosage , Radiation-Protective Agents/toxicity , Selenomethionine/administration & dosage , Selenomethionine/toxicity , Sodium Selenite/administration & dosage , Sodium Selenite/toxicity , Aerospace Medicine , Amifostine/administration & dosage , Amifostine/toxicity , Animals , Cobalt Radioisotopes , Drug Therapy, Combination , Glutathione Peroxidase/metabolism , Male , Mice , Mice, Inbred Strains , Motor Activity/drug effects , Radiation Tolerance/drug effects , Selenium Compounds/metabolism , Selenomethionine/metabolism , Sodium Selenite/metabolism , Time Factors
19.
Adv Space Res ; 12(2-3): 273-83, 1992.
Article in English | MEDLINE | ID: mdl-11537018

ABSTRACT

Effective radioprotection with minimal behavioral disruption is essential for the selection of protective agents to be used in manned spaceflight. This overview summarizes the studies on the behavioral toxicity of selected radioprotectors classified as phosphorothioates (WR-2721, WR-3689), bioactive lipids (16, 16 dimethylprostaglandin E2(DiPGE2), platelet activating factor (PAF), leukotriene C4), and immunomodulators (glucan, synthetic trehalose dicorynomycolate, and interleukin-1). Behavioral toxicity was examined in laboratory mice using a locomotor activity test. For all compounds tested, there was a dose-dependent decrease in locomotor behavior that paralleled the dose-dependent increase in radioprotection. While combinations of radioprotective compounds (DiPGE2 plus WR-2721) increased radioprotection, they also decreased locomotor activity. The central nervous system stimulant, caffeine, was able to mitigate the locomotor decrement produced by WR-3689 or PAF.


Subject(s)
Adjuvants, Immunologic/toxicity , Motor Activity/drug effects , Phospholipids/toxicity , Radiation-Protective Agents/toxicity , Sulfhydryl Compounds/toxicity , 16,16-Dimethylprostaglandin E2/toxicity , Amifostine/analogs & derivatives , Amifostine/toxicity , Animals , Caffeine/pharmacology , Central Nervous System Stimulants/pharmacology , Cord Factors/toxicity , Dose-Response Relationship, Drug , Drug Therapy, Combination , Glucans/toxicity , Interleukin-1/toxicity , Leukotriene C4/toxicity , Male , Mice , Platelet Activating Factor/toxicity
20.
Aviat Space Environ Med ; 61(10): 893-8, 1990 Oct.
Article in English | MEDLINE | ID: mdl-2241729

ABSTRACT

The effects of 10 Gray (Gy) 60 Co radiation on social behavior, locomotor activity, and body weight were assessed in individually housed male Swiss-Webster mice. In Experiment 1, aggressive behavior was evaluated prior to irradiation and for 7 d postirradiation by placing an untreated intruder in the irradiated or sham-irradiated resident's home cage for 5 min. Offensive aggressive behavior was not affected significantly by radiation until day 7 postirradiation, when attack latency increased, the frequency and duration of fighting decreased, and the frequency of bites, lunges, and chases decreased. Untreated intruder mice paired with irradiated resident mice showed a decrease in the duration of defensive upright postures and a decrease in the frequency of defensive upright postures, squeaks, and escapes on day 7 postirradiation. In Experiment 2, locomotor activity and body weight were monitored for 7 d postirradiation. Body weight was decreased in irradiated mice beginning 4 d postirradiation. Locomotor activity was suppressed in irradiated animals 90 min after irradiation and remained depressed throughout the 7-d testing period.


Subject(s)
Aggression/radiation effects , Behavior, Animal/radiation effects , Animals , Body Weight/radiation effects , Cobalt Radioisotopes/administration & dosage , Male , Mice , Motor Activity/radiation effects , Radiation Dosage , Reaction Time/radiation effects , Social Behavior
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