Patent Application: US-22927402-A

Abstract:
disclosed herein is a method for protecting humans in need of such protection from physical damage caused by ionizing radiation comprising administering to said humans on a defined basis prior to and after exposure to such radiation a plurality of antioxidants at a dosage level directly proportional to the radiation level likely to be encountered .

Description:
although brief medical x - rays themselves may not cause detectable damage , serial imaging , future screening studies ( the importance of which cannot be currently predicted ), flight exposures , military operations exposures , occupational exposures , and other factors , such as diet , disease status , and environmental exposure , and the like , may be clinically significant . relevant findings from basic scientific studies underscore this clinical concern . for example , a dose of 2 rem does not cause detectable mutations in normal human lymphocytes in culture . however , if the cells are irradiated with the same dose and treated with caffeine for a few hours after radiation exposure , an increased rate of cellular mutations is observed ( 18 ). this suggests that radiation - induced changes could be repaired in the normal course of events , but that subsequent exposure to caffeine impairs this normal cellular protective mechanism . in addition , a radiation dose that by itself would not be sufficient to induce cancer in an in vitro experimental system is able to do so in the presence of tumor promoters , such as phorbol ester , estrogen , and others ( 19 - 21 ). furthermore , x - rays increase the incidence of cancer in cell culture by several fold when combined with chemical carcinogens , certain dna viruses , ultraviolet radiation , or ozone exposure ( 22 - 26 ). clearly , the potential hazard of even small radiation doses should not be ignored , since the target population readily interacts with agents present in the diet and environment , as well as other factors present in individual lifestyles . the following risk categories are general guidelines only and refer to acute exposures . the examples listed are not totally inclusive . the actual risk for any particular person may be modified by age and health status . the actual designation for all persons should be determined by healthcare or radiation physics professionals . population groups experiencing chronic radiation exposure risk , such as radiation workers ( including commercial and military flight crews and field combat personnel ), should maintain a higher baseline antioxidant load by taking a multiple antioxidant formulation ( sevak ) two times a day . they should then take the appropriate radioprotective formulation when the acute risk of exposure is expected ( daily if necessary ). categories 2 - 4 are equivalent with respect to formulation and can be regarded to be adequate for exposures less than 15 msv effective dose when taken on a daily basis along with sevak . the categories vary with respect to dose schedule when used for acute exposures only . for example : chest x - ray , dental x - ray , abdominal x - ray , skeletal plain films , most commercial flight passengers . for example : diagnostic / screening computed tomography , urologic imaging , mammography , flight crews ( commercial and military ) and other radiation workers . for example : limited diagnostic fluoroscopy ( upper gi series , cholangiography , barium enema ). for example : prolonged fluoroscopy / interventional radiology ( coronary angiography , cerebral angiography , transluminal angioplasty ) and some military personnel in combat operations ( ground troops and seamen ). for example : radiation workers , civilian populations at risk near nuclear reactor sites , and at risk military personnel in overseas theatres of operation . category 7 : effective dose greater than 2000 msv ( not exceeding bone marrow syndrome doses ) for example : radiation workers , civilian populations at risk near nuclear reactor sites , and at risk military personnel in overseas theatres of operation . hereinafter , the term “ imaging study ” will be employed to include chest x - ray , dental x - ray , abdominal x - ray , skeletal plain films , diagnostic / screening computed tomography , urologic imaging , mammography , radionuclide imaging , limited diagnostic fluoroscopy , prolonged fluoroscopy / interventional radiology , and the like . baseline formulation ( sevak ) ( daily dose is contained in 4 capsules . normally used for personnel in categories 6 and 7 and for personnel in category 2 who are member of flight crews and radiation workers .) vitamin a ( palmitate ) 5 , 000 i . u . beta - carotene ( from natural d . salina ) 15 mg vitamin d - 3 ( cholecalciferol ) 400 i . u . natural source vitamin e ( d - alpha tocopherol ) 100 i . u . ( d - alpha tocopheryl acid succinate ) 100 i . u . buffered vitamin c ( calcium ascorbate ) 500 mg thiamine mononitrate 4 mg riboflavin 5 mg niacinamide ascorbate 30 mg d - calcium pantothenate 10 mg pyridoxine hydrochloride 5 mg cyanocobalamin 10 μg folic acid ( folacin ) 800 μg d - biotin 200 μg selenium ( l - seleno - methionine ) 100 μg chromium picolinate 50 μg zinc glycinate 15 mg calcium citrate 250 mg magnesium citrate 125 mg radioprotective formulations : ( boost formulations ) for category 1 personnel : vitamin c ( calcium ascorbate ) 250 mg natural source vitamin e 200 i . u . ( d - alpha tocopheryl acid succinate ) n - acetyl cysteine 250 mg complete dosage to be taken 1 hour prior to an imaging study . for category 2 personnel : vitamin c ( calcium ascorbate ) 500 mg natural source vitamin e 400 i . u . ( d - alpha tocopheryl acid succinate ) n - acetyl cysteine 250 mg beta - carotene ( from natural d . salina ) 15 mg alpha lipoic acid 30 mg complete dosage to be taken 1 hour prior to an imaging study or prior to each flight . for category 3 personnel : vitamin c ( calcium ascorbate ) 500 mg natural source vitamin e 400 i . u . ( d - alpha tocopheryl acid succinate ) n - acetyl cysteine 250 mg beta - carotene ( from natural d . salina ) 15 mg alpha lipoic acid 30 mg complete dosage to be taken 1 hour prior to an imaging study and 24 hours and 48 hours after the imaging study . for category 4 personnel : vitamin c ( calcium ascorbate ) 500 mg natural source vitamin e 400 i . u . ( d - alpha tocopheryl acid succinate ) n - acetyl cysteine 250 mg beta - carotene ( from natural d . salina ) 15 mg alpha lipoic acid 30 mg complete dosage to be taken 24 hours and 1 hour prior to an imaging study and 24 hours after the imaging study . for category 5 personnel : vitamin c ( calcium ascorbate ) 500 mg natural source vitamin e 400 i . u . ( d - alpha tocopheryl acid succinate ) n - acetyl cysteine 500 mg beta - carotene ( from natural d . salina ) 30 mg alpha lipoic acid 60 mg complete dosage to be taken 48 hours , 24 hours , and 1 hour prior to an imaging study and 24 hours after the imaging study . for category 6 personnel : vitamin c ( calcium ascorbate ) 1000 mg d - alpha tocopheryl acid succinate 400 i . u . alpha tocopherol 200 i . u . n - acetyl cysteine 500 mg beta - carotene ( from natural d . salina ) 50 mg alpha lipoic acid 100 mg complete dosage to be taken prior to anticipated exposure or as soon as possible after actual exposure . continue complete dosage daily for seven days after exposure . for category 7 personnel : vitamin c ( calcium ascorbate ) 2000 mg d - alpha tocopheryl acid succinate 600 i . u . alpha tocopherol 200 i . u . n - acetyl cysteine 1000 mg beta - carotene ( from natural d . salina ) 100 mg alpha lipoic acid 150 mg complete dosage to be taken prior to anticipated exposure or as soon as possible after actual exposure . continue complete dosage daily for fourteen days after exposure . it has been estimated that approximately 70 - 80 % of the cellular damage induced by ionizing radiation is caused by free radicals ( 23 ). therefore , it would be prudent to use agents that would quench these substances formed during x - ray exposure and protect the cells , organs , and total body from such injury . since world war ii , extensive studies have been undertaken to identify radioprotective compounds that have been shown to be effective when administered before exposure to irradiation ( 2 , 27 ). it is important to note that such compounds do not protect cells or organisms if they are administered after the ionizing radiation exposure . for modest radiation dose levels , the protective agents can be absorbed rapidly enough that they could be effective when given immediately before the exposure ( within an hour or two ). for higher levels of radiation dosage , it might be more desirable to achieve an established steady state of antioxidant concentration in the tissues initially , and then provide a booster dose of radioprotective agent immediately prior to exposure . research has determined that sulfhydryl ( sh ) compounds such as cysteamine , cystamine , and glutathione are among the most important and active intracellular antioxidants . cysteamine protects animals against bone marrow ( 2 , 31 ) and gastrointestinal ( 32 ) radiation syndromes . the rationale for the importance of sh compounds is further supported by observations in mitotic cells . these are the most sensitive to radiation injury in terms of cell reproductive death and are noted to have the lowest level of sh compounds . conversely , s - phase cells , which are the most resistant to radiation injury using the same criteria , have demonstrated the highest levels of inherent sh compounds . in addition , when mitotic cells were treated with cysteamine , they became very resistant to radiation ( 33 ). it has also been noted that cysteamine may directly protect cells against induced mutations ( 2 ). unfortunately , cysteamine is extremely toxic when administered to human beings and , therefore , cannot itself be utilized in a radioprotective antioxidant regimen . thus , other sh compounds sharing the same antioxidant characteristics must be considered . glutathione is a very effective antioxidant . however , when ingested by human beings it is completely hydrolyzed in the intestine and , therefore , can not be used as a radioprotective agent . however , n - acetylcysteine ( nac ) and alpha lipoic acid actively increase the intracellular levels of glutathione without causing any toxicity . these rapidly absorbed compounds are tolerated by humans very well and would provide protection against ionizing radiation damage when given prior to the exposure . indeed , these agents have also been shown to be of radioprotective value in experimental systems ( 31 - 35 ). additional antioxidants such as vitamin e ( d - alpha tocopheryl succinate ), vitamin c ( as calcium ascorbate ) and the carotenoids ( particularly natural beta - carotene ) have been shown to be of marked radioprotectant value in animals and in humans ( 2 , 36 - 50 ). a very recent report by the armed forces radiobiology research institute showed good protection by vitamin e against lethal doses of cobalt - 60 in mice ( 51 ). the natural beta - carotene was selected because it most effectively reduces radiation - induced transformation in mammalian cells in culture ( 47 ). the d - alpha tocopheryl succinate form of vitamin e was selected because it is the most effective form of this micronutrient ( 52 ) and also actively reduces the incidence of radiation - induced transformation in mammalian cells ( 53 , 54 ). this form of vitamin e is a more effective antioxidant than the more commonly utilized alpha tocopherol or other mixtures of tocopherols ( 55 ). vitamin c as calcium ascorbate is beneficial because it is the most effective nonacidic form available for human use and , therefore , is less likely to cause stomach upset , diarrhea , and other problems that are observed in some individuals when taking therapeutic doses of vitamin c . the most effective antioxidant approach to the free radical damage related to ionizing radiation - induced injury must utilize multiple micronutrients . it has been determined that multiple antioxidants are more effective than the individual agents themselves , and we propose this approach for several reasons . it is known that vitamin c and vitamin e are synergistic as antioxidants against free radicals because they are able to protect both the aqueous and lipid environments of the cells respectively . indeed , one study has shown that oral intake of both vitamin c and vitamin e reduces the levels of fecal mutagens formed during digestion more than that produced by either of the individual antioxidants ( 56 ). it also must be recognized that oxygen level may vary widely within the tissues of whole organs or within the individual cells . this is especially true during the biologic insults that may occur with radiation - induced damage . it is known that beta - carotene acts more effectively as an antioxidant in high oxygen pressures , whereas vitamin e is a more effective antioxidant at reduced oxygen pressures ( 57 ). finally , the body produces several types of free radicals ( a myriad of oxygen - derived and nitrogen - derived species ) during exposure to ionizing radiation . clearly , each antioxidant has a different affinity for each specific class of free radicals . in a parallel manner , a combination of antioxidants is more effective in reducing the growth of tumor cells than the individual agents themselves ( 58 ). therefore , to provide the most effective overall micronutrient approach to protect against radiation injury , a multiple component protocol utilized with a risk - based strategy seems essential and rational . in the interest of clarity and conserving space , references in the foregoing have been given by number , parenthetically . these numbers relate to the following : 1 . prasad kn : human radiation biology . harper and row , new york , n . y ., 1974 . 2 . prasad kn : handbook of radiobiology , crc press , boca raton , fla ., 1994 . 3 . brenner d j , elliston c d , hall e j , berdon w e : estimated risks of radiation - induced fatal cancer from pediatric ct , am j roentgenol 176 : 289 - 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