Spaceflight Pharmacology

  • Virginia WotringEmail author


Humans who have travelled in space have used medications to ease adaptation to their new environment (like anti-nausea medications) and to prevent adaptations that could prove deleterious to their long-term well-being (e.g., anti-resorptives to maintain bone mineral density). They have also treated the ordinary illnesses that humans experience and made certain that they have medication stocks available for the treatment of medical emergencies. A medical system for any space flight will be heavily reliant on medications, since surgical treatment options may not be feasible during a mission. For exploration missions, duration is a critical consideration. Longer journey length means increased likelihood of medical events occurring, which increase the supplies required; this must be balanced against the mass and volume limits inherent in a vehicle of limited size. Stability during storage is a crucial consideration for missions longer than 1 year. More research is required to understand the degradation of pharmaceutical products over time, with special attention to minimizing harmful degradation and determining how older products might be used safely. New manufacturing methods like 3D printing or expression by bioengineered microorganisms might 1 day enable crewmembers to produce fresh new supplies during the course of their mission, but there is much research and testing required to ensure safety and efficacy of the finished products.


Spaceflight pharmacology Pharmaceuticals in space flight Space motion sickness Radioprotectants Integrated medical model 


  1. 1.
    Minard CG, de Carvalho MF, Iyengar MS. Optimizing medical resources for spaceflight using the integrated medical model. Aviat Space Environ Med. 2011;82:890–4.PubMedGoogle Scholar
  2. 2.
    Komorowski M, Watkins SD, Lebuffe G, Clark JB. Potential anesthesia protocols for space exploration missions. Aviat Space Environ Med. 2013;84:226–33.PubMedGoogle Scholar
  3. 3.
    Link MM. Space medicine in Project Mercury. Washington, DC: National Aeronautics and Space Administration; 1965.Google Scholar
  4. 4.
    Johnston R, Berry C, Dietlein LF. Biomedical results of Apollo. Washington DC: National Aeronautics and Space Administration; 1975.Google Scholar
  5. 5.
    Zeitlin C, et al. Measurements of energetic particle radiation in transit to Mars on the Mars Science Laboratory. Science. 2013;340:1080–4.PubMedCentralGoogle Scholar
  6. 6.
    Tsuji K, Rahn PD, Steindler KA. 60Co-irradiation as an alternate method for sterilization of penicillin G, neomycin, novobiocin, and dihydrostreptomycin. J Pharm Sci. 1983;72:23–6.PubMedGoogle Scholar
  7. 7.
    Maggi L, et al. Chemical and physical stability of hydroxypropylmethylcellulose matrices containing diltiazem hydrochloride after gamma irradiation. J Pharm Sci. 2003;92:131–41.PubMedGoogle Scholar
  8. 8.
    Maggi L, et al. Polymers-gamma ray interaction. Effects of gamma irradiation on modified release drug delivery systems for oral administration. Int J Pharm. 2004;269:343–51.PubMedGoogle Scholar
  9. 9.
    Barbarin N, Tilquin B, de Hoffmann E. Radiosterilization of cefotaxime: investigation of potential degradation compounds by liquid chromatography-electrospray mass spectrometry. J Chromatogr A. 2001;929:51–61.Google Scholar
  10. 10.
    Crucq AS, Tilquin B. Method to identify products induced by radiosterilization. A study of cefotaxime sodium. J Pharm Belg. 1996;51:285–8.PubMedGoogle Scholar
  11. 11.
    Du B, et al. Evaluation of physical and chemical changes in pharmaceuticals flown on space missions. AAPS J. 2011;13:299–308.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Bogomolov VV, Kondratenko SN, Kovachevich IV. Testing stability of tableted acetaminophen and furosemide after 6-month storage in space flight. Aviakosm Ekolog Med. 2015;49:12–5.PubMedGoogle Scholar
  13. 13.
    Wotring VE. Chemical potency and degradation products of medications stored over 550 earth days at the International Space Station. AAPS J. 2016;18:210–6.PubMedGoogle Scholar
  14. 14.
    Lyon RC, Taylor JS, Porter DA, Prasanna HR, Hussain AS. Stability profiles of drug products extended beyond labeled expiration dates. J Pharm Sci. 2006;95:1549–60.PubMedGoogle Scholar
  15. 15.
    Cory WC, Harris C, Martinez S. Accelerated degradation of ibuprofen in tablets. Pharm Dev Technol. 2010;15:636–43.PubMedGoogle Scholar
  16. 16.
    Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287:337–44.PubMedGoogle Scholar
  17. 17.
    Putcha L, Berens KL, Marshburn TH, Ortega HJ, Billica RD. Pharmaceutical use by U.S. astronauts on space shuttle missions. Aviat Space Environ Med. 1999;70:705–8.PubMedGoogle Scholar
  18. 18.
    Wotring VE. Medication use by U.S. crewmembers on the International Space Station. FASEB J. 2015;29:4417–23.PubMedGoogle Scholar
  19. 19.
    Grabenstein JD, Filby CL, Vauter RA, Harris TR, Wilson JP. Prescribed medication use among troops deploying to Somalia: pharmacoepidemiologic analysis. Mil Med. 1995;160:571–7.PubMedGoogle Scholar
  20. 20.
    Barger LK, et al. Prevalence of sleep deficiency and use of hypnotic drugs in astronauts before, during, and after spaceflight: an observational study. Lancet Neurol. 2014;13:904–12.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Flynn-Evans EE, Barger LK, Kubey AA, Sullivan JP, Czeisler CA. Circadian misalignment affects sleep and medication use before and during spaceflight. NPJ Microgravity. 2016;(2):1–6Google Scholar
  22. 22.
    Law J, et al. Relationship between carbon dioxide levels and reported headaches on the international space station. J Occup Environ Med. 2014;56:477–83.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Dedier J, et al. Nonnarcotic analgesic use and the risk of hypertension in US women. Hypertension. 2002;40:604–8; discussion 601–603.PubMedGoogle Scholar
  24. 24.
    Bock O, Weigelt C, Bloomberg JJ. Cognitive demand of human sensorimotor performance during an extended space mission: a dual-task study. Aviat Space Environ Med. 2010;81:819–24.PubMedGoogle Scholar
  25. 25.
    Miller CA, et al. Changes in toe clearance during treadmill walking after long duration spaceflight. Aviat Space Environ Med. 2010;81:919–28.PubMedGoogle Scholar
  26. 26.
    Hu SQ, Stern RM, Koch KL. Effects of pre-exposures to a rotating optokinetic drum on adaptation to motion sickness. Aviat Space Environ Med. 1991;62:53–6.PubMedGoogle Scholar
  27. 27.
    Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014 Apr;26(2):214–24.PubMedGoogle Scholar
  28. 28.
    Currell K, et al. A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance-Part 20. Br J Sports Med. 2011;45:530–2.PubMedGoogle Scholar
  29. 29.
    Spitsin S, Koprowski H. Role of uric acid in multiple sclerosis. Curr Top Microbiol Immunol. 2008;318:325–42.PubMedGoogle Scholar
  30. 30.
    Shen H, Chen GJ, Harvey BK, Bickford PC, Wang Y. Inosine reduces ischemic brain injury in rats. Stroke. 2005;36:654–9.PubMedGoogle Scholar
  31. 31.
    Schmidt MA, Goodwin TJ. Personalized medicine in human space flight: using Omics based analyses to develop individualized countermeasures that enhance astronaut safety and performance. Metabolomics. 2013;9:1134–56.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Buxton ILO, Benet LZ. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism and elimination. In: Brunton LL, Chabner BA, Knollmann BC, editors. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill Companies Inc; 2011.Google Scholar
  33. 33.
    Putcha L. Pharmacotherapeutics in space. J Gravit Physiol. 1999;6:P165–8.PubMedGoogle Scholar
  34. 34.
    Kopacek KB. Absorption. In: The Merck Manual Online. 2007; accessed at:
  35. 35.
    Clements JA, Heading RC, Nimmo WS, Prescott LF. Kinetics of acetaminophen absorption and gastric emptying in man. Clin Pharmacol Ther. 1978;24:420–31.PubMedGoogle Scholar
  36. 36.
    Kass MA, Gordon M, Morley RE Jr, Meltzer DW, Goldberg JJ. Compliance with topical timolol treatment. Am J Ophthalmol. 1987;103:188–93.PubMedGoogle Scholar
  37. 37.
    Kruse W, et al. Measurement of drug compliance by continuous electronic monitoring: a pilot study in elderly patients discharged from hospital. J Am Geriatr Soc. 1992;40:1151–5.PubMedGoogle Scholar
  38. 38.
    Saini SD, Schoenfeld P, Kaulback K, Dubinsky MC. Effect of medication dosing frequency on adherence in chronic diseases. Am J Manag Care. 2009;15:e22–33.PubMedGoogle Scholar
  39. 39.
    Urquhart J, Vrijens B. Hedged’ prescribing for partially compliant patients. Clin Pharmacokinet. 2006;45:105–8.PubMedGoogle Scholar
  40. 40.
    Mattie H, Craig WA, Pechere JC. Determinants of efficacy and toxicity of aminoglycosides. J Antimicrob Chemother. 1989;24:281–93.PubMedGoogle Scholar
  41. 41.
    Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellette VL. How often is medication taken as prescribed? A novel assessment technique. JAMA. 1989;261:3273–7.PubMedGoogle Scholar
  42. 42.
    Takacs B, Hanak D. A prototype home robot with an ambient facial interface to improve drug compliance. J Telemed Telecare. 2008;14:393–5.PubMedGoogle Scholar
  43. 43.
    Kruse W, Weber E. Dynamics of drug regimen compliance: its assessment by microprocessor-based monitoring. Eur J Clin Pharmacol. 1990;38:561–5.PubMedGoogle Scholar
  44. 44.
    Fleisher D, Li C, Zhou Y, Pao LH, Karim A. Drug, meal and formulation interactions influencing drug absorption after oral administration. Clinical implications. Clin Pharmacokinet. 1999;36:233–54.PubMedGoogle Scholar
  45. 45.
    Elsheikh HA, Intisar AMO, Eltayeb IB, Abdullah AS. Effect of dehydration on the pharmacokinetics of oxytetracycline hydrochloride administered intravenously in goats (Capra hircus). Gen Pharmacol. 1998;31:455–8.PubMedGoogle Scholar
  46. 46.
    Crema A, Frigo GM, Lecchini S. A pharmacological analysis of the peristaltic reflex in the isolated colon of the guinea-pig or cat. Br J Pharmacol. 1970;39:334–45.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Pappano AJ. Cholinoceptor-Blocking Drugs. Chapter 8 in: Basic and Clinical Pharmacology, 12th Ed. Bertram Katzung and Anthony Trevor, Editors. McGraw Hill Education, USA; 2014.Google Scholar
  48. 48.
    Wood CD, et al. Therapeutic effects of antimotion sickness medications on the secondary symptoms of motion sickness. Aviat Space Environ Med. 1990;61:157–61.PubMedGoogle Scholar
  49. 49.
    Wood MJ, Wood CD, Manno JE, Manno BR, Redetzki HM. Nuclear medicine evaluation of motion sickness and medications on gastric emptying time. Aviat Space Environ Med. 1987;58:1112–4.PubMedGoogle Scholar
  50. 50.
    Davis JR, Jennings RT, Beck BG. Comparison of treatment strategies for Space Motion Sickness. Acta Astronaut. 1993;29:587–91.PubMedGoogle Scholar
  51. 51.
    Stewart JJ, Wood MJ, Wood CD, Mims ME. Effects of motion sickness and antimotion sickness drugs on gastric function. J Clin Pharmacol. 1994;34:635–43.PubMedGoogle Scholar
  52. 52.
    Debuys L, Henrique A. Effect of body posture on the position and emptying time of the stomach. Am J Dis Child. 1918;15:190.Google Scholar
  53. 53.
    Oosterhuis B, Jonkman JH. Pharmacokinetic studies in healthy volunteers in the context of in vitro/in vivo correlations. Eur J Drug Metab Pharmacokinet. 1993;18:19–30.PubMedGoogle Scholar
  54. 54.
    Queckenberg C, Fuhr U. Influence of posture on pharmacokinetics. Eur J Clin Pharmacol. 2009;65:109–19.PubMedGoogle Scholar
  55. 55.
    Rumble RH, Roberts MS, Denton MJ. Effects of posture and sleep on the pharmacokinetics of paracetamol (acetaminophen) and its metabolites. Clin Pharmacokinet. 1991;20:167–73.PubMedGoogle Scholar
  56. 56.
    Roberts MS, Denton MJ. Effect of posture and sleep on pharmacokinetics. I. Amoxycillin. Eur J Clin Pharmacol. 1980;18:175–83.PubMedGoogle Scholar
  57. 57.
    Renwick AG, et al. The influence of posture on the pharmacokinetics of orally administered nifedipine. Br J Clin Pharmacol. 1992;34:332–6.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Smith SM, Zwart SR, Kloeris V, Heer M. Space programs and space food systems. In: Nutritional biochemistry of space flight. New York: Nova Science; 2009. p. 3–11.Google Scholar
  59. 59.
    Ritchie LE, et al. Space Environmental Factor Impacts upon Murine Colon Microbiota and Mucosal Homeostasis. PLoS One. 2015;10:e0125792.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Schneeman BO. Gastrointestinal physiology and functions. Br J Nutr. 2002;88(Suppl 2):S159–63.PubMedGoogle Scholar
  61. 61.
    Gandia P, Saivin S, Houin G. The influence of weightlessness on pharmacokinetics. Fundam Clin Pharmacol. 2005;19:625–36.PubMedGoogle Scholar
  62. 62.
    Cintrón NM, Putcha L, Chen Y-M, Vanderploeg JM, editors. In-flight salivary pharmacokinetics of scopalamine and dextramphetamine. Houston: Space Biomedical Research Institute, Johnson Space Center; 1987. p. 25–9.Google Scholar
  63. 63.
    Cintrón NM, Putcha L, Vanderploeg JM. Inflight pharmacokinetics of acetaminophen in saliva. In: Bungo MW, Bagian TM, Bowman MA, Levitan BM, editors. Results of the life sciences DSOs conducted aboard the Space Shuttle 1981-1986. Houston: Space Biomedical Research Institute, Johnson Space Center, Houston; 1987. p. 19–23.Google Scholar
  64. 64.
    Putcha L, et al. Bioavailability of intranasal scopolamine in normal subjects. J Pharm Sci. 1996;85:899–902.PubMedGoogle Scholar
  65. 65.
    Gandia P, et al. Influence of simulated weightlessness on the oral pharmacokinetics of acetaminophen as a gastric emptying probe in man: a plasma and a saliva study. J Clin Pharmacol. 2003;43:1235–43.PubMedGoogle Scholar
  66. 66.
    Ameer B, Divoll M, Abernethy DR, Greenblatt DJ, Shargel L. Absolute and relative bioavailability of oral acetaminophen preparations. J Pharm Sci. 1983;72:955–8.PubMedGoogle Scholar
  67. 67.
    Kovachevich I, Kondratenko S, Starodubtsev AK, Repenkova LG. Pharmacokinetics of acetaminophen administered in tablets and capsules under long-term space flight conditions. Pharm Chem J. 2009;43:130–3.Google Scholar
  68. 68.
    Pavy-Le Traon A, Heer M, Narici MV, Rittweger J, Vernikos J. From space to Earth: advances in human physiology from 20 years of bed rest studies (1986–2006). Eur J Appl Physiol. 2007;101:143–94.PubMedGoogle Scholar
  69. 69.
    Krasnoff J, Painter P. The physiological consequences of bed rest and inactivity. Adv Ren Replace Ther. 1999;6:124–32.PubMedGoogle Scholar
  70. 70.
    Drummer C, Heer M, Dressendörfer RA, Strasburger CJ, Gerzer R. Reduced natriuresis during weightlessness. Clin Invest. 1993;71:678–86.Google Scholar
  71. 71.
    Norsk P, et al. Renal and endocrine responses in humans to isotonic saline infusion during microgravity. J Appl Physiolo. 1995;78:2253–9.Google Scholar
  72. 72.
    Leach CS, et al. Regulation of body fluid compartments during short-term spaceflight. J Appl Physiol. 1996;81:105–16.PubMedGoogle Scholar
  73. 73.
    Nimmo WS, Prescott LF. The influence of posture on paracetemol absorption. Br J Clin Pharmacol. 1978;5:348–9.PubMedCentralGoogle Scholar
  74. 74.
    Gauer OH, Henry JP. Circulatory basis of fluid volume control. Physiolo Rev. 1963;43:423–81.Google Scholar
  75. 75.
    Norsk P, et al. Unexpected renal responses in space. Lancet. 2000;356:1577–8.PubMedGoogle Scholar
  76. 76.
    Hargens AR, Richardson S. Cardiovascular adaptations, fluid shifts, and countermeasures related to space flight. Respir Physiol Neurobiol. 2009;169(Suppl 1):S30–3.PubMedGoogle Scholar
  77. 77.
    Hargens AR, Watenpaugh DE. Cardiovascular adaptation to spaceflight. Med Sci Sports Exerc. 1996;28:977–82.PubMedGoogle Scholar
  78. 78.
    Diedrich A, Paranjape SY, Robertson D. Plasma and blood volume in space. Am J Med Sci. 2007;334:80–5.PubMedGoogle Scholar
  79. 79.
    Montgomery LD, Parmet AJ, Booher CR. Body volume changes during simulated microgravity: auditory changes, segmental fluid redistribution, and regional hemodynamics. Ann Biomed Eng. 1993;21:417–33.PubMedGoogle Scholar
  80. 80.
    Schuck EL, Grant M, Derendorf H. Effect of simulated microgravity on the disposition and tissue penetration of ciprofloxacin in healthy volunteers. J Clin Pharmacol. 2005;45:822–31.PubMedGoogle Scholar
  81. 81.
    Leucuta SE, Vlase L. Pharmacokinetics and metabolic drug interactions. Curr Clin Pharmacol. 2006;1:5–20.PubMedGoogle Scholar
  82. 82.
    Relling MV, Giacomini KM. Pharmacogenetics. Chapter 7 in: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. Laurence Brunton, Editor. McGraw Hill Medical, New York. 2011.Google Scholar
  83. 83.
    Moskaleva N, et al. Spaceflight Effects on Cytochrome P450 Content in Mouse Liver. PLoS One. 2015;10:e0142374.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Horn JR. Important drug interactions & their mechanisms. In: Basic and Clinical Pharmacology, 12th Ed. Bertram Katzung and Anthony Trevor, Editors. McGraw Hill Education, USA; 2014.Google Scholar
  85. 85.
    Greenblatt DJ, et al. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin Pharmacol Ther. 1998;64:661–71.PubMedGoogle Scholar
  86. 86.
    Bai JP. Ongoing challenges in drug interaction safety: from exposure to pharmacogenomics. Drug Metab Pharmacokinet. 2010;25:62–71.PubMedGoogle Scholar
  87. 87.
    Lee KC, Ma JD, Kuo GM. Pharmacogenomics: bridging the gap between science and practice. J Am Pharm Assoc. 2003;50:e1–14.Google Scholar
  88. 88.
    Gomes AM, et al. Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation. Pharmacogenomics. 2009;10:579–99.PubMedGoogle Scholar
  89. 89.
    Klein K, Winter S, Turpeinen M, Schwab M, Zanger UM. Pathway-targeted pharmacogenomics of CYP1A2 in human liver. Front Pharmacol. 2010;1(129):1–20Google Scholar
  90. 90.
    Klein K, Zanger UM. Pharmacogenomics of Cytochrome P450 3A4: recent progress toward the “missing heritability” problem. Front Genet. 2013;4(12):1–15Google Scholar
  91. 91.
    Court MH, et al. The UDP-glucuronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A exon 5a/5b splice variant mRNA ratio, and decreased risk of unintentional acetaminophen-induced acute liver failure. J Pharmacol Exp Ther. 2013;345:297–307.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Court MH, et al. Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure. Drug Metab Dispos. 2014;42:28–32.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Matsusaka S, Lenz HJ. Pharmacogenomics of fluorouracil-based chemotherapy toxicity. Expert Opin Drug Metab Toxicol. 2015;11:811–21.PubMedGoogle Scholar
  94. 94.
    Storelli F, Daali Y, Desmeules J, Reny JL, Fontana P. Pharmacogenomics of oral antithrombotic drugs. Curr Pharm Des. 2015;22(13):1933–49.Google Scholar
  95. 95.
    Stingl JC, Welker S, Hartmann G, Damann V, Gerzer R. Where failure is not an option-personalized medicine in astronauts. PLoS One. 2015;10:e0140764.PubMedPubMedCentralGoogle Scholar
  96. 96.
    De Castro M, et al. Genomic medicine in the military. NPJ Genomic Med. 2016;1:15008.Google Scholar
  97. 97.
    Koeppen BM, Stanton BA. Chapter 32: Elements of Renal Function. Chapter 32 in: Berne & Levy Physiology, 6th Ed. Mosby. Maryland Heights, MO. 2010.Google Scholar
  98. 98.
    LeBlanc AD, Spector ER, Evans HJ, Sibonga JD. Skeletal responses to space flight and the bed rest analog: a review. J Musculoskelet Neuronal Interact. 2007;7:33–47.PubMedGoogle Scholar
  99. 99.
    Sibonga JD, et al. Adaptation of the skeletal system during long duration spaceflight. Clinic Rev Bone Miner Metab. 2007;5:249–61.Google Scholar
  100. 100.
    Smith SM, et al. Fifty years of human space travel: implications for bone and calcium research. Annu Rev Nutr. 2014;(34):377–400.Google Scholar
  101. 101.
    LeBlanc A, et al. Bisphosphonates as a supplement to exercise to protect bone during long duration spaceflight. Osteoporos Int. 2013;24(7):2105–14.Google Scholar
  102. 102.
    Biswas PN, Wilton LV, Shakir SA. Pharmacovigilance study of alendronate in England. Osteoporos Int. 2003;14:507–14.PubMedGoogle Scholar
  103. 103.
    Zwart SR, Pierson D, Mehta S, Gonda S, Smith SM. Capacity of omega-3 fatty acids or eicosapentaenoic acid to counteract weightlessness-induced bone loss by inhibiting NF-kappaB activation: from cells to bed rest to astronauts. J Bone Miner Res. 2010;25:1049–57.PubMedGoogle Scholar
  104. 104.
    Smith SM, et al. Benefits for bone from resistance exercise and nutrition in long duration spaceflight: evidence from biochemistry and densitometry. J Bone Miner Res. 2012;27:1896–906.PubMedGoogle Scholar
  105. 105.
    Hall JE. Parathyroid hormone, calcitonin, calcium and phosphate metabolism, vitamin D, bone, and teeth. Chapter 80 in: Guyton and Hall textbook of medical physiology, 13th Ed. Elsevier Health, USA; 2015.Google Scholar
  106. 106.
    Neer RM, et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434–41.PubMedGoogle Scholar
  107. 107.
    Jiang Y, et al. Recombinant human parathyroid hormone (1–34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res. 2003;18:1932–41.PubMedGoogle Scholar
  108. 108.
    Brixen KT, Christensen PM, Ejersted C, Langdahl BL. Teriparatide (biosynthetic human parathyroid hormone 1–34): a new paradigm in the treatment of osteoporosis. Basic Clin Pharmacol Toxicol. 2004;94:260–70.PubMedGoogle Scholar
  109. 109.
    Sumida K, et al. Once-weekly teriparatide in hemodialysis patients with hypoparathyroidism and low bone mass: a prospective study. Osteoporos Int. 2016;27:1441–50.PubMedGoogle Scholar
  110. 110.
    Bai YD, Yang FS, Xuan K, Bai YX, Wu BL. Inhibition of RANK/RANKL signal transduction pathway: a promising approach for osteoporosis treatment. Med Hypotheses. 2008;71:256–8.PubMedGoogle Scholar
  111. 111.
    Pageau SC. Denosumab. mAbs. 2009;1:210–5.PubMedPubMedCentralGoogle Scholar
  112. 112.
    McClung MR, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821–31.PubMedGoogle Scholar
  113. 113.
    Fouque-Aubert A, Chapurlat R. Influence of RANKL inhibition on immune system in the treatment of bone diseases. Joint Bone Spine. 2008;75:5–10.PubMedGoogle Scholar
  114. 114.
    Taylor KH, Middlefell LS, Mizen KD. Osteonecrosis of the jaws induced by anti-RANK ligand therapy. Br J Oral Maxillofac Surg. 2010;48(3):221–3Google Scholar
  115. 115.
    Goyden J, et al. The effect of OSM on MC3T3-E1 osteoblastic cells in simulated microgravity with radiation. PLoS One. 2015;10:e0127230.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Tamma R, et al. Oxytocin is an anabolic bone hormone. Proc Natl Acad Sci U S A. 2009;106:7149–54.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Kim WK, et al. Curcumin protects against ovariectomy-induced bone loss and decreases osteoclastogenesis. J Cell Biochem. 2011;112:3159–66.PubMedGoogle Scholar
  118. 118.
    Habold C, Momken I, Ouadi A, Bekaert V, Brasse D. Effect of prior treatment with resveratrol on density and structure of rat long bones under tail-suspension. J Bone Miner Metab. 2011;29:15–22.PubMedGoogle Scholar
  119. 119.
    Denise P, et al. Sympathetic B antagonist prevents bone mineral density decrease induced by labyrinthectomy. Aviakosm Ekolog Med. 2009;43:36–8.PubMedGoogle Scholar
  120. 120.
    Pietrzyk RA, Jones JA, Sams CF, Whitson PA. Renal stone formation among astronauts. Aviat Space Environ Med. 2007;78:A9–13.PubMedGoogle Scholar
  121. 121.
    Sellmeyer DE, Schloetter M, Sebastian A. Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet. J Clin Endocrinol Metab. 2002;87:2008–12.PubMedGoogle Scholar
  122. 122.
    Zerwekh JE, Odvina CV, Wuermser LA, Pak CY. Reduction of renal stone risk by potassium-magnesium citrate during 5 weeks of bed rest. J Urol. 2007;177:2179–84.PubMedGoogle Scholar
  123. 123.
    Whitson PA, et al. Effect of potassium citrate therapy on the risk of renal stone formation during spaceflight. J Urol. 2009;182:2490–6.PubMedGoogle Scholar
  124. 124.
    LeBlanc AD, et al. Alendronate as an effective countermeasure to disuse induced bone loss. J Musculoskelet Neuronal Interact. 2002;2:335–43.PubMedGoogle Scholar
  125. 125.
    Watanabe Y, et al. Intravenous pamidronate prevents femoral bone loss and renal stone formation during 90-day bed rest. J Bone Miner Res. 2004;19:1771–8.PubMedGoogle Scholar
  126. 126.
    Sepulveda PV, Bush ED, Baar K. Pharmacology of manipulating lean body mass. Clin Exp Pharmacol Physiol. 2015;42:1–13.PubMedPubMedCentralGoogle Scholar
  127. 127.
    J. E. Hall. Reproductive and Hormonal Functions of the Male. Chapter 81 In: Guyton and Hall textbook of medical physiology, 13th Ed. Elsevier Health, USA; 2015.Google Scholar
  128. 128.
    Bhasin S, et al. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab. 1997;82:407–13.PubMedGoogle Scholar
  129. 129.
    Wang C, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89:2085–98.PubMedGoogle Scholar
  130. 130.
    Casaburi R, et al. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170:870–8.PubMedGoogle Scholar
  131. 131.
    Snyder PJ, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85:2670–7.PubMedGoogle Scholar
  132. 132.
    Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab. 1997;82:3793–6.PubMedGoogle Scholar
  133. 133.
    Sih R, et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 1997;82:1661–7.PubMedGoogle Scholar
  134. 134.
    Chen J, Kim J, Dalton JT. Discovery and therapeutic promise of selective androgen receptor modulators. Mol Interv. 2005;5:173–88.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Macho L, Kvetnansky R, Fickova M, Popova IA, Grigoriev A. Effects of exposure to space flight on endocrine regulations in experimental animals. Endocr Regul. 2001;35:101–14.PubMedGoogle Scholar
  136. 136.
    Wimalawansa SM, Wimalawansa SJ. Simulated weightlessness-induced attenuation of testosterone production may be responsible for bone loss. Endocrine. 1999;10:253–60.PubMedGoogle Scholar
  137. 137.
    Ricci G, Catizone A, Esposito R, Galdieri M. Microgravity effect on testicular functions. J Gravit Physiol. 2004;11:P61–2.PubMedGoogle Scholar
  138. 138.
    Ricci G, Esposito R, Catizone A, Galdieri M. Direct effects of microgravity on testicular function: analysis of hystological, molecular and physiologic parameters. J Endocrinol Invest. 2008;31:229–37.PubMedGoogle Scholar
  139. 139.
    Morley JE, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism. 1997;46:410–3.PubMedGoogle Scholar
  140. 140.
    Roy TA, et al. Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. Am J Physiol Endocrinol Metab. 2002;283:E284–94.PubMedGoogle Scholar
  141. 141.
    Smith SM, Heer M, Wang Z, Huntoon CL, Zwart SR. Long duration space flight and bed rest effects on testosterone and other steroids. J Clin Endocrinol Metab. 2012;97:270–8.PubMedGoogle Scholar
  142. 142.
    Tricker R, et al. The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men: a clinical research center study. J Clin Endocrinol Metab. 1996;81:3754–8.PubMedGoogle Scholar
  143. 143.
    Bhasin S, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;335:1–7.PubMedGoogle Scholar
  144. 144.
    Bhasin S, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001;281:E1172–81.PubMedGoogle Scholar
  145. 145.
    Zachwieja JJ, et al. Testosterone administration preserves protein balance but not muscle strength during 28 days of bed rest. J Clin Endocrinol Metab. 1999;84:207–12.PubMedGoogle Scholar
  146. 146.
    Urban R. Testosterone supplementation as a countermeasure against musculoskeletal losses during space exploration. Space Flight Investigation, NASA Life Science Data Archive, 2010. Available at:
  147. 147.
    Hong MH, et al. Cell-specific activation of the human skeletal alpha-actin by androgens. Endocrinology. 2008;149:1103–12.PubMedGoogle Scholar
  148. 148.
    Li JJ, et al. Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications. J Med Chem. 2007;50:3015–25.PubMedGoogle Scholar
  149. 149.
    Dalton JT, Mukherjee A, Zhu Z, Kirkovsky L, Miller DD. Discovery of nonsteroidal androgens. Biochem Biophys Res Commun. 1998;244:1–4.PubMedGoogle Scholar
  150. 150.
    van Oeveren A, et al. Discovery of 6-N,N-bis(2,2,2-trifluoroethyl)amino- 4-trifluoromethylquinolin-2(1H)-one as a novel selective androgen receptor modulator. J Med Chem. 2006;49:6143–6.PubMedGoogle Scholar
  151. 151.
    Edwards JP, et al. New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g] quinolinone. Bioorg Med Chem Lett. 1998;8:745–50.PubMedGoogle Scholar
  152. 152.
    Bhasin S, Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care. 2009;12:232–40.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Narayanan R, Mohler ML, Bohl CE, Miller DD, Dalton JT. Selective androgen receptor modulators in preclinical and clinical development. Nucl Recept Signal. 2008;6:e010.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Page ST, Marck BT, Tolliver JM, Matsumoto AM. Tissue selectivity of the anabolic steroid, 19-nor-4-androstenediol-3beta,17beta-diol in male Sprague Dawley rats: selective stimulation of muscle mass and bone mineral density relative to prostate mass. Endocrinology. 2008;149:1987–93.PubMedGoogle Scholar
  155. 155.
    Miner JN, et al. An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate. Endocrinology. 2007;148:363–73.PubMedGoogle Scholar
  156. 156.
    Johansen KL, Mulligan K, Schambelan M. Anabolic effects of nandrolone decanoate in patients receiving dialysis: a randomized controlled trial. JAMA. 1999;281:1275–81.PubMedGoogle Scholar
  157. 157.
    Maalouf M, Durante M, Foray N. Biological effects of space radiation on human cells: history, advances and outcomes. J Radiat Res. 2011;52:126–46.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Baqai FP, et al. Effects of spaceflight on innate immune function and antioxidant gene expression. J Appl Physiol. 2009;106:1935–42.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Lehnert BE, Iyer R. Exposure to low-level chemicals and ionizing radiation: reactive oxygen species and cellular pathways. Hum Exp Toxicol. 2002;21:65–9.PubMedGoogle Scholar
  160. 160.
    Lee SJ, Hwang AB, Kenyon C. Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol. 2010;20:2131–6.PubMedPubMedCentralGoogle Scholar
  161. 161.
    Salmon AB, Richardson A, Perez VI. Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging? Free Radic Biol Med. 2010;48:642–55.PubMedGoogle Scholar
  162. 162.
    Perez VI, et al. Is the oxidative stress theory of aging dead? Biochimica et biophysica acta. 2009;1790:1005–14.PubMedPubMedCentralGoogle Scholar
  163. 163.
    Xiao M, Whitnall MH. Pharmacological countermeasures for the acute radiation syndrome. Curr Mol Pharmacol. 2009;2:122–33.PubMedGoogle Scholar
  164. 164.
    Coleman CN, Stone HB, Moulder JE, Pellmar TC. Medicine. Modulation of radiation injury. Science. 2004;304:693–4.PubMedGoogle Scholar
  165. 165.
    Singh VK, Romaine PL, Seed TM. Medical countermeasures for radiation exposure and related injuries: characterization of medicines, FDA-approval status and inclusion into the strategic national stockpile. Health Phys. 2015;108:607–30.PubMedPubMedCentralGoogle Scholar
  166. 166.
    Cakmak G, Miller LM, Zorlu F, Severcan F. Amifostine, a radioprotectant agent, protects rat brain tissue lipids against ionizing radiation induced damage: an FTIR microspectroscopic imaging study. Arch Biochem Biophys. 2012;520:67–73.PubMedGoogle Scholar
  167. 167.
    Joseph LJ, et al. Radioprotective effect of Ocimum sanctum and amifostine on the salivary gland of rats after therapeutic radioiodine exposure. Cancer Biother Radiopharm. 2011;26:737–43.PubMedGoogle Scholar
  168. 168.
    Vasin MV, et al. The characteristic of radioprotective properties of a radioprotectant B-190 at its administration after radiation. Radiats Biol Radioecol. 2008;48:730–3.PubMedGoogle Scholar
  169. 169.
    Kang AD, et al. ON01210.Na (Ex-RAD((R))) mitigates radiation damage through activation of the AKT pathway. PLoS One. 2013;8:e58355.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Chun AW, Freshwater RE, Taft DR, Gillum AM, Maniar M. Effects of formulation and route of administration on the systemic availability of Ex-RAD(R), a new radioprotectant, in preclinical species. Biopharm Drug Dispos. 2011;32:99–111.PubMedGoogle Scholar
  171. 171.
    Tamhane M, Maniar M, Ren C, Benzeroual KE, Taft DR. Disposition of ON 01210.Na (Ex-RAD(R)), a novel radioprotectant, in the isolated perfused rat liver: probing metabolic inhibition to increase systemic exposure. J Pharm Sci. 2013;102:732–40.PubMedGoogle Scholar
  172. 172.
    Bilska A, Wlodek L. Lipoic acid – the drug of the future? Pharmacol Rep. 2005;57:570–7.PubMedGoogle Scholar
  173. 173.
    Manda K, Ueno M, Anzai K. Melatonin mitigates oxidative damage and apoptosis in mouse cerebellum induced by high-LET 56Fe particle irradiation. J Pineal Res. 2008;44:189–96.PubMedGoogle Scholar
  174. 174.
    Makinde AY, et al. Effect of a metalloporphyrin antioxidant (MnTE-2-PyP) on the response of a mouse prostate cancer model to radiation. Anticancer Res. 2009;29:107–18.PubMedGoogle Scholar
  175. 175.
    Pearlstein RD, et al. Metalloporphyrin antioxidants ameliorate normal tissue radiation damage in rat brain. Int J Radiat Biol. 2010;86:145–63.PubMedGoogle Scholar
  176. 176.
    Oberley-Deegan RE, et al. The antioxidant, MnTE-2-PyP, prevents side-effects incurred by prostate cancer irradiation. PLoS One. 2012;7:e44178.PubMedPubMedCentralGoogle Scholar
  177. 177.
    Kuefner MA, et al. Effect of antioxidants on X-ray-induced gamma-H2AX foci in human blood lymphocytes: preliminary observations. Radiology. 2012;264:59–67.PubMedGoogle Scholar
  178. 178.
    Manda K, Bhatia AL. Pre-administration of beta-carotene protects tissue glutathione and lipid peroxidation status following exposure to gamma radiation. J Environ Biol. 2003;24:369–72.PubMedGoogle Scholar
  179. 179.
    Kennedy AR, Guan J, Ware JH. Countermeasures against space radiation induced oxidative stress in mice. Radiat Environ Biophys. 2007;46:201–3.PubMedGoogle Scholar
  180. 180.
    Murley JS, Kataoka Y, Weydert CJ, Oberley LW, Grdina DJ. Delayed radioprotection by nuclear transcription factor kappaB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065. Free Radic Biol Med. 2006;40:1004–16.PubMedGoogle Scholar
  181. 181.
    Weitzel DH, et al. Radioprotection of the brain white matter by Mn(III) N-butoxyethylpyridylporphyrin-based superoxide dismutase mimic, MnTnBuOE-2-PyP5+. Mol Cancer Ther. 2015;14(1):70–9.PubMedGoogle Scholar
  182. 182.
    Le Gal K, et al. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med. 2015;7:308re308.Google Scholar
  183. 183.
    Sayin VI, et al. Antioxidants accelerate lung cancer progression in mice. Sci Transl Med. 2014;6:221ra215.Google Scholar
  184. 184.
    Akpolat M, Kanter M, Uzal MC. Protective effects of curcumin against gamma radiation-induced ileal mucosal damage. Arch Toxicol. 2009;83:609–17.PubMedGoogle Scholar
  185. 185.
    Guo J, et al. Salvianic acid A protects L-02 cells against gamma-irradiation-induced apoptosis via the scavenging of reactive oxygen species. Environ Toxicol Pharmacol. 2013;35:117–30.PubMedGoogle Scholar
  186. 186.
    Ghoneum M, Badr El-Din NK, Abdel Fattah SM, Tolentino L. Arabinoxylan rice bran (MGN-3/Biobran) provides protection against whole-body gamma-irradiation in mice via restoration of hematopoietic tissues. J Radiat Res. 2013;54:419–29.PubMedPubMedCentralGoogle Scholar
  187. 187.
    Ahmad TA, et al. Gelam honey protects against gamma-irradiation damage to antioxidant enzymes in human diploid fibroblasts. Molecules. 2013;18:2200–11.PubMedPubMedCentralGoogle Scholar
  188. 188.
    Raja RB, Arunachalam KD. Anti-genotoxic potential of casein phosphopeptides (CPPs): a class of fermented milk peptides against low background radiation and prevention of cancer in radiation workers. Toxicol Ind Health. 2011;27:867–72.PubMedGoogle Scholar
  189. 189.
    Reiter RJ, Tan DX, Maldonado MD. Melatonin as an antioxidant: physiology versus pharmacology. J Pineal Res. 2005;39:215–6.PubMedGoogle Scholar
  190. 190.
    Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res. 2007;42:28–42.PubMedGoogle Scholar
  191. 191.
    Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85:495–522.PubMedGoogle Scholar
  192. 192.
    Taub DD. Novel connections between the neuroendocrine and immune systems: the ghrelin immunoregulatory network. Vitam Horm. 2008;77:325–46.PubMedGoogle Scholar
  193. 193.
    Wang G, Lee HM, Englander E, Greeley GH Jr. Ghrelin: not just another stomach hormone. Regul Pept. 2002;105:75–81.PubMedGoogle Scholar
  194. 194.
    Whitnall MH, et al. Molecular specificity of 5-androstenediol as a systemic radioprotectant in mice. Immunopharmacol Immunotoxicol. 2005;27:15–32.PubMedGoogle Scholar
  195. 195.
    Kim JS, et al. A study of the effect of sequential injection of 5-androstenediol on irradiation-induced myelosuppression in mice. Arch Pharm Res. 2015;38:1213–22.PubMedGoogle Scholar
  196. 196.
    Whitnall MH, et al. In vivo radioprotection by 5-androstenediol: stimulation of the innate immune system. Radiat Res. 2001;156:283–93.PubMedGoogle Scholar
  197. 197.
    Stickney DR, et al. 5-androstenediol improves survival in clinically unsupported rhesus monkeys with radiation-induced myelosuppression. Int Immunopharmacol. 2007;7:500–5.PubMedGoogle Scholar
  198. 198.
    Shah KG, et al. Human ghrelin ameliorates organ injury and improves survival after radiation injury combined with severe sepsis. Mol Med. 2009;15:407–14.PubMedPubMedCentralGoogle Scholar
  199. 199.
    Manda K, Ueno M, Anzai K. Cranial irradiation-induced inhibition of neurogenesis in hippocampal dentate gyrus of adult mice: attenuation by melatonin pretreatment. J Pineal Res. 2009;46:71–8.PubMedGoogle Scholar
  200. 200.
    Bhatia AL, Manda K. Study on pretreatment of melatonin against radiation -induced oxidative stress in mice. Environ Toxicol Pharmacol. 2004;18:13–20.PubMedGoogle Scholar
  201. 201.
    Manda K, Ueno M, Anzai K. Space radiation-induced inhibition of neurogenesis in the hippocampal dentate gyrus and memory impairment in mice: ameliorative potential of the melatonin metabolite, AFMK. J Pineal Res. 2008;45:430–8.PubMedGoogle Scholar
  202. 202.
    Karbownik M, Reiter RJ. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc Soc Exp Biol Med. 2000;225:9–22.PubMedGoogle Scholar
  203. 203.
    Zhou Y, Mi MT. Genistein stimulates hematopoiesis and increases survival in irradiated mice. J Radiat Res (Tokyo). 2005;46:425–33.Google Scholar
  204. 204.
    Landauer MR, Srinivasan V, Seed TM. Genistein treatment protects mice from ionizing radiation injury. J Appl Toxicol. 2003;23:379–85.PubMedGoogle Scholar
  205. 205.
    Sener G, et al. Ginkgo biloba extract protects against ionizing radiation-induced oxidative organ damage in rats. Pharmacol Res. 2006;53:241–52.PubMedGoogle Scholar
  206. 206.
    Bhatia AL, Sharma A, Patni S, Sharma AL. Prophylactic effect of flaxseed oil against radiation-induced hepatotoxicity in mice. Phytother Res. 2007;21:852–9.PubMedGoogle Scholar
  207. 207.
    Soyal D, Jindal A, Singh I, Goyal PK. Modulation of radiation-induced biochemical alterations in mice by rosemary (Rosemarinus officinalis) extract. Phytomedicine. 2007;14:701–5.PubMedGoogle Scholar
  208. 208.
    Houghton CA, Fassett RG, Coombes JS. Sulforaphane: translational research from laboratory bench to clinic. Nutr Rev. 2013;71:709–26.PubMedGoogle Scholar
  209. 209.
    Ghosh SP, et al. Gamma-tocotrienol, a tocol antioxidant as a potent radioprotector. Int J Radiat Biol. 2009;85:598–606.PubMedGoogle Scholar
  210. 210.
    Kulkarni SS, et al. Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony-stimulating factor. Int Immunopharmacol. 2012;14:495–503.PubMedGoogle Scholar
  211. 211.
    Singh VK, Brown DS, Kao TC. Tocopherol succinate: a promising radiation countermeasure. Int Immunopharmacol. 2009;9:1423–30.PubMedGoogle Scholar
  212. 212.
    Cui J, et al. Protective effects of carboxyfullerene in irradiated cells and BALB/c mice. Free Radic Res. 2013;47:301–8.PubMedGoogle Scholar
  213. 213.
    Madero-Visbal RA, et al. Harnessing nanoparticles to improve toxicity after head and neck radiation. Nanomedicine. 2012;8:1223–31.PubMedGoogle Scholar
  214. 214.
    Oliai C, Yang LX. Radioprotectants to reduce the risk of radiation-induced carcinogenesis. Int J Radiat Biol. 2014;90:203–13.PubMedGoogle Scholar
  215. 215.
    Husain M, Mehta MA. Cognitive enhancement by drugs in health and disease. Trends Cogn Sci. 2011;15:28–36.PubMedPubMedCentralGoogle Scholar
  216. 216.
    Wollseiffen P, et al. Neuro-cognitive performance is enhanced during short periods of microgravity. Physiol Behav. 2016;155:9–16.PubMedGoogle Scholar
  217. 217.
    Froestl W, Muhs A, Pfeifer A. Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors. J Alzheimers Dis. 2012;32:793–887.PubMedGoogle Scholar
  218. 218.
    Froestl W, Muhs A, Pfeifer A. Cognitive enhancers (nootropics). Part 2: drugs interacting with enzymes. J Alzheimers Dis. 2013;33:547–658.PubMedGoogle Scholar
  219. 219.
    Froestl W, Pfeifer A, Muhs A. Cognitive enhancers (nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. Disease-modifying drugs. J Alzheimers Dis. 2013;34:1–114.PubMedGoogle Scholar
  220. 220.
    Demeter E, Sarter M. Leveraging the cortical cholinergic system to enhance attention. Neuropharmacology. 2013;64:294–304.PubMedGoogle Scholar
  221. 221.
    Koh MT, Rosenzweig-Lipson S, Gallagher M. Selective GABA(A) alpha5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. Neuropharmacology. 2013;64:145–52.PubMedGoogle Scholar
  222. 222.
    Andersson H, Hallberg M. Discovery of inhibitors of insulin-regulated aminopeptidase as cognitive enhancers. Int J Hypertens. 2012;2012:789671.PubMedPubMedCentralGoogle Scholar
  223. 223.
    Estrada A, Kelley AM, Webb CM, Athy JR, Crowley JS. Modafinil as a replacement for dextroamphetamine for sustaining alertness in military helicopter pilots. Aviat Space Environ Med. 2012;83:556–64.PubMedGoogle Scholar
  224. 224.
    Gore RK, Webb TS, Hermes ED. Fatigue and stimulant use in military fighter aircrew during combat operations. Aviat Space Environ Med. 2010;81:719–27.PubMedGoogle Scholar
  225. 225.
    Zolkowska D, Andres-Mach M, Prisinzano TE, Baumann MH, Luszczki JJ. Modafinil and its metabolites enhance the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Psychopharmacology (Berl). 2015;232:2463–79.Google Scholar
  226. 226.
    Ishizuka T, Murotani T, Yamatodani A. Action of modafinil through histaminergic and orexinergic neurons. Vitam Horm. 2012;89:259–78.PubMedGoogle Scholar
  227. 227.
    Ishizuka T, Murotani T, Yamatodani A. Modanifil activates the histaminergic system through the orexinergic neurons. Neurosci Lett. 2010;483:193–6.PubMedGoogle Scholar
  228. 228.
    Karabacak Y, et al. The effect of modafinil on the rat dopamine transporter and dopamine receptors D1-D3 paralleling cognitive enhancement in the radial arm maze. Front Behav Neurosci. 2015;9(215)Google Scholar
  229. 229.
    Neale C, Camfield D, Reay J, Stough C, Scholey A. Cognitive effects of two nutraceuticals Ginseng and Bacopa benchmarked against modafinil: a review and comparison of effect sizes. Br J Clin Pharmacol. 2013;75:728–37.PubMedPubMedCentralGoogle Scholar
  230. 230.
    Muller U, et al. Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers. Neuropharmacology. 2013;64:490–5.PubMedPubMedCentralGoogle Scholar
  231. 231.
    Vernikos J. Pharmacological approaches. Acta Astronaut. 1995;35:281–95.PubMedGoogle Scholar
  232. 232.
    Pharmemsi Study Final Report (9611/91/FL, 1992).Google Scholar
  233. 233.
    O’Neill MJ, Dix S. AMPA receptor potentiators as cognitive enhancers. IDrugs. 2007;10:185–92.PubMedGoogle Scholar
  234. 234.
    Silverman JL, Oliver CF, Karras MN, Gastrell PT, Crawley JN. AMPAKINE enhancement of social interaction in the BTBR mouse model of autism. Neuropharmacology. 2013;64:268–82.PubMedGoogle Scholar
  235. 235.
    Lewis JE, et al. The effect of an aloe polymannose multinutrient complex on cognitive and immune functioning in Alzheimer’s disease. J Alzheimers Dis. 2013;33:393–406.PubMedGoogle Scholar
  236. 236.
    Bocharov EV, et al. Therapeutic efficacy of the neuroprotective plant adaptogen in neurodegenerative disease (Parkinson’s disease as an example). Bull Exp Biol Med. 2010;149:682–4.PubMedGoogle Scholar
  237. 237.
    Levy K, Lanctot KL, Farber SB, Li A, Herrmann N. Does pharmacological treatment of neuropsychiatric symptoms in Alzheimer’s disease relieve caregiver burden? Drugs Aging. 2012;29:167–79.PubMedGoogle Scholar
  238. 238.
    Pierson DL, Stowe RP, Phillips TM, Lugg DJ, Mehta SK. Epstein-Barr virus shedding by astronauts during space flight. Brain Behav Immun. 2005;19:235–42.PubMedGoogle Scholar
  239. 239.
    Crucian B, et al. Immune system dysregulation occurs during short duration spaceflight on board the space shuttle. J Clin Immunol. 2013;33:456–65.PubMedGoogle Scholar
  240. 240.
    Crucian BE, Stowe RP, Pierson DL, Sams CF. Immune system dysregulation following short- vs long duration spaceflight. Aviat Space Environ Med. 2008;79:835–43.PubMedGoogle Scholar
  241. 241.
    Meloni MA, et al. Space flight affects motility and cytoskeletal structures in human monocyte cell line J-111. Cytoskeleton (Hoboken). 2011;68:125–37.Google Scholar
  242. 242.
    Crucian BE, et al. Plasma cytokine concentrations indicate that in vivo hormonal regulation of immunity is altered during long duration spaceflight. J Interferon Cytokine Res. 2014;34:778–86.PubMedPubMedCentralGoogle Scholar
  243. 243.
    Ratikan JA, Micewicz ED, Xie MW, Schaue D. Radiation takes its Toll. Cancer Lett. 2015;368:238–45.PubMedPubMedCentralGoogle Scholar
  244. 244.
    Schaue D, Kachikwu EL, McBride WH. Cytokines in radiobiological responses: a review. Radiat Res. 2012;178:505–23.PubMedPubMedCentralGoogle Scholar
  245. 245.
    Mehta SK, et al. Stress-induced subclinical reactivation of varicella zoster virus in astronauts. J Med Virol. 2004;72:174–9.PubMedGoogle Scholar
  246. 246.
    Payne DA, Mehta SK, Tyring SK, Stowe RP, Pierson DL. Incidence of Epstein-Barr virus in astronaut saliva during spaceflight. Aviat Space Environ Med. 1999;70:1211–3.PubMedGoogle Scholar
  247. 247.
    Taylor PW. Impact of space flight on bacterial virulence and antibiotic susceptibility. Infect Drug Resist. 2015;8:249–62.PubMedPubMedCentralGoogle Scholar
  248. 248.
    Wilson JW, et al. Space flight alters bacterial gene expression and virulence and reveals a role for global regulator Hfq. Proc Natl Acad Sci U S A. 2007;104:16299–304.PubMedPubMedCentralGoogle Scholar
  249. 249.
    Nickerson CA, et al. Microgravity as a novel environmental signal affecting Salmonella enterica serovar Typhimurium virulence. Infect Immun. 2000;68:3147–52.PubMedPubMedCentralGoogle Scholar
  250. 250.
    Nickerson CA, et al. Low-shear modeled microgravity: a global environmental regulatory signal affecting bacterial gene expression, physiology, and pathogenesis. J Microbiol Methods. 2003;54:1–11.PubMedGoogle Scholar
  251. 251.
    Nickerson CA, Ott CM, Wilson JW, Ramamurthy R, Pierson DL. Microbial responses to microgravity and other low-shear environments. Microbiol Mol Biol Rev. 2004;68:345–61.PubMedPubMedCentralGoogle Scholar
  252. 252.
    Wilson JW, et al. Microarray analysis identifies Salmonella genes belonging to the low-shear modeled microgravity regulon. Proc Natl Acad Sci U S A. 2002;99:13807–12.PubMedPubMedCentralGoogle Scholar
  253. 253.
    Wilson JW, et al. Media ion composition controls regulatory and virulence response of Salmonella in spaceflight. PLoS One. 2008;3:e3923.PubMedPubMedCentralGoogle Scholar
  254. 254.
    Hammond TG, et al. Effects of microgravity on the virulence of Listeria monocytogenes, Enterococcus faecalis, Candida albicans, and methicillin-resistant Staphylococcus aureus. Astrobiology. 2013;13:1081–90.PubMedGoogle Scholar
  255. 255.
    Sullivan A, Edlund C, Nord CE. Effect of antimicrobial agents on the ecological balance of human microflora. Lancet Infect Dis. 2001;1:101–14.PubMedGoogle Scholar
  256. 256.
    Noverr MC, Huffnagle GB. Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 2004;12:562–8.PubMedGoogle Scholar
  257. 257.
    Marsland BJ, Salami O. Microbiome influences on allergy in mice and humans. Curr Opin Immunol. 2015;36:94–100.PubMedGoogle Scholar
  258. 258.
    McCoy KD, Koller Y. New developments providing mechanistic insight into the impact of the microbiota on allergic disease. Clinical immunology. 2015;159:170–6.PubMedGoogle Scholar
  259. 259.
    Shen N, Clemente JC. Engineering the Microbiome: a Novel Approach to Immunotherapy for Allergic and Immune Diseases. Curr Allergy Asthma Rep. 2015;15:39.PubMedGoogle Scholar
  260. 260.
    van Baarlen P, Wells JM, Kleerebezem M. Regulation of intestinal homeostasis and immunity with probiotic lactobacilli. Trends Immunol. 2013;34:208–15.PubMedGoogle Scholar
  261. 261.
    Dong H, Rowland I, Thomas LV, Yaqoob P. Immunomodulatory effects of a probiotic drink containing Lactobacillus casei Shirota in healthy older volunteers. Eur J Nutr. 2013;52(8):1853–63.PubMedGoogle Scholar
  262. 262.
    Aggarwal J, Swami G, Kumar M. Probiotics and their effects on metabolic diseases: an update. J Clin Diagn Res. 2013;7:173–7.PubMedPubMedCentralGoogle Scholar
  263. 263.
    Magrone T, Jirillo E. The interplay between the gut immune system and microbiota in health and disease: nutraceutical intervention for restoring intestinal homeostasis. Curr Pharm Des. 2013;19:1329–42.PubMedGoogle Scholar
  264. 264.
    Saulnier DM, et al. The intestinal microbiome, probiotics and prebiotics in neurogastroenterology. Gut Microbes. 2013;4:17–27.PubMedPubMedCentralGoogle Scholar
  265. 265.
    van Lierop MJ, et al. Org 214007-0: a novel non-steroidal selective glucocorticoid receptor modulator with full anti-inflammatory properties and improved therapeutic index. PLoS One. 2012;7:e48385.PubMedPubMedCentralGoogle Scholar
  266. 266.
    Israeli M, et al. The immune-modulator AS101 reduces anti-HLA antibodies in sera of sensitized patients: a structural approach. Int Immunopharmacol. 2012;13:483–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.International Space UniversityStrasbourgFrance

Personalised recommendations