Prospects for Inhalation Delivery of Medical Protectors against Radiation Damage

Abstract—The possibilities of improving medical protectors administered by inhalation for urgent assistance in emergency situations are discussed in this paper. The advantages of this method of administration are characterized, and the expediency of using portable dry powder inhalers as a technical means of drug delivery is substantiated. The sources containing information on the inhalation use of drugs from various pharmacological groups has been examined. Radioprotective agents (cystamine, indraline, naphthyzine), radioprotective agents for prophylactic use (estradiol), means of preventing and arresting the primary reaction to radiation (ondansetron, metoclopramide, metacin), radiomitigators (analogs of granulocyte colony stimulating factor (G-CSF), growth hormone, betaleukin), and incorporated binding agents radionuclides (pentacin) should be considered as the most promising medical preparations for inhalation under exposure to radiation factors. This is determined by the presence of effective inhalation forms approved for medical use and registered in the Russian Federation, as well as their technological feasibility.

This is a preview of subscription content, access via your institution.

REFERENCES

  1. 1

    Khalimov, Y.S., Grebenyuk, A.N., Legeza, V.I., et al., The current state and prospects for improving specialized care for acute bone marrow syndrome of radiation etiology, Voen.-Med. Zh., 2013, vol. 334, no. 1, pp. 25–32.

    PubMed  PubMed Central  Google Scholar 

  2. 2

    Weers, J.G. and Miller, D.P., Formulation design of dry powders for inhalation, J. Pharm. Sci., 2015, vol. 104, no. 10, pp. 3259–3288.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3

    Vasin, M.V., Classification of radioprotective agents as a reflection of the current state and prospects for the development of radiation pharmacology, Radiats. Biol. Radioekol., 2013, vol. 53, no. 5, pp. 459–467.

    CAS  Google Scholar 

  4. 4

    Grebenyuk, A.N., Zatsepin, V.V., Nazarov, V.B., and Vlasenko, T.N., Modern opportunities of drug prevention and early therapy of radiation injuries, Voen.-Med. Zh., 2011, vol. 332, no. 2, pp. 13–17.

    Google Scholar 

  5. 5

    Grebenyuk, A.N. and Legeza, V.I., Prospects for the use of radioprotectors to improve the effectiveness of medical antiradiation protection of the Armed Forces, Voen.-Med. Zh., 2013, vol. 334, no. 7, pp. 46–50.

    Google Scholar 

  6. 6

    Zherebchenko, P.G., The effect of radioprotectors in the inhalation route of administration, Med. Radiol., 1978, no. 2, pp. 74–77.

  7. 7

    Vasin, M.V., Sredstva profilaktiki i lecheniya luchevykh porazhenii (Means for the Prevention and Treatment of Radiation Injuries), Moscow, 2006.

    Google Scholar 

  8. 8

    Grebenyuk, A.N., Legeza, V.I., and Zatsepin, V.V., Radiation accidents: experience of medical protection and modern strategy of pharmacological support, Radiats. Gigiena, 2012, vol. 5, no. 3, pp. 53–57.

    Google Scholar 

  9. 9

    Kraev, S.Yu., Drachev, I.S., and Seleznev, A.B., Study of the possibility of reducing the side effects of cystamine administered by inhalation, in Mezhdunar. konf. “Problemy khimicheskoi zashchity i reparatsii pri radiatsionnykh vozdeistviyakh,” Tezisy dokladov (Int. Conf. “Problems of Chemical Protection and Reparation under Radiation Exposure,” Abstracts of Papers), Dubna, 2018, pp. 81–83.

  10. 10

    Formulyar lekarstvennykh sredstv meditsinskoi sluzhby Vooruzhennykh Sil Rossiiskoi Federatsii (Formulary of Medicines of the Medical Service of the Armed Forces of the Russian Federation), 5th ed., Fisun, A.Ya. and Miroshnichenko, Yu.V., Eds., Moscow: GVKG im. Burdenko, 2014.

  11. 11

    Grebenyuk, A.N. and Gladkikh, V.D., Current state and prospects for the development of drugs for the prevention and early therapy of radiation injuries, Radiats. Biol. Radioekol., 2019, vol. 59, no. 2, pp. 132–149.

    Google Scholar 

  12. 12

    Grebenyuk, A.N., Legeza, V.I., Gladkikh, V.D., et al., Prakticheskoe rukovodstvo po ispol’zovaniyu meditsinskikh sredstv protivoradiatsionnoi zashchity pri chrezvychainykh situatsiyakh i obespecheniyu imi avariinykh mediko-sanitarnykh formirovanii i regional’nykh avariinykh tsentrov (A Practical Guide on the Use of Medical Equipment for Radiation Protection in Emergency Situations and Their Provision to Emergency Medical and Sanitary Units and Regional Emergency Centers), Moscow: Kommentarii, 2015.

  13. 13

    Miroshnichenko, Y.V., Boyarintsev, V.V., Grebenyuk, A.N., et al., The use of modern first-aid kits and bags in the elimination of the consequences of emergency situations, Kreml. Med., Klin. Vestn., 2013, no. 2, pp. 176–181.

  14. 14

    Metodicheskie ukazaniya po poryadku primeneniya meditsinskikh sredstv protivoradiatsionnoi zashchity (Methodical Instructions on the Order of the Use of Medicines for Radiation Protection), Moscow: GVMU MO RF., 2011.

  15. 15

    Zemlyannikov, D.A. and Avetisov, G.M., Issues of radioprotection of specialists of emergency rescue units of the Ministry of Defense of the Russian Federation, Med. Katastrof., 2014, no. 4 (88), pp. 15–17.

  16. 16

    Vasin, M.V., Antipov, V.V., Komarova, S.N., et al., Radioprotective properties of indralin when used together with cystamine and mexamine, Radiats. Biol. Radioekol., 2011, vol. 51, no. 2, pp. 243–246.

    CAS  Google Scholar 

  17. 17

    Vasin, M.V., Antipov, V.V., Komarova, S.N., et al., Radioprotective properties of indralin when used together with cystamine and mexamine, Radiats. Biol. Radioekol., 2011, vol. 51, no. 2, pp. 243–246.

    CAS  Google Scholar 

  18. 18

    Grebenyuk, A.N., Zatsepin, V.V., Aksenova, N.V., et al., The effect of sequential use of the drug B-190 and interleukin-1β on the survival rate and bone-marrow hematopoiesis of irradiated mice, Radiats. Biol. Radioekol., 2010, vol. 50, no. 4, pp. 475–480.

    CAS  Google Scholar 

  19. 19

    Grebenyuk, A.N., Aksenova, N.V., Zatsepin, V.V., et al., The effect of sequential use of B-190 and interleukin-1β on the dynamics of the number of peripheral blood cells and the functional status of neutrophils in irradiated mice, Radiats. Biol. Radioekol., 2013, vol. 53, no. 3, pp. 290–295.

    CAS  Google Scholar 

  20. 20

    Vasin, M.V., Ushakov, I.B., Kovtun, V.Y., et al., Effect of a combined use of quercetin and indralin on the postradiation recovery of the hematopoietic system in acute radiation sickness, Radiats. Biol. Radioekol., 2011, vol. 51, no. 2, pp. 247–251.

    CAS  Google Scholar 

  21. 21

    Evdokimov, V.I., Poisk i analiz izobretenii po profilaktike i lecheniyu radiatsionnykh porazhenii (1994–2010 gg.) (Search and Analysis of Inventions for the Prevention and Treatment of Radiation Injuries (1994–2010)), St. Petersburg: Vseros. Tsentr Ekstr. Radiats. Med. im. A.M. Nikiforova, MChS Rossii, 2012.

  22. 22

    Drachev, I.S., Turlakov, Y.S., Bykov, V.N., et al., Prophylactic radioprotective efficacy of naphthyzine with its inhalation and intratracheal administration, Klin. Bol’nitsa, 2014, vol. 2, no. 8, pp. 25–30.

    Google Scholar 

  23. 23

    Kuna, P., Dostál, M., Neruda, O., et al., Acute toxicity and radioprotective effects of amifostine (WR-2721) or cystamine in single whole body fission neutrons of irradiated rats, J. Appl. Biomed., 2004, vol. 2, no. 1, pp. 43–49.

    CAS  Article  Google Scholar 

  24. 24

    Blumberg, A.L., Nelson, D.F., Gramkowski, M., et al., Clinical trials of WR-2721 with radiation therapy, Int. J. Radiat. Oncol. Biol. Phys., 1982, vol. 8, pp. 561–563.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25

    Koukourakis, M.I., Panteliadou, M., Abatzoglou, I.M., et al., Postmastectomy hypofractionated and accelerated radiation therapy with (and without) subcutaneous amifostine cytoprotection, Int. J. Radiat. Oncol. Biol. Phys., 2013, vol. 85, no. 1, pp. 7–13.

    Article  CAS  Google Scholar 

  26. 26

    Praetorius, N.P. and Mandal, T.K., Alternate delivery route for amifostine as a radio/chemo-protecting agent, J. Pharm. Pharmacol., 2008, vol. 60, no. 7, pp. 809–815.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27

    Lockhart, S.P., Inhaled thiol and phosphorothiol radioprotectors fail to protect the mouse lung, Radiother. Oncol., 1990, vol. 19, no. 2, pp. 187–191.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28

    Grebenyuk, A.N., Bykov, V.N., Myasnikov, V.A., et al., Experimental evaluation of the antiradiation efficacy of β-estradiol in terms of survival rates and bone marrow hematopoiesis of mice exposed to X-ray radiation, Radiats. Biol. Radioekol., 2012, vol. 52, no. 2, pp. 175–180.

    CAS  Google Scholar 

  29. 29

    Degano, B., Prévost, M.C., Berger, P., et al., Estradiol decreases the acetylcholine-elicited airway reactivity in ovariectomized rats through an increase in epithelial acetylcholinesterase activity, Am. J. Respir. Crit. Care Med., 2001, vol. 164, no. 10, pp. 1849–1854.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30

    Myers, J.R. and Sherman, C.B., Should supplemental estrogens be used as steroid-sparing agents in asthmatic women?, Chest, 1994, vol. 106, no. 1, pp. 318–319.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31

    Pelissier, C., de Kervasdoue, A., Chuong, V.T., et al., Clinical evaluation, dose-finding and acceptability of aerodiol, the pulsed estrogen therapy for treatment of climacteric symptoms, Maturitas, 2001, vol. 37, no. 3, pp. 181–189.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32

    Wang, J., Ben-Jebria, A., and Edwards, D.A., Inhalation of estradiol for sustained systemic delivery, J. Aerosol Med., 1999, vol. 12, no. 1, pp. 27–36.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33

    Order of the Chief of the Main Military Medical Directorate of the Ministry of Defense of the Russian Federation dated July 12, 2011, no. 77 “On the Approval of the Collection of Inventories of Sets of Medical Equipment for the Military Level of the Medical Service of the Rf Armed Forces for Wartime.”

  34. 34

    Legeza, V.I., Seleznev, A.B., and Drachev, I.S., Experimental evaluation of the effectiveness of selective antagonists of serotonin 5HT3-receptors as a means of preventing the symptom complex of the primary response to irradiation in radiation accidents, Med.-Biol. Sots.-Psikhol. Probl. Bezop. Chrezv. Sit., 2011, no. 2, pp. 93–97.

  35. 35

    Khalimov, Y.S., Grebenyuk, A.N., Karamullin, M.A., et al., Modern possibilities of providing therapeutic assistance in the event of massive sanitary losses of the radiation profile, Voen.-Med. Zh., 2012, vol. 333, no. 2, pp. 24–31.

    PubMed  PubMed Central  Google Scholar 

  36. 36

    Inhaled ondansetron and dyspnea: clinical trials, 2013. https://clinicaltrials.gov/ct2/show/NCT01851993. Accessed September 5, 2019.

  37. 37

    Grebenyuk, A.N., Legeza, V.I., and Tarumov, R.A., Radiomitigators: prospects for use in the system of medical anti-radiation protection, Voen.-Med. Zh., 2014, vol. 335, no. 6, pp. 39–43.

    Google Scholar 

  38. 38

    Bosquillon, C., Preat, V., and Vanbever, R., Pulmonary delivery of growth hormone using dry powders and visualization of its local fate in rats, J. Control. Release, 2004, vol. 96, no. 1, pp. 233–244.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39

    Niven, R.W., Lott, F.D., and Cribbs, J.M., Pulmonary absorption of recombinant methionyl human granulocyte colony stimulating factor (r-huG-CSF) after intratracheal instillation to the hamster, Pharm. Res., 1993, vol. 1, no. 3, pp. 1604–1610.

    Article  Google Scholar 

  40. 40

    Niven, R.W., Lott, F.D., Ip, A.Y., et al., Pulmonary delivery of powders and solutions containing recombinant human granulocyte colony-stimulating factor (rhG-CSF) to the rabbit, Pharm. Res., 1994, vol. 11, pp. 1101–1109.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41

    Yu, J. and Chien, Y.W., Pulmonary drug delivery: physiologic and mechanistic aspects, Crit. Rev. Ther. Drug Carrier Syst., 1997, vol. 14, pp. 395–453.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42

    Rose, R.M., Kobzik, L., Dushay, K., et al., The effect of aerosolized recombinant human granulocyte macrophage colony-stimulating factor on lung leukocytes in nonhuman primates, Am. Rev. Respir. Dis., 1992, vol. 146, pp. 1279–1286.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43

    Reed, J.A., Ikegami, M., Cianciolo, E.R., et al., Aerosolized GMCSF ameliorates pulmonary alveolar proteinosis in GMCSF-deficient mice, Am. J. Physiol., 1999, vol. 276, no. 1, pp. 556–563.

    Google Scholar 

  44. 44

    Wylam, M.E., Ten, R., Prakash, U.B.S., et al., Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis, Eur. Respir. J., 2006, vol. 27, no. 2, pp. 585–593.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45

    Yamamoto, H.A., Yamaguchi, E., Agata, H., et al., Combination therapy of whole lung lavage and GM-CSF inhalation in pulmonary alveolar proteinosis, Pediatr. Pulmonol., 2008, vol. 43, pp. 828–830.

    PubMed  Article  PubMed Central  Google Scholar 

  46. 46

    Arai, T., Hamano, E., Inoue, Y., et al., Serum neutralizing capacity of gm-csf reflects disease severity in a patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF, Respir. Med., 2004, vol. 98, pp. 1227–1230.

    PubMed  Article  PubMed Central  Google Scholar 

  47. 47

    Bykova, A.F., Ivanov, I.M., and Grebenyuk, A.N., Problems and prospects of inhalation use of substances of peptide and protein structure as potential medical means of anti-radiation protection, Med.-Biol. Sots.-Psikhol. Probl. Bezop. Chrezv. Sit., 2018, no. 2, pp. 60–69.

  48. 48

    Tazawa, R., Nakata, K., Inoue, Y., et al., Granulocyte-macrophage colony-stimulating factor inhalation therapy for patients with idiopathic pulmonary alveolar proteinosis: a pilot study, and long-term treatment with aerosolized granulocyte-macrophage colony-stimulating factor: a case report, Respirology, 2006, vol. 11, no. 1, pp. 61–64.

    Article  Google Scholar 

  49. 49

    Heslet, L., Bay, C., and Nepper-Christensen, S., Acute radiation syndrome (ARS)—treatment of the reduced host defense, Int. J. Gen. Med., 2012, no. 5, pp. 105–115.

  50. 50

    Thipphawong, J., Inhaled cytokines and cytokine antagonists, Adv. Drug Deliv. Rev., 2006, vol. 58, pp. 1089–1105.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51

    Niven, R.W., Delivery of biotherapeutics by inhalation aerosol, Crit. Rev. Ther. Drug Carrier. Syst., 1995, vol. 12, pp. 151–231.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52

    Machida, M., Hayashi, M., and Awazu, S., Pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) after intratracheal administration to rats, Biol. Pharm. Bull., 1996, vol. 19, pp. 259–262.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53

    Machida, M., Hayashi, M., and Awazu, S., The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats, Biol. Pharm. Bull., 2000, vol. 23, pp. 84–86.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54

    Colthorpe, P., Farr, S.J., Smith, I.J., et al., The influence of regional deposition on the pharmacokinetics of pulmonary-delivered human growth hormone in rabbits, Pharm. Res., 1995, vol. 12, pp. 356–359.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55

    Folkesson, H.G., Hedin, L., and Westrom, B.R., Lung to blood passage of human growth hormone after intratracheal instillation: stimulation of growth in hypophysectomized rats, J. Endocrinol., 1992, vol. 134, pp. 197–203.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56

    Türker, S., Onur, E., and Ozer, Y., Nasal route and drug delivery systems, Pharm. World Sci., 2004, vol. 26, pp. 137–142.

    PubMed  Article  PubMed Central  Google Scholar 

  57. 57

    Devrim, B., Bozkír, A., and Canefe, K., Preparation and evaluation of poly(lactic-co-glycolic acid) microparticles as a carrier for pulmonary delivery of recombinant human interleukin-2: II. In vitro studies on aerodynamic properties of dry powder inhaler formulations, Drug Dev. Ind. Pharm., 2011, vol. 37, no. 11, pp. 1376–1386.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58

    Ivanov, I.M., Nikiforov, A.S., Trofimova, V.S., et al., Comparative study of the effect of permeability enhancers on the effectiveness of a model protein (insulin) when administered by inhalation, Med.-Biol. Sots.-Psikhol. Probl. Bezop. Chrezv. Sit., 2018, no. 4, pp. 76–83.

  59. 59

    Rozhdestvenskii, L.M., The past and the future of radiobiology of antiradiation agents at the Institute of Biophysics, Ministry of Health of the USSR—State Research Center, Burnazyan Federal Medical Biophysical Center of Russia, in Sbornik statei, posvyashchennykh 70-letiyu federal’nogo gosudarstvennogo byudzhetnogo uchrezhdeniya “Gosudarstvennyi nauchnyi tsentr Rossiiskoi Federatsii, Federal’nyi meditsinskii biofizicheskii tsentr imeni A.I. Burnazyana” (1946–2016) (Collection of Articles Dedicated to the 70th Anniversary of the Federal State Budgetary Institution “State Scientific Center of the Russian Federation—Burnazyan Federal Medical Biophysical Center ”(1946–2016)), Il’in, L.A., Uib, V.V., and Samoilov, A.S., Gen. Eds., Moscow: FGBU GNTs FMBTs im. A.I. Burnazyana FMBA Rossii, 2016, pp. 80–89.

  60. 60

    Peron, N., Le Guen, P., Andrieu, V., et al., Inhalation therapy: inhaled generics, inhaled antidotes, the future of anti-infectives and the indications of inhaled pentamidine, Rev. Mal. Respir., 2013, vol. 30, no. 10, pp. 832–842.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61

    Koizumi, A., Fukuda, S., Yamada, Y., et al., Dosage of DTPA administration by inhalation, in Int. Congr. Int. Radiat. Protect. Assoc., Hiroshima, Japan, 2000. http://www.irpa.net/irpa10/cdrom/00302.pdf.

    Google Scholar 

  62. 62

    Grémy, O., Tsapis, N., Chau, Q., et al., Preferential decorporation of americium by pulmonary administration of dtpa dry powder after inhalation of aged PuO(2) containing americium in rats, Radiat. Res., 2010, vol. 174, no. 5, pp. 637–644.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  63. 63

    Gervelas, C., Serandour, A.L., Geiger, S., et al., Direct lung delivery of a dry powder formulation of DTPA with improved aerosolization properties: effect on lung and systemic decorporation of plutonium, J. Control. Release, 2007, vol. 118, no. 1, pp. 78–86.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64

    Instructions for use of the medicinal product for medical use B-190 (PN002437/02-230813).

  65. 65

    Instructions for the use of the medicinal product for medical use Naftizin (LP 000807-160317).

  66. 66

    Instructions for the use of the medicinal product for medical use Latran (LP 001889-260813).

  67. 67

    Instructions for use of the medicinal product for medical use Metoclopramide (PN002081/01-270110).

  68. 68

    Instructions for use of the medicinal product for medical use Metacin (LSR-008566/10-230810).

  69. 69

    Instructions for the use of the medicinal product for medical use Filgrastim (LSR-002698/10-310310).

  70. 70

    Instructions for the use of a medicinal product for medical use Rastan (LS-001603-040411).

  71. 71

    Instructions for use of the medicinal product for medical use Betaleukin (PN000222/01-201207).

  72. 72

    Instructions for the use of a medicinal product for medical use Pentacin (LP00051-272016).

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yu. A. Proshina.

Additional information

Translated by N. Smolina

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ivanov, I.M., Nikiforov, A.S., Yudin, M.A. et al. Prospects for Inhalation Delivery of Medical Protectors against Radiation Damage . Biol Bull Russ Acad Sci 47, 1669–1679 (2020). https://doi.org/10.1134/S106235902012002X

Download citation

Keywords:

  • medical protective equipment
  • radioprotectors
  • radiomitigators
  • primary reaction to radiation
  • incorporated radionuclides
  • dry powder inhalers