Abstract
In this article, we scientifically evaluate the bio-oxidative procedure known as oxygen-ozone therapy. Research over a decade has established a comprehensive framework for understanding and recommending this type of autohemotherapy in vascular diseases. In contrast, a non-specific immunomodulation therapy, using heavily oxidized and denatured blood, has been recently used in studies involving a total of approximately 3000 patients and has led to ‘disappointing’ results. Such a treatment appears to be an inappropriate example of the so-called minor autohemotherapy, and its poor outcomes may discourage any further studies. Therefore it appears necessary to clarify that the use of only a minimal ozone dose and a valid experimental protocol is likely to produce beneficial results. Millions of people suffer from chronic limb, brain, and heart ischemia, and such patients may benefit if appropriate ozone therapy could be implemented. Accordingly, we propose the need for a well designed, multicenter, clinical trial to be conducted.
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References
Nakao A, Sugimoto R, Billiar TR, et al. Therapeutic antioxidant medical gas. J Clin Biochem Nutr 2009; 44: 1–13.
Rokitanski O, Rokitanski A, Steiner J, et al. Die ozontherapie bei peripheren, arteriellen Durchblutungs-strörugen; linik, biochemische und blutgasanalytische untersuchungen. Wasser IOA, Ozon-Weltkongress; Berlin, 1981: 53–75.
Matassi R, D’Angelo F, Bisetti P, et al. Terapia con ozono per via parenterale nelle arteropatie obliteranti periferiche: meccanismo biochimico e risultati clinici. Il Giornale di Chirurgia 1987; VIII: 109–11.
De Monte A, van der Zee H, Bocci V. Major ozonated autohemotherapy in chronic limb ischemia with ulcerations. J Altern Complement Med 2005; 11: 363–7.
Hernandez F, Menéndez S, Wong R. Decrease of blood cholesterol and stimulation of antioxidative response in cardiopathy patients treated with endovenous ozone therapy. Free Radic Biol Med 1995; 19: 115–9.
Biedunkiewicz B, Tylicki L, Nieweglowski T, et al. Clinical efficacy of ozonated autohemotherapy in hemodialyzed patients with intermittent claudication: an oxygen controlled study. Int J Artif Organs 2004; 27: 29–34.
Di Paolo N, Bocci V, Garosi G, et al. Extracorporeal blood oxygenation and ozonation (EBOO) in man: preliminary report. Int J Artif Organs 2000; 23: 131–41.
Di Paolo N, Bocci V, Salvo DP, et al. Extracorporeal blood oxygenation and ozonation (EBOO): a controlled trial in patients with peripheral artery disease. Int J Artif Organs 2005; 28: 1039–50.
Torre-Amione G, Anker SD, Bourge RC, et al. Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebocontrolled randomised trial. Lancet 2008; 371: 228–36.
Travagli V, Zanardi I, Bernini P, et al. Effects of ozone blood treatment on the metabolite profile of human blood. Int J Toxicol 2010; 29: 165–74.
Mustafa MG. Biochemical basis of ozone toxicity. Free Radic Biol Med 1990; 9: 245–65.
Pryor WA. Mechanisms of radical formation from reactions of ozone with target molecules in the lung. Free Radic Biol Med 1994; 17: 451–65.
Tager IB, Balmes J, Lurmann F, et al. Chronic exposure to ambient ozone and lung function in young adults. Epidemiology 2005; 16: 751–9.
Ruidavets JB, Cournot M, Cassadou S, et al. Ozone air pollution is associated with acute myocardial infarction. Circulation 2005; 111: 563–9.
Kampa M, Castanas E. Human health effects of air pollution. Environ Pollut 2008; 151: 362–7.
Jerrett M, Burnett RT, Pope 3rd CA, et al. Long-term ozone exposure and mortality. N Engl J Med 2009; 360: 1085–95.
Bastacky J, Lee CYC, Goerke J, et al. Alveolar lining layer is thin and continuous: low-temperature scanning electron microscopy of rat lung. J Appl Physiol 1995; 79: 1615–28.
Cho HY, Zhang LY, Kleeberger SR. Ozone-induced lung inflammation and hyperreactivity are mediated via tumor necrosis factor-alpha receptors. Am J Physiol Lung Cell Mol Physiol 2001; 280: L537–46.
Last JA, Gohil K, Mathrani VC, et al. Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes. Toxicol Appl Pharmacol 2005; 208: 117–26.
Uppu RM, Cueto R, Squadrito GL, et al. What does ozone react with at the air/lung interface? Model studies using human red blood cell membranes. Arch Biochem Biophys 1995; 319: 257–66.
Bocci V. Is it true that ozone is always toxic? The end of a dogma. Toxicol Appl Pharmacol 2006; 216: 493–504.
Search strategy used to create CAM on PubMed (PubMed’s Complementary Medicine Subset) [online]. Available from URL: http: //www.nlm.nih.gov/ bsd/pubmed_subsets/comp_med_strategy.html [Accessed 2010 Mar 2].
Forman HJ. Hydrogen peroxide: the good, the bad and the ugly. In: Valacchi G, Davis P, editors. Oxidants in biology. Dordrecht: Springer, 2008: 1–17.
Barrera G, Pizzimenti S, Dianzani MU. Lipid peroxidation: control of cell proliferation, cell differentiation and cell death. Mol Aspects Med 2008; 29: 1–8.
Yang G, Wu L, Jiang B, et al. H2 S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 2008; 322: 587–90.
Long EK, Picklo Sr MJ. Trans-4-hydroxy-2-hexenal, a product of n-3 fatty acid peroxidation: make some room HNE. Free Radic Biol Med 2010; doi: 10.1016/j. Epub.
Bocci V, Borrelli E, Travagli V, et al. The ozone paradox: ozone is a strong oxidant as well as a medical drug. Med Res Rev 2009; 29: 646–82.
Battino R, Rettici TR, Tominaga T. The solubility of oxygen and ozone in liquids. J Phys Chem Ref Data 1983; 12: 163–78.
Pryor WA, Squadrito GL, Friedman M. The cascade mechanism to explain ozone toxicity: the role of lipid ozonation products. Free Radical Biol Med 1995; 19: 935–41.
Bocci V. Ozone: a new medical drug. 2nd ed. Dordrecht: Springer Science, 2011.
Bocci V. Scientific and medical aspects of ozone therapy: state of the art. Arch Med Res 2006; 37: 425–35.
Bocci V, Aldinucci C. Biochemical modifications induced in human blood by oxygenation-ozonation. J Biochem Mol Toxicol 2006; 20: 133–8.
Travagli V, Zanardi I, Silvietti A, et al. A physicochemical investigation on the effects of ozone on blood. Int J Biol Macromol 2007; 41: 504–11.
Bocci V, Zanardi I, Michaeli D, et al. Mechanisms of action and chemicalbiological interactions between ozone and body compartments: a critical appraisal of the different administration routes. Curr Drug Ther 2009; 4: 159–73.
Bocci V, Valacchi G, Corradeschi F, et al. Studies on the biological effects of ozone: 7. Generation of reactive oxygen species (ROS) after exposure of human blood to ozone. J Biol Regul Homeost Agents 1998; 12: 67–75.
Bocci V, Valacchi G, Corradeschi F, et al. Studies on the biological effects of ozone: 8. Effects on the total antioxidant status and on interleukin-8 production. Mediators Inflamm 1998; 7: 313–7.
Shinriki N, Suzuki T, Takama K, et al. Susceptibilities of plasma antioxidants and erythrocyte constituents to low levels of ozone. Haematologia 1998; 29: 229–39.
Carballal S, Alvarez B, Turell L, et al. Sulfenic acid in human serum albumin. Amino Acids 2007; 32: 543–51.
Aldini G, Vistoli G, Regazzoni L, et al. Albumin is the main nucleophilic target of human plasma: a protective role against proatherogenic electrophilic reactive carbonyl species? Chem Res Toxicol 2008; 21: 824–35.
Mendiratta S, Qu ZC, May JM. Enzyme-dependent ascorbate recycling in human erythrocytes: role of thioredoxin reductase. Free Radic Biol Med 1998; 25: 221–8.
Halliwell B. Antioxidant defence mechanisms: from the beginning to the end (of the beginning). Free Radic Res 1999; 31: 261–72.
Packer L, Roy S, Sen CK. Alpha-lipoic acid: a metabolic antioxidant and potential redox modulator of transcription. Adv Pharmacol 1997; 38: 79–101.
Antunes F, Cadenas E. Estimation of H2 O2 gradients across biomembranes. FEBS Lett 2000; 475: 121–6.
Stone JR, Yang S. Hydrogen peroxide: a signaling messenger. Antioxid Redox Signal 2006; 8: 243–70.
Miller NJ, Rice-Evans C, Davies MJ, et al. A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. Clin Sci 1993; 84: 407–12.
Valacchi G, Bocci V. Studies on the biological effects of ozone: 11. Release of factors from human endothelial cells. Mediat Inflamm 2000; 9: 271–6.
Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 1994; 12: 141–79.
Valacchi G, Bocci V. Studies on the biological effects of ozone: 10. Release of factors from ozonated human platelets. Mediat Inflamm 1999; 8: 205–9.
Awasthi YC, Ansari GA, Awasthi S. Regulation of 4-hydroxynonenalmediated signaling by glutathione S-transferase. Methods Enzymol 2005; 401: 379–407.
Yamamoto Y. Fate of lipid hydroperoxides in blood plasma. Free Radic Res 2000; 33: 795–800.
Petras T, Siems WG, Grune T. 4-Hydroxynonenal is degraded to mercapturic acid conjugate in rat kidney. Free Radic Biol Med 1995; 19: 685–8.
Poli G, Schaur RJ, Siems WG, et al. 4-Hydroxynonenal: a membrane lipid oxidation product of medicinal interest. Med Res Rev 2008; 28: 569–631.
Takahashi Y, Takahashi S, Yoshimi T, et al. Increases in the mRNA levels of γ-glutamyltransferase and heme oxygenase-1 in the rat lung after ozone exposure. Biochem Pharmacol 1997; 53: 1061–4.
Dianzani MU. 4-Hydroxynonenal and cell signalling. Free Radic Res 1998; 28: 553–60.
Cheng JZ, Sharma R, Yang Y, et al. Accelerated metabolism and exclusion of 4-hydroxynonenal through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative stress. J Biol Chem 2001; 276: 41213–23.
Yang YS, Sharma R, Sharma A, et al. Lipid peroxidation and cell cycle signaling: 4-hydroxynonenal, a key molecule in stress mediated signaling. Acta Biochim Pol 2003; 50: 319–36.
Petersen DR, Doorn JA. Reactions of 4-hydroxynonenal with proteins and cellular targets. Free Radic Biol Med 2004; 37: 937–45.
Siems W, Grune T. Intracellular metabolism of 4-hydroxynonenal. Mol Aspects Med 2003; 24: 167–75.
Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43: 109–42.
Hobbs AJ. Soluble guanylate cyclase: the forgotten sibling. Trends Pharmacol Sci 1997; 18: 484–91.
Wang R. Two’s company, three’s a crowd: can H2 S be the third endogenous gaseous transmitter? FASEB J 2002; 16: 1792–8.
Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radical. Nat Med 2007; 13: 688–94.
Wood KC, Gladwin MT. The hydrogen highway to reperfusion therapy. Nat Med 2007; 13: 673–4.
Calabrese EJ. Hormesis is central to toxicology, pharmacology and risk assessment. Hum Exp Toxicol 2010; 29: 249–61.
Benson H, Friedman R. Harnessing the power of the placebo effect and renaming it “remembered wellness”. Annu Rev Med 1996; 47: 193–9.
Schulz S, Häussier U, Mandic R, et al. Treatment with ozone/oxygen-pneumoperitoneum results in complete remission of rabbit squamous cell carcinomas. Int J Cancer 2008; 122: 2360–7.
Viru A, Tendzegolskis Z. Plasma endorphin species during dynamic exercise in humans. Clin Physiol 1995; 15: 73–9.
Goldstein BD, Balchum OJ. Effect of ozone on lipid peroxidation in the red blood cell. Exp Biol Med 1967; 126: 356–8.
Bocci V, Borrelli E, Valacchi G, et al. Quasi-total-body exposure to an oxygenozone mixture in a sauna cabin. Eur J Appl Physiol Occup Physiol 1999; 80: 549–54.
Bocci V, Zanardi I, Travagli V, et al. Oxygenation-ozonation of blood during extracorporeal circulation: in vitro efficiency of a new gas exchange device. Artif Organs 2007; 31: 743–8.
Abraham NG, Kappas A. Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 2008; 60: 79–127.
Jacobs MT. Untersuchung uber zwishenfalle und typische komplikationen in der ozon-sauerstofftherapie. OzoNachrichten 1982; 5: 1–5.
Allegra C, Antignani PL, Schachter I, et al. Propionyl-L-carnitine in Leriche-Fontaine stage II peripheral arterial obstructive disease. Ann Vasc Surg 2008; 22: 552–8.
Tylicki L, NiewgŁowski T, Biedunkiewicz B, et al. Beneficial clinical effects of ozonated autohemotherapy in chronically dialysed patients with atherosclerotic ischemia of the lower limbs: pilot study. Int J Artif Organs 2001; 24: 79–82.
Tylicki L, Nieweglowski T, Biedunkiewicz B, et al. The influence of ozonated autohemotherapy on oxidative stress in hemodialyzed patients with atherosclerotic ischemia of lower limbs. Int J Artif Organs 2003; 26: 297–303.
Tylicki L, Biedunkiewicz B, Nieweglowski T, et al. Ozonated autohemotherapy in patients on maintenance hemodialysis: influence on lipid profile and endothelium. Artif Organs 2004; 28: 234–7.
Bulmer J, Bolton AE, Pockley AG. Effect of combined heat, ozonation and ultraviolet irradiation (VasoCare) on heat shock protein expression by peripheral blood leukocyte populations. J Biol Regul Homeost Agents 1997; 11: 104–10.
Bocci V, Travagli V, Zanardi I. Maybe oxygen-ozone therapy blocks the progression of cardiovascular disorders? Cardiovasc Hematol Disord Drug Targets 2009; 9: 78–85.
Garber GE, Cameron DW, Hawley-Foss N, et al. The use of ozone-treated blood in the therapy of HIV infection and immune disease: a pilot study of safety and efficacy. AIDS 1991; 5: 981–4.
Hooker MH, Gazzard BG. Ozone-treated blood in the treatment of HIV infection [letter]. AIDS 1992; 6: 131.
Olin JW. A multicenter, randomized, double-blind, placebo-controlled study of immune modulation therapy in patients with symptomatic peripheral arterial diseases: the SIMPADICO trial. Smaller Late-Breaking Clinical Trials I, American College of Cardiology 55th Annual Scientific Sessions; 2006 Mar 11–14; Atlanta (GA).
Torre-Amione G, Sestier F, Radovancevic B, et al. Effects of a novel immune modulation therapy in patients with advanced chronic heart failure: results of a randomized, controlled, phase II trial. J Am Coll Cardiol 2004; 44: 1181–6.
Sliwa K, Ansari AA. Immunosuppression as therapy for congestive heart failure. Lancet 2008; 371: 184–6.
Bocci V. Non-specific immunomodulation in chronic heart failure [letter]. Lancet 2008; 371: 2083.
Bocci V. The failure of the ACCLAIM trial is due to an irrational technology. Int J Cardiol 2010; 139: 304–5.
Bocci V, Zanardi I, Travagli V. The irrationality of a non-specific immunomodulation therapy used in cardiovascular diseases deserves a critical comment. Atherosclerosis 2010; 211: 38–9.
Bocci V, Aldinucci C, Mosci F, et al. Ozonation of human blood induces a remarkable upregulation of heme oxygenase-1 and heat stress protein-70. Mediators Inflamm 2007; 26785. doi: 10.1155/2007/26785.
Di Filippo C, Luongo M, Marfella R, et al. Oxygen/ozone protects the heart from acute myocardial infarction through local increase of eNOS activity and endothelial progenitor cells recruitment. Naunyn Schmiedebergs Arch Pharmacol 2010; 382: 287–91.
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Bocci, V., Zanardi, I. & Travagli, V. Ozone: A New Therapeutic Agent in Vascular Diseases. Am J Cardiovasc Drugs 11, 73–82 (2011). https://doi.org/10.2165/11539890-000000000-00000
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DOI: https://doi.org/10.2165/11539890-000000000-00000