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Superoxide dismutase for therapeutic use: Clinical experience, dead ends and hopes

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Summary

The clinical trials performed with bovine superoxide dismutase (SOD) are reviewed. SOD, applied intraarticularly at a dosage of 2–16 mg, proved to be effective in osteoarthritis of the knee joint in three placebo-controlled and one steroid-controlled double-blind trials. Its efficacy in other inflammatory joint disorders is documented by uncontrolled trials. Similarly, some controlled and many open studies support the efficacy of locally injected SOD in periarticular inflammation. Systemic treatment of rheumatoid arthritis by SOD at the dosages indicated yielded disappointing results. Well documented, though open uncontrolled studies demonstrated beneficial effects of locally administered SOD in radiation cystitis, interstitial cystitis and Peyronie's disease. Tolerance is good, but allergic reactions at low incidence have to be anticipated. Human SOD derived from recombinant microorganisms is being developed to explore its therapeutic potential particularly in ischemia-reperfusion damage, adult respiratory distress or similar conditions.

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References

  1. Steinman HM: Superoxide Dismutases: Protein chemistry and structure function relationships. In W Oberley (ed.). Superoxide dismutase. Vol. 1. CRC Press, Boca Raton, Florida: 11–68, 1982

    Google Scholar 

  2. Flohé L: Die unerwunschte Sauerstoffaktivierung dokumentiert am Beispiel bestimmter Entzündungen: der Weg zur Anwendung der Superoxiddismutase. In EF Elstner, W Bors, W Wilmanns (eds). Reaktive Sauerstoffspezies in der Medizin. Springer-Verlag, Berlin: 16–21, 1986

    Google Scholar 

  3. Huber W, Saifer MGP: Orgotein, the drug version of bovine Cu/Zn superoxide dismutase: I. A summary account of safety and pharmacology in laboratory animals. In AM Michelson, JM McCord, I Fridovich (eds). Superoxide and Superoxide Dismutases. Academic Press, London - New York - San Francisco: 517–536, 1977

    Google Scholar 

  4. McCord JM, Fridovich I: Superoxide dismutase: an enzymatic function for erythrocuprein (hemocuprein). J Biol Chem 244:6049–6055, 1969

    Google Scholar 

  5. Lund-Olesen K, Menander KB: Orgotein: a new antiinflammatory metalloprotein drug: preliminary evaluation of clinical efficacy and safety in degenerative joint disease. Curr Ther Res 16:706–717, 1974

    Google Scholar 

  6. Menander-Huber KB, Huber W: Orgotein, the drug version of bovine Cu/Zn superoxide dismutase: II. A summary account of clinical trials in man and animals. In AM Michelson, JM McCord, I Fridovich (eds). Superoxide and Superoxide Dismutases. Academic Press, London: 537–549, 1977

    Google Scholar 

  7. Babior BM, Kipnes RS, Curnutte JT Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest 52:741–744, 1973

    Google Scholar 

  8. Lowrie DB, Aber VR: Superoxide production by rabbit alveolar macrophages. Life Sci 21:1575–1584, 1977

    Google Scholar 

  9. Flohé L, Beckmann R, Giertz H, Loschen G: Oxygen-centered free radicals as mediators of inflammation. In H Sies (ed.). Oxidative Stress. Academic Press, London: 403–435, 1985

    Google Scholar 

  10. Johnston RB Jr., Lehmeyer JE, Guthrie LA: Generation of superoxide dismutase anion and chemiluminescence by human monocytes during phagocytosis and on contact with surface-bound immunoglobulin G. J Exp Med 143:1551–1556, 1976

    Google Scholar 

  11. Ryan US: Phagocytic properties of endothelial cells. Abstr. 4-ICOR, 4th International Congress on Oxygen Radicals, San Diego, 1987

  12. Hamers MN, Roos D: Oxidative stress in human neutrophilic granulocytes: host defence and self-defence. In H Sies (ed.). Oxidative Stress, Academic Press, London: 351–381, 1985

    Google Scholar 

  13. Goldstein IM, Roos D, Kaplan HB, Weissmann G: Complement and immunoglobulins stimulate superoxide production by human leukocytes independently of phagocytosis. J Clin Invest 56:1155–1163, 1977

    Google Scholar 

  14. Washida N, Sagawa A, Tamoto K, Koyama J: Comparative studies on superoxide anion production by polymorphonuclear leukocytes stimulated with various agents. Biochim Biophys Acta 631:371–379, 1980

    Google Scholar 

  15. Simchowitz L, Mehta J, Spilberg I: Chemotactic factor-induced generation of superoxide radicals by human neutrophils: effect of metabolic inhibitors and antiinflammatory drugs. Arthritis Rheum 22:755–763, 1979

    Google Scholar 

  16. Flohé L, Martin W, Loschen G, Gunzler WA: Is Leukotriene B4-induced chemotaxis mediated by superoxide? In AM Michelson, JV Bannister (eds). Life Chemistry Reports, Suppl. 2. Harwood Academic Publishers, Chur, London, Paris, New York: 318–324, 1984

    Google Scholar 

  17. Hartung HP, Parnham MJ, Winkelmann J, Englberger W, Hadding U: Platelet activating factor (PAF) induces the oxidative burst in macrophages. Int J Immunopharmacol 5:115–121, 1983

    Google Scholar 

  18. Zimmermann R, Flohé L, Weser U, Hartmann HJ: Inhibition of lipid peroxidation in isolated inner membrane of rat liver mitochondria by superoxide dismutase. FEBS Lett 29:117–120, 1973

    Google Scholar 

  19. Wefers H, Sies H: Oxidation of glutathione by the superoxide radical to the disulfide and the sulfonate yielding singlet oxygen. Eur J Biochem 137:29–36, 1983

    Google Scholar 

  20. McCord JM: Free radicals and inflammation: protection of synovial fluid by superoxide dismutase. Science 185:529–531, 1974

    Google Scholar 

  21. Kreisl C, Lengfelder E: Hyaluronic acid degradation by reactions producing activated oxygen species. In AM Michelson, JV Bannister (eds). Life Chemistry Reports, Suppl 2. Harwood Academic Publishers, Chur, London, Paris, New York: 81–86, 1984

    Google Scholar 

  22. Greenwald RA: Effect of oxygen-derived free radicals on connective tissue macromolecules. In WH Bannister and JV Bannister (eds). Biological and Clinical Aspects of Superoxide and Superoxide Dismutase. Development in Biochemistry. Vol. XIB, Elsevier/North-Holland, New York and Amsterdam: 160–171, 1980

    Google Scholar 

  23. Borel JP, Braquet P, Monboisse JC, Maquart FX, Randoux A: Effects of oxygen radicals, PAF-acether and leukotrienes on collagen metabolism. In RA Greenwald, G Cohen (eds). Oxy Radicals and Their Scavenger Systems. Cellular and Medical Aspects. Elsevier/North-Holland, New York and Amsterdam: 334–338, 1983

    Google Scholar 

  24. Carp H, Janoff A: In vitro suppression of serum elestase-inhibitory capacity by reactive oxygen species generated by phagocytosing polymorphonuclear leukocytes. J Clin Invest 63:793–797, 1979

    Google Scholar 

  25. McCord J, English DK, Petrone WF: A role for superoxide in granulocyte mediated inflammation. In WH Bannister, JV Bannister (eds). Biological and Clinical Aspects of Superoxide and Superoxide Dismutase. Developments in Biochemistry, Vol. XIB. Elsevier/North-Holland, New York and Amsterdam: 154–159, 1980

    Google Scholar 

  26. Lunec J, Hill C: Some immunological consequences of free radical production in rheumatoid arthritis. In W Bors, M Saran, C Hill (eds). Oxygen Radicals and Biology. Walter de Gruyter. Berlin, New York: 939–945, 1984

    Google Scholar 

  27. McCord JM, English DK, Petrone WF: A role for superoxide in granulocyte mediated inflammation. In WH Bannister, JV Bannister (eds). Advances in Inflammation Research, Raven Press, New York: 273, 1979

    Google Scholar 

  28. Flohé L, Giertz H, Beckmann R: Free radical scavengers as antiinflammatory drugs? In IL Bonta, MA Bray, MJ Parnham (eds). Handbook of Inflammation, vol. 5. Elsevier Science Publishers B.V., Amsterdam: 255–281, 1985

    Google Scholar 

  29. Flohé L, Biehl G, Hofer H, Kadrnka F, Kölbel R, Puhl W: Effectiveness of superoxide dismutase in osteoarthritis of the knee joint. Results of a double blind multicenter clinical trial. In WH Bannister, JV Bannister (eds). Biological and Clinical Aspects of Superoxide and Superoxide Dismutase. Developments in Biochemistry, vol. 11 B. Elsevier, New York - Amsterdam - Oxford: 424–430, 1980

    Google Scholar 

  30. Puhl W, Biehl G, Kölbel R, Hofer H: Ergebnis einer multizentrischen Orgotein-Prüfung bei Gonarthrose. Europ J Rheumatol Inflamm 4:264–270, 1981

    Google Scholar 

  31. Huskisson EC, Scott J: Orgotein in osteoarthritis of the knee joint. Europ J Rheumatol Inflamm 4:212–218, 1981

    Google Scholar 

  32. Lund-Olesen K, Menander-Huber KB: Intra-articular orgotein-therapy in osteoarthritis of the knee. A doubleblind, placebo-controlled trial. Arzneim-Forsch/Drug Res 33:1199–1203, 1983

    Google Scholar 

  33. Gammer W, Broback LG: Clinical comparison of orgotein and methylprednisolone acetate in the treatment of osteoarthrosis of the knee joint. Scand J Rheumatol 13:108–112, 1984

    Google Scholar 

  34. Greenwald RA: Therapeutic benefits of oxygen radical scavenger treatments remain unproven. J Free Rad in Biol & Med 1:173–177, 1985

    Google Scholar 

  35. Puhl W Sies H (eds): Abakterielle artikuläre und periartikuläre Entzündungen-Superoxid-Dismutase-Biochemie und therapeutischer Einsatz. perimed Fachbuch-Verlagsgesellschaft mbh; Erlangen, 1982

  36. Beckmann R, Flohé L, Wilsmann KM: 10 Jahre therapeutische Erfahrungen mit Superoxid-Dismutase. Medizin Suppl. 1:1–16, 1987

    Google Scholar 

  37. Menander-Huber K: Double-blind controlled clinical trials in man with bovine copper-zinc superoxide dismutase (Orgotein). In WH Bannister, JV Bannister (eds). Biological and Clinical Aspects of Superoxide and Superoxide Dismutase, Developments in Biochemistry, Elsevier, New York - Amsterdam - Oxford, 11B:408–423, 1980

    Google Scholar 

  38. Camus JP, Ermerit I, Michelson AM, Prier A, Koeger AC, Merlet C: Superoxyde dismutase et polyarthrite rhumatoide. Rev Rhum 47:489–492, 1980

    Google Scholar 

  39. Goebel KM, Storck U, Neurath F: Intrasynovialorgotein-therapy in rheumatoid arthritis. Lancet 1:1015–1017, 1981

    Google Scholar 

  40. Goebel KM: Storck U: Effect of intraarticular orgotein versus a corticosteroid on rheumatoid arthritis of the knees. Am J Med 74:124–128, 1983

    Google Scholar 

  41. Müller U, Moll G: Über die Behandlung der Epicondylitis mit lokal injiziertem Orgotein (Doppelblindstudie). Rheumatologie 42:21–24, 1983

    Google Scholar 

  42. De Samtis E, Rosa MA, Di Giovanni C, Casparini G: Studio comparativo in dopio cieco cross-over tra orgoteina e metilprednisolone. Ort e Traum 2:413–418, 1982

    Google Scholar 

  43. Marberger H, Huber W, Bartsch G, Schulte TL: Orgotein: a new antiinflammatory metalloprotein drug evaluation of clinical efficacy and safety in inflammatory conditions of the urinary tract. Int Urol Nephrpol 6:61–74, 1974

    Google Scholar 

  44. Marberger H, Bartsch G, Huber W, Menander KB, Schulte TL: Orgotein: a new drug for the treatment of radiation cystitis. Curr ther Res 18:466–475, 1975

    Google Scholar 

  45. Marberger H, Huber W, Menander-Huber KB, Bartsch G: Orgotein: a new drug for the treatment of radiation cystitis. Europ J Rheumatol Inflamm 4:244–249, 1981

    Google Scholar 

  46. Frick J, Danner Ch, Kunit G: Klinische Erfahrungen mit Orgotein bei urologischen Erkrankungen. Europ J Rheumatol Inflamm 4:260–263, 1981

    Google Scholar 

  47. Kadrnka F: Ergebnisse einer multizentrischen Orgoteinprüfung bei Strahlen- und interstitiellen Cystitiden. Europ J. Rheumatol Inflamm 4:237–243, 1981

    Google Scholar 

  48. Haubensak K, Konrad G: Die Behandlung der Schrumpfharnblasen mit Orgotein. Urologe B 22:134–137, 1982

    Google Scholar 

  49. Reuß K, Carl P: Behandlung des Ulcus simplex vesicae und der ulcerierenden radiogenen Cystitis mit Superoxiddismutase. Urologe A 22:290–293, 1983

    Google Scholar 

  50. Schilling A, Chaussy Ch, Schüller J, Staehler G, Walther V: Superoxiddismutase (SOD): Erste Erfahrungen bei der Anwendung eines neuen anti-inflammatorischen Prinzips in der Behandlung der ulzerierenden Zystitis und der Induratio penis plastica (IPP). Verh Dtsch Ges Urol 32:404–405, 1980

    Google Scholar 

  51. Smith BH: Subclinical peyronie's disease. Am J Clin Pathol 52:385–390, 1969

    Google Scholar 

  52. Devine CJ: Surgery of the penis and urethra. In Campbell's Urology. Vol 3, Saunders Company, Philadelphia - London - Toronto: 2390–2437, 1979

    Google Scholar 

  53. Schubert GE: Induratio penis plastica (IPP), pathomorphologische Gesichtspunkte. In L Weissbach, EA Boedefeld, T Widmann (eds). Berichtsband IPP-Symposium. M. Brimberg, Druck- und Verlagsgesellschaft mbH, Aachen: 23–37, 1984

    Google Scholar 

  54. Weissbach L, Boedefeld EA, Widmann T (eds). Berischtsband IPP-Symposium. M. Brimberg, Druck- und Verlagsgesellschaft mbH, Aachen, 1984

    Google Scholar 

  55. Schilling A: Erfahrungen bei der Behandling der Induratio penis plastica mit Orgotein und ihre Sicherheit. In L Weissbach, EA Boedefeld, T Widmann (eds). Berichtsband IPP-Symposium. M. Brimberg, Druck- und Verlagsgesellschaft mbH, Aachen, 88–92, 1984

    Google Scholar 

  56. Edsmyr F, Huber W, Menander KB: Orgotein efficacy in ameliorating side effects due to radiation therapy. I. doubleblind, placebo-controlled trial in patients with bladder tumors. Curr ther Res 19:198–211, 1976

    Google Scholar 

  57. Edsmyr F, Menander-Huber KB: Orgotein efficacy in ameliorating side effects due to radiation therapy. Europ J Rheumatol Inflamm 4:228–236, 1981

    Google Scholar 

  58. Edsmyr F: Superoxide dismutase efficacy in ameliorating side effects of radiation therapy: double-blind, placebocontrolled trials in patients with bladder and prostate tumors. In AM Autor (ed.). Pathology of Oxygen, Academic Press, New York: 215–326, 1982

    Google Scholar 

  59. De Luca E, Marletta F, Patané C, Reforgiato AM, Tomaselli S: LOrgoteina nella prevenzione della mucosite da raggi a livello oro-faringeo. Med Praxis 4:29–36, 1983

    Google Scholar 

  60. Michelson AM, Puget K: Oxygen radicals: Physiological and medical aspects, with specific reference to high energy irradition. In W Bors, M Saran, D Tait (eds). Oxygen Radicals in Chemistry and Biology, Walter de Gruyter, Berlin - New York, 831–840, 1984

    Google Scholar 

  61. Wilsmann KM: Ten years of clinical experience with SOD treatment in inflammatory disorders. In G Rotilio (ed.). Superoxide and Superoxide Dismutase in Chemistry, Biology and Medicine. Elsevier Science Publishers, Amsterdam - New York - Oxford: 500–507, 1986

    Google Scholar 

  62. Schramm G, Mauch C, Wilsmann K: Peroxinorm®, Superoxid-Dismutase (INN Orgotein), Dokumentation über Nebenwirkungen 1981–1986, Grünenthal GmbH, Stolberg, FRG, 1987

    Google Scholar 

  63. McCord J: Superoxide Dismutase: rationale for use in reperfusion injury and inflammation. J Free Rad in Biol & Med 2:307–310, 1986

    Google Scholar 

  64. Ratych RE, Bulkley GB: Free-radical-mediated postischemic reperfusion injury in the kidney. J Free Rad in Biol & Med 2:311–319, 1986

    Google Scholar 

  65. Wendel A, Tiegs G: Leukotriene D4 mediates galactosamine/endotoxin-induced hepatitis in mice. Biochem Pharmacol 36:1867, 1987

    Google Scholar 

  66. Till GO, Ward PA: Lung injury secondary to chemotactic factor-induced leukocyte activation. Agents Actions 12:383–396, 1983

    Google Scholar 

  67. Till GO, Beauchamp C, Menapace D, Tourtellotte W Jr, Kunkel R, Johnson KJ, Ward PA: Oxygen radical dependent lung damage following thermal injury of rat skin. J Trauma 23:269–277, 1983

    Google Scholar 

  68. Sherman K, Dafni N, Leiman-Hurwith J, Groner Y: Nucleotide sequence and expression of human chromosome 21-encoded superoxide dismutase mRNA. Proc Nat Acad Sci (Wash.) 80:5465–5469, 1983

    Google Scholar 

  69. Hallewell RA, Masiarz FR, Najarian RC, Puma JP, Quiroga MR, Randolph A, Sanchez-Pescador R, Scandella CJ, Smith B, Steimer KS, Mullenbach GT. Human Cu/Zn superoxide dismutase cDNA: Isolation of clones synthesising high levels of active or inactive enzyme from an expression library. Nucleic Acids Research 13:2017–2034, 1985

    Google Scholar 

  70. Flohé L, Kim SMA, Ötting F, Saunders D, Schwertner E, Steffens GJ, Blaber R, Masiarz F, Scandella C, Hallewell R: Comparison of human Cu/Zn superoxide dismutase derived from erythrocytes, recombinant E. coli and recombinant yeast. In G Rotilio (ed.). Superoxide and Superoxide Dismutase in Chemistry, Biology and Medicine, Elsevier Science Publishers, Amsterdam - New York - Oxford: 266–269, 1986

    Google Scholar 

  71. Schneider J, Friderichs E, Giertz H: Comparison of the protective effects by human and bovine superoxide dismutase against ischemia and reperfusion induced impairment of kidney function in anesthetized rats. Free Radical Biol & Med 3:21–26, 1987

    Google Scholar 

  72. Fincke U Schneider J, Friderichs E, Giertz H, Flohé L: Recombinant human superoxide dismutase (r-hSOD) enhances the myocardial salvage after fibrinolytic recanalization in canine coronary artery thrombosis. Abstr. 4-ICOR, 4th International Congres on Oxygen Radicals, San Diego, 1987

  73. Fincke U, Schneider J, Friderichs E, Giertz H, Flohé L: Enhanced myocardial salvage by combined treatment with recombinant single-chain urokinase-type plasminogen activator and recombinant human superoxide dismutase in a canine coronary thrombosis model. Arzneim-Forsch/Drug Res 38 (1):138–142, 1988

    Google Scholar 

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    Leopold Flohé

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Flohé, L. Superoxide dismutase for therapeutic use: Clinical experience, dead ends and hopes. Mol Cell Biochem 84, 123–131 (1988). https://doi.org/10.1007/BF00421046

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