SOD

Scientific Name(s):Superoxide dismutase, orgotein

Uses

SOD has been used for the treatment of soft tissue inflammation in horses and dogs, human inflammatory diseases, and chronic bladder inflammations.

Dosing

There is a single clinical trial in which SOD was administered intratracheally in premature infants. Injection of SOD in 8 to 32 mg doses has been reported. Most clinical trials of SOD have measured its level as an outcome, rather than a treatment.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.

Interactions

Not documented.

Adverse Reactions

The main complaint seems to be pain at the injection site.

Toxicology

SOD has been recognized as a remarkably nontoxic compound.

Chemistry

Superoxide dismutase (SOD, orgotein) is an ubiquitous enzyme that has received attention because of its therapeutic activity and because of claims that its ingestion may improve health and lengthen the human lifespan.

Uses and Pharmacology

A highly reactive superoxide free radical is generated as a toxic metabolite in a wide range of normal biological reactions that reduce oxygen. Since the superoxide radical is toxic to normal living cells, the enzyme superoxide dismutase which is present in all cells catalyzes the conversion of superoxide to the harmless components oxygen and hydrogen peroxide. 1

At least 3 distinct types of the enzyme are found in humans and other mammals. 2 In mammals, SOD is usually confined to intracellular areas; only traces of the enzyme are found extracellularly. 3

White blood cells involved in the acute inflammatory response release large amounts of superoxide, which appears to contribute to the destruction of bacteria. Similarly, the amount of superoxide released at the site of an inflamed joint has been shown to cause extensive and rapid degradation of synovial fluid. SOD generally protects the fluid against this degradation. Furthermore, it protects the leucocytes themselves from free radical damage. 4

Although intravenous infusion of SOD has little anti-inflammatory activity due to its rapid renal clearance, the local injection of SOD has proven to be an effective treatment for a variety of inflammatory disorders. SOD's mechanism of action remains speculative. It protects leukocytes and macrophages against lysis induced by phagocytosis, probably by stabilizing membranes involved in the inflammatory events. In turn this reduces the release of cellular inflammants, thereby interrupting the cycle that maintains inflammation. 5

Low levels of SOD at birth appear to be related to the development of infant respiratory distress syndrome. 2 Furthermore, alterations in the superoxide level and the activity of SOD have been implicated in the development of a wide variety of chronic disorders, including diabetes and renal diseases. 6

Anti-inflammatory

Superoxide has been successfully used to treat human inflammatory diseases. In West Germany, where orgotein has been in general medical use for some years, the drug is injected locally for the management of osteoarthritis, sports injuries, 7 and knee joint osteoarthritis. 8

Animal data

See Veterinary Uses.

Clinical data

In a placebo-controlled study in patients with osteoarthritis of the knee, intra-articular orgotein, given as two 16 mg doses, was effective in reducing symptoms for up to 3 months after treatment. 9 One double-blind study showed that intra-articular (IA) orgotein was superior to IA aspirin (a nontraditional route of administration) in the treatment of rheumatoid arthritis of the knee. 10 The anti-inflammatory effectiveness of IM orgotein is good but less effective than that of IM gold in the treatment of active rheumatoid arthritis (52% improvement with orgotein vs 86% with gold after 6 months of treatment); the investigators concluded that SOD is a safe and effective drug for the short-term treatment of rheumatoid arthritis. 11

Other uses

In some countries, the drug has also been approved for local use in the treatment of chronic bladder inflammations including radiation-induced and interstitial cystitis. 12 , 13 SOD therapy has also been suggested for the treatment of hyperuricemic syndromes 14 and the management of acute paraquat poisoning. 15 Studies are underway to evaluate the effects of orgotein therapy in aiding cancer patients to tolerate radiation therapy.

SOD is currently in Phase III clinical trials to improve rejection rates after kidney transplantation and has been thought to be of use in the managment of “reperfusion injury” following an acute myocardial infarction. A recent study, however, found no clinical benefit for the intravenous administration of SOD to patients with acute myocardial infarction who underwent percutaneous transluminal angioplasty; no improvement in left ventricular function was observed in these patients, suggesting that the effects of SOD in this population may be limited. 16

SOD has been investigated for the treatment of infant respiratory distress syndrome. While initial studies were criticized because the SOD preparation could not effectively penetrate into pulmonary cells, subsequent experiments with SOD encapsulated in liposomes and SOD complexed with polyethylene glycol have enhanced the effectiveness of this treatment. In addition, transgenic mouse cells that express superoxide may be administered by inhalation in the near future; this “gene therapy” would increase the SOD-producing capacity of pulmonary epithelial cells in patients at risk for developing oxygen-associated lung disorders. 2

Other studies are currently underway to investigate the effectiveness of SOD in reducing oxygen radical damage following myocardial infarction or surgery where perfusion is reduced, including renal transplants. 2 , 17

The superoxide radical has been implicated in the development of hepatic cirrhosis, and a reduction in the concentration of this radical by SOD treatment could be a theoretical way to limit the progression of this disease. 18

SOD is obtained for clinical use through genetically engineered biotechnology sources.

Health food claims

Several reports have described an association between free radicals and aging. One researcher suggested that lifespans could be increased by 5 to 10 years by reducing body weight and increasing the levels of free-radical scavengers such as ascorbic acid, selenium and alpha-tocopherol. 19 Some data indicate that longer-lived animal species have a higher internal degree of protection against free radicals. 20

Based on such reports, some health food manufacturers have promoted products containing SOD as a nutritional supplement. These oral supplements have been said to remove wrinkles and age lines, slow the aging process, and give a longer, healthier life.

There is no published data to support these claims. SOD is a labile enzyme that is rapidly degraded by gastric acids when ingested. It is essentially unabsorbed after oral administration even when enteric coated, and confers no pharmacologic activity when taken orally. While many foods (red meats, vegetables) are rich in SOD, their SOD is degraded when ingested and is rendered enzymatically inactive. The inactivity of oral SOD supplementation has been confirmed by at least one team that examined the effect of an oral SOD supplement on tissue SOD levels in mice. The animals received a diet containing 0.004% SOD, equivalent to 10 times the “recommended” intake for humans. No differences were found in the levels (activity) of two forms of SOD in tissue or blood between the control and treated groups. 21 Additionally, the analysis of 12 brands of SOD tablets purchased from health food stores indicated that one product contained zero activity and ten contained less than 20% of the labeled activity claim. 22

Veterinary uses

Parenteral SOD is approved for the treatment of soft tissue inflammation in horses and dogs. The compound has been used successfully in a variety of veterinary disorders including canine allergic dermatitis, canine lick granuloma, and upper respiratory infections in cats.

Dosage

There is a single clinical trial in which SOD was administered intratracheally in premature infants. Injection of SOD in 8 to 32 mg doses has been reported. 9 , 10 Most clinical trials of SOD have measured its level as an outcome.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.

Interactions

None well documented.

Adverse Reactions

The main complaint seems to be pain at the injection site.

Toxicology

The safety of SOD has been investigated in numerous animal models using doses up to 40,000 times the average human clinical dose of 0.1 mg/kg/day. Abnormalities were noted rarely following acute or chronic parenteral administration in mice, rats, dogs and monkeys. SOD did not induce embryonic or teratogenic changes in rats or rabbits. Parenteral administration resulted in occasional allergic sensitization in guinea pigs, but did not cause allergic reactions in horses treated for up to 6 months. 23 No immune suppression was noted after doses of up to 50 mg/kg. SOD has not been found to cause drug interactions with a variety of antibacterial agents or steroidal and nonsteroidal anti-inflammatory drugs in animals and man. 6 Pain at the injection site is usually the most common clinical complaint.

The minimal lethal dose in animals was greater than 40,000 times the anticipated human clinical dose. 24

Bibliography

1. McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 1969;244:6049.
2. Koppa SD. Superoxide Dismutase: A Scavenger for Health. Drug Therapy 1993;23(4):47.
3. McCord JM. Free Radicals and Inflammation: Protection of Synovial Fluid by Superoxide Dismutase. Science 1974;185:529.
4. Salin ML, McCord JM. Free Radicals and Inflammation: Protection of phagocytosing leukocytes by superoxide dismutase. J Clin Invest 1975;56:1319.
5. Michelson AM, et al. Superoxide and Superoxide Dismutases. London: Academic Press, 1977.
6. Adachi T, et al. Quantitative and qualitative changes of extracellular-superoxide dismutase in patients with various diseases. Clin Chim Acta 1994;229(1–2):123.
7. Huber W, Menander-Huber KB. Orgotein. Clin Rheum Dis 1980;6(3):1.
8. Huskisson EC, Scott J. Orgotein in osteoarthritis of the knee joint. Eur J Rheum 1981;4:212.
9. McIlwain H, et al. Intra-articular orgotein in osteoarthritis of the knee: a placebo-controlled efficacy, safety, and dosage comparison. Am J Med 1989;87:295.
10. Goebel KM, et al. Intrasynovial orgotein therapy in rheumatoid arthritis. Lancet 1981;1:1015.
11. Walravens M, Dequeker J. Comparison of gold and orgotein treatment in rheumatoid arthritis. Curr Ther Res 1976;20:62.
12. Kadrnka F. [Results of a multicenter orgotein study in radiation induced and interstitial cystitis.] Eur J Rheum 1981;4:237.
13. Marberger H,et al. Orgotein: a new drug for the treatment of radiation cystitis. Curr Ther Res 1975;18:466.
14. Proctor PH, et al. Superoxide-dismutase therapy in hyperuricaemic syndromes. Lancet 1978;2:95.
15. Patterson CE, Rhodes ML. The effect of superoxide dismutase on paraguat mortality in mice and rats. Toxicol and Appl Pharmacol 1982;62:65.
16. Flaherty JT, et al. Recombinant human superoxide dismutase (h-SOD) fails to improve recovery of ventricular function in patients undergoing coronary angioplasty for acute myocardial infarction. Circulation 1994;89(5):1982.
17. FDC Reports, December 12, 1984.
18. Lewis KO, Paton A. Could superoxide cause cirrhosis? Lancet 1982;2(8291):188.
19. Harman D. The aging process. Proc Soc Nat Acad Sci 1981;78:7124.
20. Tolmasoff JM, et al. Superoxide dismutase: correlation with life-span and specific metabolic rate in primate species. Proc Soc Nat Acad Sci 1980;77:2777.
21. Zidenberg-Cherr S, et al. Dietary superoxide dismutase does not affect tissue levels. Am J Clin Nutrit 1983;37:5.
22. DDI (Diagnostic Data, Inc.), Annual Stockholder Report. October 1981.
23. Carson S, et al. Safety tests of orgotein, an anti-inflammatory protein. Toxicol Applied Pharmacol 1973;26:184.
24. 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 1974;16:706.

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