Strategies to expand the therapeutic potential of superoxide dismutase by exploiting delivery approaches.

The overproduction of free radicals can cause oxidative-stress damage to a range of biomolecules, and thus potentially contribute to several pathologies, from neurodegenerative disorders to cardiovascular diseases and metabolic disorders. Endogenous antioxidant enzymes, such as superoxide dismutase (SOD), play an important role in diminishing oxidative stress. SOD supplementation could therefore be an effective preventive strategy to reduce the risk of free-radical overproduction. However, the efficacy of SOD administration is hampered by its rapid clearance. Several different approaches to improve the bioavailability of SOD have been explored in recent decades. This review intends to describe the rationale that underlie the various approaches and chemical strategies that have led to the most recent advances in SOD delivery. This critical description includes SOD conjugates, SOD loaded into particulate carriers (micelles, liposomes, nanoparticles, microparticles) and the most promising and suitable formulations for oral delivery, with a particular emphasis on reports of preclinical/clinical results. Likely future directions are also considered and reported.

Superoxide dismutase enzymosomes: carrier capacity optimization, in vivo behaviour and therapeutic activity.

PURPOSE: A strategy not usually used to improve carrier-mediated delivery of therapeutic enzymes is the attachment of the enzymes to the outer surface of liposomes. The aim of our work was to design a new type of enzymosomes with a sufficient surface-exposed enzyme load while preserving the structural integrity of the liposomal particles and activity of the enzyme. METHODS: The therapeutic antioxidant enzyme superoxide dismutase (SOD) was covalently attached to the distal terminus of polyethylene glycol (PEG) polymer chains, located at the surface of lipid vesicles, to obtain SOD-enzymosomes. RESULTS: The in vivo fate of the optimized SOD-enzymosomes showed that SOD attachment at the end of the activated PEG slightly reduced the residence time of the liposome particles in the bloodstream after IV administration. The biodistribution studies showed that SOD-enzymosomes had a similar organ distribution profile to liposomes with SOD encapsulated in their aqueous interior (SOD-liposomes). SOD-enzymosomes showed earlier therapeutic activity than both SOD-liposomes and free SOD in rat adjuvant arthritis. SOD-enzymosomes, unlike SOD-liposomes, have a therapeutic effect, decreasing liver damage in a rat liver ischemia/reperfusion model. CONCLUSIONS: SOD-enzymosomes were shown to be a new and successful therapeutic approach to oxidative stress-associated inflammatory situations/diseases.

Modulation of neuropathic pain in experimental diabetes mellitus

The main objective of the current article is to investigate the diabetic polyneuropathy which represents a major preoccupation within the context of high incidence of diabetes mellitus (DM) and its complications. Moreover, neuropathy may develop despite intensive hyperglycaemic control. The effect of Zn and black grape seed polyphenols (BGSP) in streptozotocin diabetic rats was studied. Zn and BGSP were administered by gavage, daily, for 16 weeks to Wistar rats that have been rendered diabetic by a single i.v. injection of streptozotocin (55 mg/kg body weight). Dysalgesia was investigated under the conditions of nociceptive stimulation through the following tests: the thermoalgesic mechanism through the tail-flick test, the hot plate test and the plantar test, and the mechanoalgesic mechanism through the algesimetric test. Thermal hyperalgesia detected in the diabetic group is significantly reduced (p < 0.001) through the administration of polyphenols, or even better, of Zn. Diabetes-associated mechanical hyperalgesia decreased significantly (p < 0.001) probably through the inhibition of the NMDA receptors. Administration of Zn or BGSP to the diabetic group improves glycosylated haemoglobin (HbA1c) values but does not bring them to normal. The present data suggest a favourable effect of Zn and BGSP in inhibiting diabetic complications by several mechanisms

Superoxide dismutase administration, a potential therapy against oxidative stress related diseases: several routes of supplementation and proposal of an original mechanism of action.

Oxidative stress, involved in many diseases, is defined as an impaired balance between reactive oxygen species (ROS) production and antioxidant defences. Antioxidant enzymes such as superoxide dismutase (SOD) play a key role in diminishing oxidative stress. Thus, the removal of ROS by exogenous SODs could be an effective preventive strategy against various diseases. The poor bioavailability of exogenous SODs has been criticized. However, improvements in SOD formulation may overcome this limitation and boost interest in its therapeutic properties. Here, we provide a review of animal and human studies about SODs supplementation in order to evaluate their therapeutic value. Protective effects have been observed against irradiation, carcinogenesis, apoptosis and neurodegeneration. SODs administration has also been reported to alleviate inflammatory, infectious, respiratory, metabolic and cardiovascular diseases and genitourinary and fertility disorders, raising the question of its mechanism of action in these diverse situations. Some authors have shown an increase in endogenous antioxidant enzymes after exogenous SODs administration. The induction of endogenous antioxidant defence and, consequently, a decrease in oxidative stress, could explain all the effects observed. Further investigations need to be carried out to test the hypothesis that SODs supplementation acts by inducing an endogenous antioxidant defence.

Effects of Greek legume plant extracts on xanthine oxidase, catalase and superoxide dismutase activities

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Legumes are considered to have beneficial health implications, which have been attributed to their phytochemical content. Polyphenols are considered the most important phytochemical compounds extensively studied for their antioxidant properties. The aim of the present study was to examine the effects of potent antioxidant legume plant extracts on xanthine oxidase (XO), catalase (CAT) and superoxide dismutase (SOD) activities. XO exerts a dual role, as it is the major contributor of free radicals during exercise while it generates uric acid, the most potent antioxidant molecule in plasma. CAT and SOD are two of the main enzymes of the antioxidant defence of tissues. We demonstrate that the majority of the extracts inhibited XO activity, but they had no effect on CAT inhibition and SOD induction when used at low concentrations. These results imply that the tested extracts may be considered as possible source of novel XO inhibitors. However, we have shown that allopurinol administration, a known XO inhibitor, before exercise reduces performance and induces oxidative stress in rats. Considering the fact that the extracts examined had an inhibitory effect on XO activity, possibly posing a restriction in their characterization as antioxidants, phytochemical antioxidant administration before exercise should probably be reconsidered (AU)

Enzymosomes with surface-exposed superoxide dismutase: in vivo behaviour and therapeutic activity in a model of adjuvant arthritis.

Acylated Superoxide Dismutase (Ac-SOD) enzymosomes, liposomal enzymatic systems expressing catalytic activity in the intact form, were previously characterized. The main scope of the present work was to investigate the biological behaviour of Ac-SOD inserted in the lipid bilayer of liposomes, in comparison with SOD located in the aqueous compartment of liposomes. Two types of liposomes were used: conventional liposomes presenting an unmodified external surface and long circulating liposomes coated with poly (ethylene glycol) (PEG). Liposomal formulations of Ac-SOD and SOD were prepared and labelled with indium-111 and their in vivo fate compared. Data obtained led us to the conclusion that, for liposomes coated with PEG the in vivo fate was not influenced by the insertion of Ac-SOD in the lipid bilayers. The potential therapeutic effect of Ac-SOD enzymosomes was compared with SOD liposomes in a rat model of adjuvant arthritis. A faster anti-inflammatory effect was observed for Ac-SOD enzymosomes by monitoring the volume of the inflamed paws. The present results allowed us to conclude that Ac-SOD enzymosomes are nano-carriers combining the advantages of expressing enzymatic activity in intact form and thus being able to exert therapeutic effect even before liposomes disruption, as well as acting as a sustained release of the enzyme.

Targeting superoxide dismutase to renal proximal tubule cells inhibits nephrotoxicity of cisplatin and increases the survival of cancer-bearing mice.

Because cis-diamminedichloroplatinum(II) (cisplatin) which generates reactive oxygen species induces renal dysfunction, administration of a large dose for killing cancer cells is highly limited. We recently synthesized a cationic superoxide dismutase (SOD) (hexamethylenediamine-conjugated SOD, AH-SOD) which rapidly accumulates in renal proximal tubule cells and inhibits oxidative injury of the kidney. Treatment of Ehrlich ascites tumor cells (EATC)-bearing mice with cisplatin sufficient for killing tumor cells increased their motality. The motality of cisplatin-treated EATC-bearing mice was markedly decreased by AH-SOD. These results suggest that targeting SOD to renal proximal tubule cells might permit the administration of high doses of cisplatin and related anticancer agents without causing renal injury.

Subcutaneous administration of superoxide dismutase entrapped in long circulating liposomes: in vivo fate and therapeutic activity in an inflammation model.

PURPOSE: We are exploring liposomal delivery with the aim to change the pharmacokinetics and biodistribution of SOD to increase its therapeutic activity. From a practical point of view, a convenient route of administration would be the subcutaneous (s.c.) route. Liposomal size has been shown to be the most important factor influencing the rate and extent of drainage of liposomes from the s.c. injection site. METHODS: To monitor the in vivo fate of the subcutaneous administered SOD-containing liposomes in rats with a chronic arthritis inflammation, the liposomes were labeled by the co-encapsulation of the 111In-DTPA complex in the internal water space. RESULTS: Over the initial 10h-observation period post-injection, the small-sized poly(ethyleneglycol)-liposomes (mean size about 110 nm) left the site of injection to a 2-fold higher extent (45% of the injected dose) as compared to large-sized poly(ethyleneglycol)-liposomes (mean size about 450 nm). Small-sized liposomes gave a 17-fold higher uptake in the inflamed foot than the large-sized liposomes. Comparing the localization in the inflamed foot with the non-inflamed foot, uptake was more than 15-fold higher for the small-sized liposomes as compared to the large-sized liposomes. After s.c. administration, small-sized SOD-liposomes showed substantial higher activity than large-sized SOD-liposomes. S.C. administration of small-sized SOD-liposomes is equally effective as i.v. administration of the same liposomes. I.V. administration of the large-sized SOD-liposomes yielded a significantly higher activity as compared to s.c. administration. CONCLUSIONS: These results indicate that small-sized poly(ethyleneglycol)-liposomes can be used for the targeting of SOD to arthritic sites after subcutaneous administration.

Preclinical trials of human erythrocyte superoxide dismutase injection.

OBJECTIVE: To assess the quality of human erythrocyte superoxide dismutase (SOD) injection reaching the official standard for its clinical uses. METHODS: Human erythrocyte SOD injection prepared by McCord-Fridovich's method without column chromatography but with some modifications was used in preclinical trials, to observe the general pharmacology and pharmacodynamics of the product. RESULTS: The quality of human erythrocyte SOD injection conformed to the official standard of a biological product, which was found to be non-toxic and did not have any effects on the central and autonomic nervous systems as well as cardiovascular and respiratory systems. The efficacy of anti-inflammation and promotion of immuno-regulation especially on carrageenan and adjuvant-induced polyarthritis were shown in animals. CONCLUSION: Human erythrocyte SOD injection is appropriate for prophylactic and therapeutic uses in clinical trials.

Intravenous administration of superoxide dismutase entrapped in long circulating liposomes. II. In vivo fate in a rat model of adjuvant arthritis.

Rheumatoid arthritis (RA) is a prevalent and debilitating autoimmune disease that affects the joints. RA is characterized by an infiltration of the affected joint by blood-derived cells. In response to activation, these cells generate reactive oxygen species, resulting in an oxidative stress situation. One approach to counteract this oxidative stress situation is the use of antioxidants as therapeutic agents. The free radical scavenger enzyme superoxide dismutase (SOD) may be used as a therapeutic agent in rheumatoid arthritis, but its rapid elimination from the circulation is a major limitation. Targeted delivery of SOD may overcome this limitation. In this study, the utility of PEGylated liposomes (PEG-liposomes) for targeting SOD to arthritic sites was explored. The targeting of SOD to arthritic sites following intravenous administration of both PEG-liposomes and positively charged liposomes lacking PEG but containing stearylamine (SA-liposomes) in rats with adjuvant arthritis was studied. At 24 h post injection, the blood levels of long circulating liposomes with a mean size of 0.11 micrometer and 0.20 micrometer were 8- and 3-fold higher, respectively, as compared to the SA-liposomes. The majority of SOD administered in liposomal form remains within the liposomes when they circulate in the bloodstream. The highest target uptake was observed with PEG-liposomes with a mean size of 0.11 micrometer and the lowest uptake with the SA-liposomes. These results demonstrate that SOD can be targeted to inflamed sites most efficiently via small-sized PEG-liposomes. Small-sized PEG-coated liposomes are to be preferred if prolonged circulation and enhanced localization of SOD at arthritic sites are desired.

Safety and pharmacokinetics of multiple doses of recombinant human CuZn superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome.

OBJECTIVES: To examine the safety and pharmacokinetics of multiple intratracheal (IT) doses of recombinant human CuZn superoxide dismutase (rhSOD) in premature infants with respiratory distress syndrome who are at risk for developing bronchopulmonary dysplasia (BPD). Methods. Thirty-three infants (700 to 1300 g) were randomized and blindly received saline, 2.5 mg/kg or 5 mg/kg rhSOD IT within 2 hours of surfactant administration. Infants were treated every 48 hours (as long as endotracheal intubation was required) up to 7 doses. Serial blood and urine studies, chest radiographs, neurosonograms, SOD concentration and activity measurements, and tracheal aspirate (TA) inflammatory markers were assessed throughout the 28-day study. RESULTS: SOD concentrations in serum (0.1 [0.05/0.15] microg/mL-geometric mean with lower/upper confidence intervals), tracheal aspirates (TA) (0.2 [0.1/0.3] microg/mL) and urine (0.3 [0.2/0.4] microg/mL) were similar at baseline in all 3 groups and did not change significantly in the placebo group. In the rhSOD treatment groups, SOD concentrations were increased on day 3 and did not change significantly thereafter over the 14-day dosing period (also measured on days 5, 7, and 13). SOD concentrations averaged 0.4 [0.3/0.5] microg/mL in serum, 0.8 [0.6/1.2] microg/mL in TA and 1.1 [1.0/1.3] microg/mL in urine for the low-dose group and 0.6 [0.5/0.7] microg/mL in serum, 1.1 [0.9/1.5] microg/mL in TA, and 2.2 [1.6/2.9] microg/mL in urine for the high-dose group over the 14-day dosing period. Enzyme activity directly correlated with SOD concentration and rhSOD was active even when excreted in urine. TA markers of acute lung injury (neutrophil chemotactic activity, albumin concentration) were lower in the rhSOD agroups compared with placebo. No significant differences in any clinical outcome variable were noted between groups. CONCLUSIONS: These data indicate that multiple IT doses of rhSOD increase the concentration and activity of the enzyme in serum, TA and urine, reduce TA lung injury markers and are well-tolerated. Further clinical trials examining the efficacy of rhSOD in the prevention of BPD are warranted.

Epidermal localization and protective effects of topically applied superoxide dismutase.

Data from the literature, as well as our previous work, indicate a protective effect of superoxide dismutase (SOD) in topical application against UV-induced cutaneous damage. In the present article we show that pre-treatment of the skin with SOD protects against PUVA-induced inflammatory reactions not only in murine, but also in human skin. Using fluorescently labelled Cu,Zn SOD, epifluorescence microscopy and digital image processing, we demonstrate that the FITC fluorescence localizes in the stratum corneum and upper granulosa, as well as in the epidermal cell layer surrounding the lumina of the hair follicles. These findings were similar for murine and human skin. Since autofluorescence was eliminated by a special filter, it can be ascertained that the fluorescence observed in the tissues was due to FITC-labelled SOD.

Safety and pharmacokinetics of recombinant human superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome.

OBJECTIVE: As a first step in the evaluation of recombinant human CuZn superoxide dismutase (rhSOD) in the prevention of neonatal lung injury, safety and pharmacokinetics of intratracheally (IT) administered rhSOD were studied. METHODS: Twenty-six preterm infants weighing 750 to 1250 g with respiratory distress syndrome were studied in three sequential groups (placebo, 0.5, and 5 mg/kg). Placebo or rhSOD was administered IT 30 minutes after the first surfactant dose. Serial blood and urine studies, rhSOD levels, tracheal aspirate fluid (TAF) markers of acute inflammation, radiographs, and ultrasounds were performed over the 28-day study period. RESULTS: Serum SOD concentrations were similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.1 to 0.2 microgram/mL). In the 0.5-mg/kg group, levels were highest at 12 hours (geometric mean 0.7, upper-lower limit 0.5 to 0.8 microgram/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were highest at 6 hours (geometric mean 3.0, upper-lower limit 2.3 to 4.0 micrograms/mL) and returned to baseline by day 4. Concentrations of SOD in TAF were also similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.2 to 0.3 microgram/mL). There were no significant increases in the placebo group, but levels in the 0.5-mg/kg group were highest when first sampled at 24 hours (geometric mean 1.1, upper-lower limit 0.8 to 1.4 micrograms/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were also highest when sampled at 24 hours (geometric mean 1.4, upper-lower limit 0.9 to 2.1 micrograms/mL) and returned to baseline by day 4. Urine levels were highest at 12 hours in both the 0.5-mg/kg (geometric mean 1.3, upper-lower limit 1.0 to 1.7 micrograms/mL) and 5-mg/kg infants (geometric mean 6.4, upper-lower limit 3.9 to 10.4 micrograms/mL) and decreased significantly by day 2 to 3. rhSOD activity assays (serum, TAF, and urine) demonstrated that the enzyme still possessed significant activity. No adverse effects of rhSOD were found. TAF neutrophil chemotactic activity and albumin concentrations, important acute lung injury markers, were significantly lower in the high-dose rhSOD group compared with the other groups. CONCLUSIONS: Data suggest that a single IT dose of rhSOD results in significant increases in both concentration and activity of the antioxidant in serum, TAF, and urine for 2 to 3 days. The enzyme appears to be well tolerated, and TAF inflammatory markers are reduced after administration. This has important implications in rhSOD trials to prevent acute and chronic lung injury in preterm neonates.

Clinical surfactant preparations mediate SOD and catalase uptake by type II cells and lung tissue.

Pulmonary surfactant mixtures are rapidly taken up by alveolar type II cells and thus may serve as vectors for the pulmonary delivery of antioxidant enzymes to the alveolar epithelium. We prepared emulsions of Survanta with superoxide dismutase (CuZn-SOD) and catalase and quantified their cellular uptake both in vitro and in vivo. Incubations of fetal lung epithelial cells with an emulsion of Survanta plus SOD and catalase mixtures resulted in significant augmentation of SOD and catalase activities (12.8 +/- 4.6 U SOD/microgram DNA; 7.49 +/- 2.21 U catalase/microgram DNA). These numbers were significantly greater than those obtained in controls (1.8 U SOD/microgram DNA; 0.55 +/- 0.52 U catalase/microgram DNA, Survanta alone (0.43 U SOD/microgram DNA; 0.16 U catalase/microgram DNA), and SOD and catalase alone (3.47 +/- 5.2 U SOD/microgram DNA; 4.24 +/- 3.0 U catalase/microgram DNA). Intratracheal instillation of the Survanta plus SOD and catalase mixture resulted in significant augmentation of enzymes by the rat lung homogenates. Confocal microscopic analysis revealed the presence of antioxidant enzymes in the cytoplasm of epithelial cells. We concluded that Survanta supplementation, in addition to replenishing surfactant stores, can also enhance the delivery of antioxidant enzymes to alveolar epithelium both in vitro and in vivo.

Pharmacokinetics of superoxide dismutase in rats after oral administration.

The kinetic behaviour of bovine erythrocyte Cu-Zn SOD was investigated in Sprague Dawley male rats after subcutaneous and oral administrations of doses ranging from 0 center dot 5 to 20 mg kg-1. Studies have been carried out with SOD and SOD encapsulated into liposomes containing or not containing ceramides. The maximum concentration (Cmax) in blood cell pellets ranged from 8 center dot 65 to 11 center dot 03 U/mg haemoglobin (Hb) after subcutaneous injection, and from 4 center dot 48 to 8 center dot 23 U/mg Hb after oral administration. The maximum concentrations were reached in 5 h (t max) for the two routes. Comparison between the areas under the curves (AUCs) obtained after subcutaneous and oral administration allowed the calculation of relative bioavailability (F'). The maximum bioavailability after oral administration was 14% for free SOD, 22% for SOD encapsulated into liposomes, and 57% when ceramides were added to liposomes. Poor SOD bioavailability was enhanced by liposome encapsulation, and ceramide addition seemed to be beneficial for oral encapsulated SOD administration.

[The modification of Cu, Zn-superoxide dismutase by monomethoxypolyethylene glycol improves the indices of the experimental therapy of the ischemic myocardium in rats]. / Modifikatsiia Cu, Zn-superoksiddismutazy monometoksipoliétilenglikolem uluchshaet pokazateli ékpserimental'noi terapii ishemizirovannogo miokarda krys.

Mice were used to make a comparative study of the biological distribution of intravenous preparations of native and monomethoxypolyethylene glycol-modified superoxide dismutase isolated from bovine liver, as well as native and aldehyde dextran. The study demonstrated that the biodistribution of the native enzymes from various sources was, however, equal, but in the mouse liver there was a higher accumulation of SOD isolated from the rat liver. AD-SOD was found to have a longer half-life in the blood and in the liver of mice, in particular, while MPEG-SOD showed 10, 15, and 16 times longer in the lungs, blood and heart of the animals examined, respectively. The elevated accumulation of MPEG-SOD in some organs was used for their treatment, particularly for experimental therapy of rat myocardial ischemia. A rat model of ischemia demonstrated that the intravenous bolus administration of MPEG-SOD reduced the size of a myocardial necrotic area by 40% as compared to a 13% decrease when the other compounds were assayed. The findings suggest that the MPEG-SOD preparation is promising for decreasing reperfusion injuries of the cardiovascular system and the lungs.

Pharmacokinetics of extracellular-superoxide dismutase in the vascular system.

Extracellular-superoxide dismutase C (EC-SOD C) is a secretory tetrameric Cu- and Zn-containing glycoprotein which has high affinity for heparin and heparan sulfate. Upon intravenous injection into rabbits, recombinant human (rh) EC-SOD C was found to be rapidly 97-98% sequestered to the vascular wall, forming an equilibrium with the plasma phase. Recombinant EC-SOD truncation variants with reduced, T216, and without, T213, heparin affinity were found to be sequestered to a reduced extent and not at all, respectively, establishing the importance of the heparin affinity for this behaviour. The halflife of rhEC-SOD C in the vasculature was of the order of 20 h. Injection of large doses resulted in saturation of the binding of rhEC-SOD C to the vascular wall. Scatchard analysis revealed a heterogeneity in affinity of the ligands on the vascular wall. The maximal binding capacity was very high. The equilibration of rhEC-SOD C to the vascular wall of an organ, clamped during enzyme injection, and the primary equilibration phase was studied by comparing binding to a clamped and reperfused kidney with binding to the contralateral control kidney. rhEC-SOD C injected in a low dose was found to equilibrate very slowly to the reperfused kidney with a halftime of about 2 h. With higher rhEC-SOD C doses, at which evidence for saturation is seen, and with the variant rhEC-SOD with reduced heparin affinity. T216, very rapid equilibrations were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue distribution of 125I-labelled bovine superoxide dismutase (SOD) in the rat.

Bovine copper/zinc superoxide dismutase (SOD) was labelled with 125I using the chloramine-T method. The tissue distribution of 125I-SOD (dose of SOD 5 mg/kg) was studied with whole-body and microautoradiography at various times after an intravenous injection. The distribution of 125I-SOD showed a remarkable organ specificity in that the localization of the enzyme to the kidneys and the urinary tract completely dominated the autoradiograms. The time pattern of localization of 125I-SOD also gives a clear picture of the renal handling of the enzyme in that, as a consequence of the renal elimination, the enzyme rapidly disappears from the circulation with an elimination half time of about 6 min. Up to 20 min. after the injection, there were high concentrations of 125I-SOD in the renal pelvis, ureter and urinary bladder showing that in addition to renal uptake there was an initial substantial urinary excretion of the enzyme. From the microautoradiography it is clear that the grains were exclusively localized over proximal tubular cells and tended to be concentrated at the luminal rather than the peritubular side of tubule. This would be compatible with renal uptake secondary to glomerular filtration of 125I-SOD, which is what one would expect from the renal handling of a protein with a molecular weight around 31,000 and an isoelectric point around pH 5.4. Pretreatment with a large dose of SOD (88 mg/kg) tended to competitively decrease the renal uptake of labelled SOD after 5 min. and apparently further increase its renal excretion. However, a noticeable renal uptake of 125I-SOD was still apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-inflammatory activity of superoxide dismutases: comparison of enzymes from different sources in different models in rats: mechanism of action.

Comparison of the anti-inflammatory properties of superoxide dismutases from different sources using different models (carrageenan and adriamycin induced inflammation, adjuvant-induced arthritis) in rats shows a very wide range of activity from extremely good to zero. Neither circulating life time nor intracellular penetration are of importance. The mechanism of biological activity of the SODs is discussed in detail, and binding to an interphase situation on the outer cell surface is postulated. As a consequence of these various considerations it is predicted that clinical application of human Cu-SOD in humans may well be much less spectacular than is commonly assumed, and indeed may be somewhat disappointing.