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This is of some clinical importance, since an antiinflammatory pharmaceutical preparation rich in SOD ("orgotein") is used in veterinary medicine and recently has been shown to be both effective and apparently safe in the treatment. Catalase has also been used in the treatment of arthritic disease in man with reported success. (195). Likewise, the action of such established antiflammatory drugs as the corticosteroids, (196) penicillamine,(197) and many non-steroidal antiinflammatory agents (1,76-183,198-200) may be at least partially dependent upon interference with active oxygen metabolism in phagocytes.
Further, peroxidase release from eosinophils may playa similar role in inhibition of the inflammatory response (201) while the antioxidant properties of ceruloplasmin may also give this compound antiinflammatory properties.(21,128).
An illustrative (albeit circumstantial) model for the role of superoxide in rheumatoid arthritis can be postulated as follows: Granulocytes tend to be concentrated at sites of active rheumatic disease, presumably in response to the presence of immune complexes and other immunomodulator substances. Superoxide, peroxide, and other active oxygen species produced further kindle the inflammatory process by specific mechanisms such as those outlined in Figure 4. Catalysis of radical oxidations by transition-sernies metals may also play a role. Agents such as ectopic SOD may interfere with this process by destroying active oxygen species or increasing peroxide fluxes, thus interfering with one or more of the mechanisms detailed above and in Figure 4.
Since SOD is one of the most substrate-specific enzymes known, at first sight its efficacy in rheumatoid arthritis and other lesions strongly implies a role for active oxygen species in such diseases and a role for superoxide-destroying agents in their treatment. However, there are serious problems with such an assumption.
With this caution, active oxygen species may play a significant role in the etiology of other inflammatory lesions in man, For example, SOD is reported to be effective in the treatment of lupus erythematosis,(43,158) and unique light-activated, superoxide-dependent lymphocyte clastogenic factors present in the serum of patients with lupus and other collagen diseases may account for some of the photosensitivity of this group of disorders.(157-159). Both direct and indirect production of active oxygen species may also have a role in the pathophysiology of gout and other hyperuricemic syndromes.(24,26,173,138,203,204). For example, urate, a reducing agent, is present in the extracellular environment at concentrations approximating 0.3 mMolar (130). Like many reducing agents, it apparently has both antioxidative (3O-134) and autooxidative (24) properties. In fact, it may have taken over some of the functions of ascorbate in primates.(133). Likewise, xanthine oxidase is an effective producer of oxygen radical species, while urate itself stimulates the production of active species of oxygen by phagocytes (203,204) and may protect cycloepoxigenase from autooxidation.(131) The effectiveness of SOD in the treatment of urate-induced inflammatory disease in Dalmations suggests a role for superoxide in this lesion.(138).