Aldose Reductase Inhibitor Decreases Nerve Sorbitol Accumulation
NEW YORK (Reuters Health) - The aldose reductase inhibitor AS-3201 inhibits sorbitol accumulation in the nerves of patients with diabetic sensorimotor polyneuropathy, according to a report in the October issue of Diabetes Care.
Increased nerve sorbitol resulting from increased aldose reductase enzyme activity has been associated with nerve damage with decreased conduction velocity in animals with diabetes, the authors explain, suggesting that treatments that reduce nerve sorbitol levels might prevent or reverse nerve damage.
Dr. Vera Bril from University of Toronto, Ontario, and colleagues measured sorbitol and fructose levels in sural nerves from patients with diabetic sensorimotor polyneuropathy before and after 12 weeks of treatment with AS-3201, a selective, reversible, and potent inhibitor of the aldose reductase enzyme system.
Mean nerve sorbitol concentrations fell by 65.2% after treatment with AS-3201 5 mg/day and by 83.5% after treatment with AS-3201 20 mg/day, compared with the placebo group, the authors report.
Sural nerve fructose concentrations were inhibited to a similar degree, the report indicates.
There was a dose-dependent penetration of AS-3201 into sural nerves, the researchers note, but sural nerve levels of AS-3201 did not correlate with nerve sorbitol levels.
Patients treated with the higher dose of AS-3201 showed improvement in nerve conduction velocity, the investigators report, but vibratory perception threshold and Toronto Clinical Neuropathy Score did not change during this brief study.
"An effective disease-modifying treatment is on the horizon," Dr. Bril told Reuters Health. "For the first time, we may see disease regression with a disease modifying treatment."
"A long term phase III study [of AS-3201] has started," Dr. Bril said. Nerve function will be measured, and symptoms and signs will also be summarized in a clinical score to determine efficacy over a longer interval.
"There is great hope for the treatment of diabetic sensorimotor polyneuropathy," Dr. Bril concluded.
Source: Diabetes Care 2004;27:2369-2375. [ Google search on this article ]
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