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© 2004 by the American Diabetes Association, Inc.
Pathophysiology/Complications |
Aldose Reductase Inhibition by AS-3201 in Sural Nerve From Patients With Diabetic Sensorimotor Polyneuropathy
1 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
2 Dainippon Pharmaceuticals, Ann Arbor, Michigan
Address correspondence and reprint requests to Vera Bril, MD, EN11-209, Toronto General Hospital, University Health Network, 200 Elizabeth St., Toronto, Ontario, Canada, M5G 2C4. E-mail: vera.bril{at}utoronto.ca
OBJECTIVE—The primary purpose of this investigation was to determine whether AS-3201, a new aldose reductase inhibitor, penetrates the sural nerve and inhibits sorbitol and fructose accumulation in patients with diabetic sensorimotor polyneuropathy (DSP). An additional aim was to determine whether any changes in nerve function would manifest with AS-3201 therapy.
RESEARCH DESIGN AND METHODS—Patients with mild to moderate DSP based on nerve conduction studies were randomized into one of three treatment groups in a double-blind fashion: placebo or AS-3201 at 5 or 20 mg/day. After 12 weeks of administration, the sural nerve was biopsied for measurement of sorbitol, fructose, and AS-3201.
RESULTS—At baseline, no important clinical, electrophysiological, or laboratory differences were found between the three groups. The nerve sorbitol concentration of 3.14 x 10–2 nmol/mg wet nerve in patients in the placebo group was inhibited by 65 and 84% in patients on AS-3201 at 5 and 20 mg/day, respectively (P < 0.001). Fructose levels were similarly inhibited. Sensory nerve conduction velocities improved by 
1 m/s (P < 0.05).
CONCLUSIONS—AS-3201 penetrates the sural nerve and inhibits sorbitol accumulation in patients with DSP. Additional studies are needed to confirm the electrophysiological suggestion that AS-3201 delays progression or leads to regression of DSP.
Abbreviations: ARI, aldose reductase inhibitor • DSP, diabetic sensorimotor polyneuropathy • NCS, nerve conduction study • NCV, nerve conduction velocity • TCNS, Toronto Clinical Neuropathy Score • VPT, vibration perception threshold
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