Increased flux through the polyol pathway mediated by the enzyme aldose reductase may be associated with the development of diabetic neuropathy. Fifty-four diabetic patients (median age 56 yr, range 25–65 yr) with chronic neuropathic symptoms were randomly allocated to placebo or aldose reductase inhibition (300 or 600 mg ponalrestat IC1128436) groups for 24 wk. Patients with vibration perception thresholds (VPTs) >35 V at the great toe or thermal difference thresholds (TTs) >10°C on the dorsum of the foot were excluded from the trial. No significant changes were observed in symptoms of pain, numbness, or paresthesia between ponalrestat and placebo groups, and there were no improvements in VPT or TT at several sites. Posterior tibial nerve conduction velocity changed from 35.3 ± 4.9 m/s at baseline to 33.4 ±4.0 m/s at 24 wk (NS) with placebo compared with 37.6 ± 5.6 vs. 37.2 ± 8.7 m/s (NS) with 300 mg ponalrestat and 34.5 ± 6.1 vs. 36.2 ± 6.8 m/s (NS) with 600 mg ponalrestat. Further studies are indicated with intervention at an earlier stage in the evolution of neuropathy and for longer periods.

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