EPALRESTAT, AN ALDOSE REDUCTASE INHIBITOR, IMPROVES AN IMPAIRED GENERATION OF OXYGEN-DERIVED FREE-RADICALS BY NEUTROPHILS FROM POORLY CONTROLLED NIDDM PATIENTS

OBJECTIVE - To study the in vivo effect of epalrestat (Epa), an aldose reductase inhibitor, on the generation of oxygen-derived free radical s by neutrophils from poorly controlled NIDDM patients (HbA(1c) >10%). RESEARCH DESIGN AND METHODS - A total of 31 diabetic patients were ra ndomly divided into two groups: an Epa(+) group of 16 patients treated with 150 mg/day epalrestat and an Epa(-) group of 15 patients treated without epalrestat. A control group of 20 age- and sex-matched normal healthy subjects also participated. HbA(1c), postprandial plasma gluc ose (PPG), and neutrophil bactericidal function were measured before a nd at the end of the drug treatment period (4 weeks). Neutrophil bacte ricidal function was measured as chemiluminescence amplified by a Cypr idina luciferin analog (CLA), which is dependent on O-2(-) generation, and by luminol (L), which is highly dependent on OCl- generation, in response to formyl-methonyl-leucyl-phenylalanine (fMLP). RESULTS - At the start of the experiment, both CLA-dependent chemiluminescence (CLA -DCL) and L-dependent chemiluminescence (L-DCL) were clearly decreased in diabetic subjects (64 and 54%, respectively; P < 0.05) compared wi th control subjects (2,182 +/- 144 and 3,221 +/- 173 kc.min(-1).10(-6) cells, respectively). At the end of the experiment, CLA-DCL and L-DCL in the Epa(+) group were significantly improved by 44 and 46%, respec tively; however, these values were still lower than the corresponding results in the control group. HbA(1c) and PPG in both the Epa(+) and E pa (-) groups were significantly higher than in the control group, and treatment had no effect on either HbA(1c) or PPG. CONCLUSIONS - These data suggest that epalrestat may be a useful drug to prevent infectio n by improving the impaired O-2(-) and OCl- generation by neutrophils from poorly controlled NIDDM patients.