Clinical studies with an aldose reductase inhibitor in the autonomic and somatic neuropathies of diabetes.
Clinical investigations with the aldose reductase inhibitor (ARI) sorbinil in diabetic patients with neuropathy are described. Cardiac autonomic neuropathy was studied in 36 patients, in a double-blind, placebo-controlled, randomized, noncrossover trial. Patients received sorbinil (250 mg qd) or placebo over 6 weeks after a one-week baseline period. Diabetic control did not change over the study period, as indicated by unchanged glycohemoglobin. Response was assessed by expiration/inspiration (E/I) ratios on EKG during 6 c/min respiration and resting minimum heart rate, both measures of vagal function. In the sorbinil group, E/I ratios improved from 1.074 +/- 0.012 to 1.096 +/- 0.020 (P less than 0.03) with a slight decrease in the placebo group from 1.112 +/- 0.023 to 1.105 +/- 0.023 (P = NS). The difference between the week 6 and week 0 changes in each group was significant (P less than 0.01). Resting minimum heart rate decreased in the sorbinil group from 76.4 +/- 2.3 to 66.8 +/- 2.4 beats/min (P less than 0.001), with a mean change of 10 +/- 2. In the placebo group, heart rate was unchanged (77.9 +/- 3.9 to 77.5 +/- 3.3). The two sample t tests of the within-group differences were likewise significant (P less than 0.001). These changes in both E/I ratio and resting minimum heart rate are consistent with a sorbinil-related improvement in cardiac parasympathetic nerve function. Several isolated cases with apparent sorbinil-related improvement in autonomic symptoms will also be described. Studies of somatic neuropathy have previously shown improvement in nerve conduction velocities with sorbinil. In a study of 11 patients with severely painful diabetic neuropathy treated with sorbinil for 3 weeks [placebo-controlled in single-blind fashion (n = 8)], pains (as assessed on a 0 to 20 rating scale) improved from a mean score of 16 down to 8, with deterioration following drug withdrawal. Objective improvements in sensation and strength were observed in some cases. In this group of patients, statistically significant improvements in nerve conduction velocity, E/I ratios, and resting minimal heart rate, similar to those previously discussed, were also documented. Somatosensory-evoked potentials studies in the 36-patient study showed significant improvements in peripheral conduction and cortical responses. Sorbinil toxicity in 106 patients was 11.3%, with sex incidence of 7/73 males (9.6%) and 5/33 females (15.2%).(ABSTRACT TRUNCATED AT 400 WORDS)
Jaspan
J B
JB
Towle
V L
VL
Maselli
R
R
Herold
K
K
D000328:Adult; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D001342:Autonomic Nervous System Diseases / Q000188:drug therapy* / Q000517:prevention & control; D002986:Clinical Trials as Topic; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000517:prevention & control; D004311:Double-Blind Method; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D048289:Imidazolidines; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D010543:Peroneal Nerve / Q000187:drug effects; D011897:Random Allocation; D012119:Respiration / Q000187:drug effects; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D048289:Imidazolidines; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; C026411:sorbinil