sorbinil and Peripheral-Nervous-System-Diseases

The effect of 250 mg day-1 of the aldose reductase inhibitor, Sorbinil, upon peripheral nerve function was assessed in 23 adult diabetics with clinical neuropathy. Sorbinil was given for 4 weeks to 10 subjects, while 13 received placebo in this double-blind study. Open label treatment with Sorbinil was then continued for 52 weeks in 10 of the 23 subjects. Red cell sorbitol, hemoglobin A1c, vibratory sensation, median nerve sensory and motor conduction velocities were measured at 0, 4 and 52 weeks. There were no measurable changes in peripheral nerve function after 4 weeks of Sorbinil treatment. After 52 weeks significant improvement was found in the median nerve motor and sensory conduction velocities. This was associated with no change in blood glucose control but a reduction of erythrocyte sorbitol levels.

Topics: Adult; Aged; Aldehyde Reductase; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Electromyography; Erythrocytes; Female; Humans; Imidazoles; Imidazolidines; Male; Median Nerve; Middle Aged; Neural Conduction; Peripheral Nervous System Diseases; Vibration

In this placebo-controlled double-blind clinical trial, ARI-treatment was accompanied by small but statistically significant improvements in clinical and electrophysiological indices. These improvements were associated with a lowering of nerve sorbitol levels and significant improvements in quantitative structural parameters. These data suggest that an activated polyol-pathway plays a continuous pathogenetic role even in advanced clinically overt diabetic neuropathy, and that the metabolic abnormalities mediated by the polyol pathway are intimately associated with structural and functional changes and ultimately clinical symptoms. The regenerative and reparative responses to a potent ARI like sorbinil suggest that advanced neuroanatomical changes believed to underlie overt clinic polyneuropathy are at least partly reversible, and that extrapolated over longer treatment periods ARI's may substantially ameliorate the structural changes and the clinical symptoms associated with diabetic neuropathy. As indicated by animal studies ARI's may become valuable adjuncts to the therapeutical arsenal not only in the treatment of diabetic neuropathy and other chronic diabetic complications, but also as a prophylactic regimen, provided that safe compounds can be developed.

Topics: Aldehyde Reductase; Axons; Diabetic Neuropathies; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Nerve Regeneration; Neurons; Peripheral Nervous System Diseases; Ranvier's Nodes; Sorbitol

Clinical investigations with the aldose reductase inhibitor sorbinil in patients with peripheral neuropathy due to diabetes are described. After an improvement in motor and sensory nerve conduction velocities was demonstrated in asymptomatic diabetic patients taking sorbinil (compared with velocities during a placebo period), 11 patients with painful diabetic neuropathy were treated with sorbinil for three weeks without alterations in diabetic management or control. Therapy was placebo-controlled in a single-blind fashion in eight patients. Pain (assessed by or on a zero to 20 rating scale), which had been constant for many months before entry into the study and unresponsive to numerous medications, improved from a mean score of 16 to 8 and returned when the drug was discontinued. Objective improvement in sensation and strength were observed in some cases. Improvements in nerve conduction velocity and cardiac autonomic function were also documented. Cardiac autonomic neuropathy was studied in 36 patients in a double-blind, placebo-controlled, randomized, noncrossover trial. Patients received one 250-mg sorbinil tablet or one placebo tablet daily for six weeks, after a one-week baseline period. Glycemic control did not change during the study period, as indicated by unaltered glycohemoglobin levels. Response was assessed by expiration-inspiration ratios, obtained on electrocardiography during six cycles per minute respiration, and by resting minimal heart rate, both measures of vagal function. In the sorbinil-treated group, expiration-inspiration ratios improved from 1.074 +/- 0.012 to 1.096 +/- 0.020 (p less than 0.03). There was a slight decrease in the ratios in the placebo-treated group, from 1.112 +/- 0.023 to 1.105 +/- 0.023 (not significant). The difference between the Week 0 to Week 6 changes in each group was significant (p less than 0.01). Resting minimal heart rate decreased in the sorbinil-treated group from 76.4 +/- 2.3 to 66.8 +/- 2.8 +/- 2.4 beats per minute (p less than 0.001), with a mean change of 10 +/- 2. In the placebo-treated group, heart rate was unchanged (77.9 +/- 3.9 to 77.5 +/- 3.3 beats per minute). The two-sample t test of the within-group differences was also significant (p less than 0.001). The changes in both expiration-inspiration ratios and resting minimal heart rate are consistent with a sorbinil-related improvement in cardiac parasympathetic nerve function. Several isolated cases of apparent sorbinil-related improvements

Topics: Adolescent; Adult; Aged; Aldehyde Reductase; Autonomic Nervous System Diseases; Diabetic Neuropathies; Double-Blind Method; Drug Eruptions; Electrocardiography; Evoked Potentials, Somatosensory; Female; Heart Rate; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Neural Conduction; Neuralgia; Peripheral Nervous System Diseases; Random Allocation; Sugar Alcohol Dehydrogenases

We examined the hypothesis that the polyol accumulation resulting from chronic galactose supplementation in the diet produces endoneurial edema that can be prevented by inhibition of aldose reductase. We explored the potential of nuclear magnetic resonance (NMR) spectroscopy to quantitate and characterize the water accumulation in the sciatic nerve in this "galactose neuropathy." The data demonstrate a 16% increase in gravimetrically determined total water content of nerve in the galactose-fed rat after 8 mo of this diet and a 50% increase in the T1 relaxation time for nerve water as determined by NMR spectroscopy. Prolongation of the T1 relaxation time reflects increased rotation of water in a magnetic field, consistent with an extracellular site of the additional water. Simultaneous feeding of sorbinil to inhibit aldose reductase resulted in normalization of both total nerve water and of the prolongation of T1 relaxation time. These data define the NMR-spectroscopic state of endoneurial edema in the galactose-fed rat and suggest specific application to the investigation of the role of aldose reductase in human diabetic neuropathy.

Topics: Animals; Galactose; Humans; Imidazoles; Imidazolidines; Magnetic Resonance Spectroscopy; Male; Peripheral Nervous System Diseases; Rats; Rats, Inbred Strains; Sciatic Nerve

Nerve conduction slowing, a hallmark of both experimental and human diabetic neuropathy, is improved or corrected by administration of aldose reductase inhibitors such as sorbinil. Recent experiments in animals attribute acutely reversible nerve conduction slowing in diabetes to a myo-inositol-related defect in nerve sodium-potassium adenosinetriphosphatase, which generates the transmembrane sodium and potassium potentials necessary for nerve impulse conduction and the sodium gradient necessary for sodium-dependent uptake of substrates. This myo-inositol-related abnormality in sodium-potassium adenosinetriphosphatase function is currently viewed as a cyclic metabolic defect involving sequential alteration of sodium-dependent myo-inositol uptake, myo-inositol content, myo-inositol incorporation into membrane phospholipids, and phospholipid-dependent sodium-potassium adenosinetriphosphatase function in peripheral nerve. Aldose reductase inhibitors have been shown to normalize both nerve myo-inositol content and nerve sodium-potassium adenosinetriphosphatase activity. These observations suggest that the acute effects of aldose reductase inhibitors on nerve conduction in both animals and humans with diabetes may be mediated by correction of an underlying myo-inositol-related nerve sodium-potassium adenosinetriphosphatase defect. Furthermore, this sorbinil-corrected sodium-potassium adenosinetriphosphatase defect in diabetic nerve may contribute to other biochemical, functional, and structural abnormalities present in diabetic peripheral neuropathy.

Topics: Aldehyde Reductase; Animals; Biological Transport; Diabetic Neuropathies; Humans; Imidazoles; Imidazolidines; Inositol; Neural Conduction; Peripheral Nerves; Peripheral Nervous System Diseases; Sodium-Potassium-Exchanging ATPase; Sorbitol; Sugar Alcohol Dehydrogenases