Clinical and neurophysiological studies with the aldose reductase inhibitor, sorbinil, in symptomatic diabetic neuropathy

Abstract

Summary. The effect of sorbinil (200 mg daily for 4 weeks) was examined in 13patients, mean age 59.7years (range 42-72 years), with symptomatic diabetic neuropathy of mean duration 6years (range 1-18years). In this double-blind, placebo-controlled crossover trial, studies were made of motor, sensory and autonomic nerve function, severity of painful symptoms and duration of sleep. One patient was withdrawn because of an adverse reaction to sorbinil. In the other 12, constant mean values for glycosylated haemoglobin A1 between 11% and 12% indicated stable though not ideal diabetic control throughout the study. Example values for nerve conduction velocity on placebo and active treatment were: 44.3 +_ 5.9 and 44.8 + 5.1 metres/s (mean + SD) for median motor nerve, 38.4+8.2 and 37.2+7.7metres/s for median sensory nerve. Thus there was no significant effect of sorbinil on conduction velocity in these or any other of the motor and sensory nerves tested. Abnormal autonomic function was not improved by sorbinil. Subjective pain scores on a 10 cm visual analogue scale were 4.2 + 2.4 on placebo and 4.3 + 2.4 after sorbinil. Duration of sleep on placebo and active treatment was 6.1 _+ 1.6 and 6.2 + 1.7 h/night, respectively. We were not able to detect any beneficial effect of sorbinil on painful diabetic neuropathy in our patients.Key words: Aldose reductase inhibitor, sorbinil, diabetic neuropathy.Peripheral neuropathy is a common complication of diabetes mellitus and in some patients severe pain may be experienced which is refractory to conventional treatments. Impaired nerve function may be related to inadequate control of blood glucose levels [1,2]. Recently, improvement in glycaemic control using continuous subcutaneous insulin infusion [3,4] and intensive intermittent subcutaneous insulin injections [5] have been associated with an observed improvements in neurophysiological function. Unfortunately, there are many difficulties in implementing such regimens so that normal or near normal blood glucose levels cannot be achieved in many patients. Effective alternative treatments for symptomatic diabetic neuropathy would therefore be valuable.Sorbitol and fructose accumulate in the nerves of diabetic animals and man in proportion to the degree of hyperglycaemia [6,7] and have been implicated in the impaired nerve conduction [8,9]. Inhibition of aldose reductase, the first and rate-limiting enzyme in the polyol pathway, has a beneficial effect on nerve conduction in rats with spontaneous galactosaemia and with streptozotocin-induced diabetes [6,/0]. Sorbinil, a non-competitive inhibitor of aldose reductase, has recently become available for use in man. Initial reports have suggested that treatment with this inhibitor may improve motor and sensory nerve conduction velocities [11] and reduce painful symptoms and weakness [12] in patients with diabetic neuropathy. In the present study we have examined the effects of this drug in patients with symptomatic diabetic neuropathy. Subjects and methods Subjects and study designA ran...

Effects of Ponalrestat, an Aldose Reductase Inhibitor, on Neutrophil Killing of Escherichia Coli and Autonomic Function in Patients With Diabetes Mellitus

“…We observed no effect of ponalrestat on autonomic nerve function, and this result is consistent with previous studies (10)(11)(12). There are several reasons why ponalr- Values are means ± SD.…”

“…In addition, many studies in animals support the hypothesis that polyol pathway activation by hyperglycemia might cause nerve damage (7). The aldose reductase inhibitor class of drugs have been shown to prevent nerve damage in diabetic animals (7), but in humans, results of clinical trials with these drugs in diabetic autonomic neuropathy have been disappointing and have produced, at best, only slight treatment effects (8,9) or none at all (10)(11)(12). There have been no reported clinical trials in which the effects of aldose reductase inhibitor drugs on neutrophil function were assessed.…”

Aldose Reductase Inhibitors: The End of an Era or the Need for Different Trial Designs?

“…Short-term trials with improvement (reversal) of diabetic neuropathy as the objective and with either a parallel-controlled or a crossover design constitute the majority of the previous studies (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)24,26,28,29,35). Two long-term trials with the objective of slowing progression with a parallel-controlled design have been completed (36,43).…”

Diabetic Neuropathy Part 1

“…Despite numerous trials of various aldose reductase inhibitors, none have been shown to prevent neuropathy or the progression of deficits. 11,102–104 …”