Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Three-year inhibition of aldose reductase on development of symptomatic neuropathy in diabetic patients. Natural progression of diabetic peripheral neuropathy in the Zenarestat study population. Tolrestat for mild diabetic neuropathy. A 52-week, randomized, placebo-controlled trial. Peripheral and autonomic nerve function in 259 diabetic patients with peripheral neuropathy treated with ponalrestat (an aldose reductase inhibitor) or placebo for 18 months. United Kingdom/Scandinavian Ponalrestat Trial. Tolrestat in the primary prevention of diabetic neuropathy. Limited benefit of treatment of diabetic polyneuropathy with an aldose reductase inhibitor: a 24-week controlled trial. Clinical and neurophysiological studies of aldose reductase inhibitor ponalrestat in chronic symptomatic diabetic peripheral neuropathy. Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study. Effect of Tolrestat on oesophageal transit time and cholecystic motility in type 2 diabetic patients with asymptomatic diabetic neuropathy. [Diabetic neuropathy: treatment trial with an aldose reductase inhibitor (Sorbinil)]. [Tolrestat in the therapy of diabetic peripheral neuropathy: is this drug really useful?]. One-year treatment with the aldose reductase inhibitor, ponalrestat, in diabetic neuropathy. Long-term effects of tolrestat on symptomatic diabetic sensory polyneuropathy. Six-month treatment with sorbinil in asymptomatic diabetic neuropathy. Failure to improve abnormal nerve function. Neurophysiological variables and fibrinolysis in insulin-dependent diabetes treated with an aldose reductase inhibitor or placebo. A double-blind randomized study. The sorbinil retinopathy trial: neuropathy results. Sorbinil Retinopathy Trial Research Group. Aldose reductase inhibition ameliorates pupillary light reflex and F-wave latency in patients with mild diabetic neuropathy. Aldose reductase inhibition in diabetic neuropathy: clinical and neurophysiological studies of one year's treatment with sorbinil. Cardiac abnormalities in diabetic patients with neuropathy: effects of aldose reductase inhibitor administration. A multicentre trial of the aldose-reductase inhibitor tolrestat, in patients with symptomatic diabetic peripheral neuropathy. North European Tolrestat Study Group. A multicentre trial of the aldose-reductase inhibitor, tolrestat, in patients with symptomatic diabetic neuropathy. Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. Treatment of diabetic autonomic neuropathy with an aldose reductase inhibitor. Diabetic neuropathy in the upper limb and the effect of twelve months sorbinil treatment. A 12-month randomized controlled study of the aldose reductase inhibitor ponalrestat in patients with chronic symptomatic diabetic neuropathy. Prolonged aldose reductase inhibition in chronic peripheral diabetic neuropathy: effects on microangiopathy.
To determine whether the aldose reductase inhibitor (ARI) zenarestat improves nerve conduction velocity (NCV) and nerve morphology in diabetic peripheral polyneuropathy (DPN).
                A 52-week, randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with the ARI zenarestat was conducted in patients with mild to moderate DPN. NCV was measured at baseline and study end. Contralateral sural nerve biopsies were obtained at 6 weeks and at the study's end for nerve sorbitol measurement and computer-assisted light morphometry to determine myelinated nerve fiber density (number of fibers/mm2 cross-sectional area) in serial bilateral sural nerve biopsies.
                Dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by significant improvement in NCV. In a secondary analysis, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter (<5 microm) sural nerve myelinated fibers.
                Aldose reductase pathway inhibition improves NCV slowing and small myelinated nerve fiber loss in DPN in humans, but >80% suppression of nerve sorbitol content is required. Thus, even low residual levels of aldose reductase activity may be neurotoxic in diabetes, and potent ARIs such as zenarestat may be required to stop or reverse progression of DPN. nan The aim of this study was to report the baseline and natural progression of diabetic peripheral neuropathy over 12 months in a large mild-to-moderate neuropathy population.
                Patients from a multicentered trial of zenarestat, an aldose reductase inhibitor, had serial measures of neurologic function, including nerve conduction studies (NCSs), quantitative sensory testing (QST), and clinical neuropathy rating scores at baseline and at 12 months. Baseline population descriptors and changes in neurologic function in placebo-treated patients were analyzed.
                Sural sensory velocity (P = 0.0008 [95% CI -1.04 to -0.27]), median sensory amplitude (P = 0.0021 [-1.3 to -0.29]), median distal motor latency (P = 0.002 [0.09-0.28]), cool thermal QST (P = 0.0005 [0.27-0.94]), and Michigan Neuropathy Screening Instrument results (P = 0.0087 [0.04-0.30]) declined significantly from baseline in the placebo population. NCS changes from baseline were independent of baseline HbA1c stratification.
                The neurologic decline over 12 months is evident when measured by NCS and cool thermal QST. Other measures (vibration QST, neuropathy rating scores, monofilament examination) are insensitive to changes over 12 months in a mild-to-moderate affected population of this size. To evaluate the effectiveness and safety of tolrestat, an aldose-reductase inhibitor, in patients with mild diabetic autonomic and peripheral neuropathy.
                Randomized, placebo-controlled, double-blind 52-week trial.
                University hospital clinic.
                Forty-five diabetic patients with asymptomatic autonomic neuropathy identified by at least one pathologic cardiovascular reflex test result.
                All patients were given placebo during a 4-week run-in period (single-blind). Twenty patients were randomly assigned to continue to receive placebo, and 25 were assigned to treatment with tolrestat (200 mg/d given in the morning).
                At 12 months, improvements in nerve functions occurred in patients receiving tolrestat. Compared with baseline values, postural hypotension decreased by a value of 5.9 mm Hg (95% Cl, 1.6 to 8.7); deep-breathing, maximum/minimum heart rate (expiration/inspiration ratio) increased by a value of 0.026 (Cl, 0.015 to 0.036); and lying-to-standing heart rate ratio (30:15 ratio) increased by a value of 0.032 (Cl, 0.027 to 0.052). In the placebo group, all test results except postural hypotension deteriorated. Vibration perception threshold at the malleolus and great toe of the dominant leg improved in the tolrestat group (-1.4; Cl, -3.69 to -1.09) but tended to worsen in the placebo group during the study period. No important side effects were detected in either group.
                The progression of mild diabetic autonomic and peripheral neuropathy may be halted or even reversed by pharmacologic intervention with the aldose-reductase inhibitor tolrestat. The potential of the aldose reductase inhibitor ponalrestat (600 mg daily) to ameliorate diabetic neuropathy was evaluated in 259 diabetes mellitus patients with peripheral neuropathy (defined by abnormal vibration perception threshold and abnormal peroneal motor conduction velocity) in a double-blind placebo-controlled clinical trial running for 18 months. Overall, no beneficial effect of ponalrestat on vibration perception thresholds, nerve conduction velocities, and nerve action potential amplitudes was detected. Because vibration perception thresholds and conduction velocities in median, peroneal, and sural nerves did not deteriorate in the placebo group, the potential of ponalrestat to prevent the expected deterioration in peripheral nerve function that occurs with an increased duration of diabetes was not tested. Patients with an abnormal heart rate reaction to standing (abnormal 30:15 ratio; n = 84) on ponalrestat did not deteriorate in this autonomic nerve function test as shown in those on placebo. In conclusion, ponalrestat did not improve peripheral nerve function in diabetes mellitus patients with signs of peripheral neuropathy, although it did ameliorate a deterioration in autonomic nerve function in diabetic patients with signs of autonomic neuropathy. To compare the effects of tolrestat and placebo in patients with subclinical diabetic neuropathy.
                Non-insulin-dependent diabetes mellitus (NIDDM) patients with early involvement of the autonomic nervous system were identified by only one pathological (outside the 99% confidence interval of the normal population) squatting test (vagal or sympathetic). Fifty-seven patients entered a randomized, placebo-controlled, double-blind, parallel 52-week study of tolrestat at a dose of 200 mg/day. Cardiovascular reflex tests (squatting vagal and sympathetic tests, pressure gain, deep breathing, lying-to-standing, Valsalva maneuver, and orthostatic hypertension), vibration thresholds, tendon reflexes, and muscle strength were assessed throughout the study.
                At 12 months, nerve function significantly improved in patients receiving tolrestat and deteriorated in patients taking placebo. At baseline, the squatting vagal test was normal in 16 patients in the tolrestat group and in 15 patients in the placebo group. At 12 months, 25 patients taking tolrestat had a normalized squatting test, but only 6 patients taking placebo did (P = 0.02). Vibration perception threshold improved by a value of 6 +/- 3 V in the tolrestat group (P < 0.001) and deteriorated by a value of 3 +/- 1.8 V (P < 0.001) in the placebo group.
                Tolrestat may be useful in the primary prevention of diabetic neuropathy. The effects of the aldose reductase inhibitor, sorbinil, on symptomatic symmetrical diabetic polyneuropathy were studied during a 6-month period in a double-blind parallel group placebo-controlled trial. Twenty-seven patients received sorbinil and 28 placebo. The patients were assessed by clinical examination, neurophysiological measurements, sensory threshold determinations and tests of autonomic nerve function. No major clinical benefit was seen in the sorbinil-treated patients and no differences in sensory thresholds were observed. In three out of nine neurophysiological tests (motor nerve conduction velocity of the posterior tibial nerve, F-wave latency and sensory distal latency of the ulnar nerve) and one out of five tests of autonomic nerve function (heart rate variation during deep breathing) significant differences between the patient groups evolved in favour of sorbinil treatment. An overall evaluation of the temporal development of these and remaining neurophysiological and autonomic variables suggested a small but significant benefit from sorbinil treatment. There was no evidence of continuing improvement throughout the treatment period and beneficial effects observed were no greater than those seen in previous trials of considerably shorter treatment periods. It is concluded that sorbinil treatment results in some improvement in peripheral nerve function in symptomatic diabetic polyneuropathy, but that the long-term effect may be of limited value. 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 ICI 128436) groups for 24 wk. Patients with vibration perception thresholds (VPTs) greater than 35 V at the great toe or thermal difference thresholds (TTs) greater than 10 degrees 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. The purpose of this study was to evaluate the efficacy of fidarestat, a novel aldose reductase (AR) inhibitor, in a double-blind placebo controlled study in patients with type 1 and type 2 diabetes and associated peripheral neuropathy.
                A total of 279 patients with diabetic neuropathy were treated with placebo or fidarestat at a daily dose of 1 mg for 52 weeks. The efficacy evaluation was based on change in electrophysiological measurements of median and tibial motor nerve conduction velocity, F-wave minimum latency, F-wave conduction velocity (FCV), and median sensory nerve conduction velocity (forearm and distal), as well as an assessment of subjective symptoms.
                Over the course of the study, five of the eight electrophysiological measures assessed showed significant improvement from baseline in the fidarestat-treated group, whereas no measure showed significant deterioration. In contrast, in the placebo group, no electrophysiological measure was improved, and one measure significantly deteriorated (i.e., median nerve FCV). At the study conclusion, the fidarestat-treated group was significantly improved compared with the placebo group in two electrophysiological measures (i.e., median nerve FCV and minimal latency). Subjective symptoms (including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia) benefited from fidarestat treatment, and all were significantly improved in the treated versus placebo group at the study conclusion. At the dose used, fidarestat was well tolerated, with an adverse event profile that did not significantly differ from that seen in the placebo group.
                The effects of fidarestat-treatment on nerve conduction and the subjective symptoms of diabetic neuropathy provide evidence that this treatment alters the progression of diabetic neuropathy. The aim of the present study was to investigate the influence of Tolrestat, an aldose-reductase inhibitor, on both oesophageal and cholecystic motility in Type-2 diabetic patients with asymptomatic diabetic neuropathy. Sixty-six patients were randomly assigned to receive Tolrestat 200 mg once daily (33 patients) or were left without specific treatment (33 patients) for 12 months. Efficacy and safety evaluation were done at 4.5 and 12 months by persons blinded to the patient treatment regimen. Scintigraphic evaluation of oesophageal motility showed significant changes in transit time for Tolrestat at 12 months (p < 0.001). There was no significant effect of Tolrestat on cholecystic function in cholecystography, although diabetic patients taking Tolrestat showed a trend toward improvement. The vibration perception threshold at two sites of the dominant leg improved by at least 3 volts in the Tolrestat group and remained unchanged or slightly deteriorated in the control group. Tendon reflexes and blood pressure fall after standing were improved in the Tolrestat group. In conclusion, one-year treatment with Tolrestat significantly improved oesophageal motility and vibration perception in Type-2 diabetic patients with asymptomatic diabetic neuropathy. nan The authors have studied the effect of the treatment with an aldose reductase inhibitor, tolrestat, on the peripheral diabetic neuropathy during a placebo controlled randomised trial. 74 diabetics affected by peripheral neuropathy were divided in two groups of 39 (group A) and 35 (group B) patients comparable as to age, sex, duration of diabetes and severity of the neurological symptoms. The group A was treated with tolrestat orally 200 my once daily for six months, the group B was treated with placebo. After six months an improvement of analysed symptoms (pain and paraesthesias) and objective assessments (NCV-DB) was observed in patients treated with tolrestat (group A) significantly higher than in patients treated with placebo (group B). A light improvement was found also during a control effected after three months of treatment with tolrestat. The improvement after six months of therapy was mild but significant; therefore the authors conclude that the tolrestat is an useful drug in the treatment of the peripheral diabetic neuropathy in addition to attainment of a better glycemia's control. A double blind placebo controlled trial was performed to evaluate the effects of the aldose reductase inhibitor, ponalrestat, on symptomatic diabetic neuropathy. After a 4-week placebo run-in phase, 60 patients were 2:1 randomized to receive either 600 mg ponalrestat or placebo once daily over 12 months. Forty-six patients, 30 of whom were treated with ponalrestat and 16 with placebo, completed the study. Motor and sensory nerve conduction, thermal and vibration sensation thresholds, heart rate variation at rest, E/I ratio, pupillary dilation velocity and pupillary reflex latency were determined at baseline and after 6 and 12 months. Neuropathic symptom scores were assessed every 3 months. Among the fifteen nerve function parameters studied, only trends in favour of ponalrestat were noted for heart rate variation and E/I ratio after 6 months (P = 0.06), but no significant differences between the groups could be demonstrated during the study. No adverse reactions were observed. It is concluded that one-year treatment with ponalrestat has no beneficial effects on symptoms or electrophysiological parameters in diabetic neuropathy. Tolrestat is an aldose reductase inhibitor that is undergoing extensive clinical investigation for the treatment of diabetic complications including polyneuropathy. As part of a larger European trial, we report here the results from a single clinical center on the efficacy of tolrestat in patients with confirmed diabetic neuropathy. The trial was conducted in two phases: a 6-month double-blind, placebo-controlled phase, and a 6-month open-label phase in which most patients were treated with tolrestat. Following the double-blind phase, motor and sensory nerve conduction velocity had significantly deteriorated in the placebo group, which did not occur during treatment with tolrestat. Deterioration of vibration threshold also occurred during placebo treatment and did not occur with tolrestat. During the open-label phase, motor nerve condition velocity and vibration threshold improved with tolrestat. Moreover, the deterioration of motor nerve conduction velocity and vibration threshold that had occurred in patients initially treated with placebo, was stopped during open-label treatment with tolrestat. The effect of long-term treatment with the aldose reductase inhibitor sorbinil (125 mg daily for 6 mo) was examined in 22 diabetic patients with subclinical abnormalities of nerve function. This was a placebo-controlled, double-blind crossover trial in which each of the two treatment periods lasted 6 mo. Peripheral nerve function was assessed electrophysiologically and by quantitative sensory testing; autonomic function was assessed by measurement of five cardiovascular reflexes and of mean heart rate from a 24-h ECG recording. Measurement of erythrocyte sorbitol concentrations demonstrated very significant inhibition of aldose reductase activity with sorbinil treatment, but no concomitant improvement in either peripheral or autonomic nerve function was observed. In a double-blind study we randomized insulin-dependent diabetics (n = 19) into a group (n = 12) given daily 250 mg Sorbinil, a potent aldose reductase inhibitor reported to ameliorate diabetic neuropathy, and another group (n = 7) given placebo for 1 year. Objective, neurophysiological variables (biothesiometry, electromyography, nyctometri) were followed throughout the study and correlated with fibrinolytic variables in blood. We found that Sorbinil did not improve any of the selected neurophysiological variables. Neither did Sorbinil induce marked changes in the fibrinolytic activities of the extrinsic, tissue-type plasminogen activator (t-PA), or in the intrinsic factor XII-dependent or factor XII-independent (urokinase-like) plasminogen activator systems. We found no effect of Sorbinil on the activity of the fast-reacting inhibitor (PA-I) of plasminogen activator. Levels of PA-I in plasma influence the amounts of t-PA precipitated in euglobulins. We randomized 497 patients, aged 18 to 56 years with insulin-dependent diabetes mellitus for 1 to 15 years' duration, to treatment with sorbinil, an aldose reductase inhibitor, or to a placebo. Nearly 30% of patients showed worsening of clinical measures of distal symmetric polyneuropathy at maximum follow-up, with very little difference in rates in the two groups. We studied nerve conduction in 192 patients. For the median motor, median sensory, and peroneal nerves, there were no benefits in maximum amplitudes over the follow-up period. For the median motor and median sensory nerves, changes in velocities were not significantly different in the two randomized treatment groups. For the peroneal nerve, at the 30-month and maximum follow-up visits, the distribution of changes in nerve conduction velocity showed an overall improvement in the sorbinil group and a decline in the placebo group. The difference in distributions was statistically significant. Overall, we found no evidence that the early clinical signs and symptoms of diabetic neuropathy were altered by sorbinil. The present study was conducted to investigate the effect of an aldose reductase inhibitor, epalrestat, on autonomic and somatic neuropathy at an early stage in type 2 diabetic patients by assessing the pupillary light reflex and minimum latency of the F-wave.
                A total of 30 diabetic patients with subclinical or mild diabetic neuropathy were randomly allocated to a control group (n = 15) and epalrestat (150 mg/day) group (n = 15). After 24 weeks, the pupillary light reflex test, cardiovascular autonomic function tests, and nerve conduction study were performed.
                The beneficial effect of epalrestat on the pupillary light reflex was observed in the minimum diameter after light stimuli (P = 0.044), constriction ratio (P = 0.014), and maximum velocity of constriction (P = 0.008). Among cardiovascular autonomic nerve functions, the ratio of the longest expiratory R-R interval to the shortest inspiratory R-R interval during deep breathing was significantly improved by epalrestat (P = 0.037). Minimum latencies of F-wave of median and tibial motor nerves were significantly shortened by epalrestat (P = 0.002 and P = 0.001, respectively); however, no significant effects were observed in motor or sensory nerve conduction velocity.
                These observations suggest that epalrestat may have therapeutic value at the early stage of diabetic neuropathy and that the pupillary light reflex and minimum latency of F-wave may be useful indicators of diabetic neuropathy. In a double-blind placebo-controlled trial the effect of Sorbinil (250 mg daily) on diabetic neuropathy was examined. After a 2-month run-in placebo period (with three major assessments) 21 patients were randomized to Sorbinil and 10 to placebo, and all were studied for a further 12 months with neurophysiological measurements at 3-month intervals of nerve conduction velocity in multiple nerves, autonomic function tests, vibration thresholds as well as clinical examination and an extensive self-assessment of symptoms. Two subjects on Sorbinil treatment developed a hypersensitivity reaction and were withdrawn. Metabolic control and severity of neuropathy was not significantly different between groups. There were no changes in symptoms as judged by self-assessment scores. No patient entered the trial with neuropathic ulcers but ulceration developed in 4 patients during Sorbinil treatment and in 1 of the placebo group. No beneficial effect of Sorbinil was demonstrated on either the clinical manifestation or on the neurophysiological measurements made in these neuropathic diabetic patients over 12 months of treatment. The goal of this study was to determine whether treatment with an aldose reductase inhibitor (ARI) has beneficial effects on asymptomatic cardiac abnormalities in diabetic patients with neuropathy.
                Diabetic subjects with neuropathy (n = 81) with either a low diastolic peak filling rate or impaired augmentation of left ventricular (LV) ejection fraction (LVEF) during maximal bicycle exercise were identified by gated radionuclide ventriculography. Coronary artery disease, left ventricular hypertrophy, and valvular heart disease were excluded by clinical evaluation, myocardial perfusion imaging, and echocardiography. Subjects were randomized to receive blinded treatment with either the placebo or the ARI zopolrestat 500 or 1,000 mg daily for 1 year.
                After 1 year of ARI treatment, there were increases in resting LVEF (P < 0.02), cardiac output (P < 0.03), LV stroke volume (P < 0.004), and exercise LVEF (P < 0.001). In placebo-treated subjects, there were decreases in exercise cardiac output (P < 0.03), stroke volume (P < 0.02), and end diastolic volume (P < 0.04). Exercise LVEF increased with ARI treatment independent of blood pressure, insulin use, or the presence of baseline abnormal heart rate variability. There was no change in resting diastolic filling rates in either group.
                Diabetic patients with neuropathy have LV abnormalities that can be stabilized and partially reversed by ARI treatment. One hundred and ninety patients with symptomatic diabetic peripheral neuropathy took part in a double blind multicentre trial of either placebo or tolrestat 200 mg once daily for 6 months. Painful and paraesthetic symptoms, vibration sensory threshold, and nerve conduction velocity (NCV) were assessed as efficacy end-points during the trial. There was an equally marked improvement of painful symptoms during the trial in the tolrestat and placebo groups. A difference in the improvement of paraesthetic symptoms was found however in favour of the placebo group at 24 weeks (p less than 0.02). The deterioration in mean vibration threshold of the tolrestat group was less than placebo at 24 weeks at all 3 sites measured, and reached significance at the carpal site (p less than 0.05). Significant improvements in median motor NCV and in the mean NCV of the four motor nerves were also seen in tolrestat treated patients at 24 weeks compared to placebo (p less than 0.05). In addition, significant changes in favour of tolrestat were seen when the number of motor nerves per patient with NCV increased during the trial was analysed (p less than 0.001). Concordance analysis of patients with increased mean motor NCV and improvement in painful symptoms demonstrated a positive effect for tolrestat compared to placebo (p less than 0.02). Mild reversible elevations of hepatic transaminases were seen in a few patients treated with tolrestat, with no other significant adverse effects. Tolrestat may therefore be helpful in diabetic peripheral neuropathy, where there is little opportunity for therapeutic intervention apart from effort to achieve normoglycaemic control. The effects of the aldose-reductase inhibitor, tolrestat, on chronic symptomatic diabetic sensorimotor neuropathy were studied during a placebo-controlled, randomised, 52-week multicentre trial. Of the four tolrestat doses investigated, only the highest dose group, 200 mg once daily, showed subjective and objective benefit over baseline and placebo, and further analyses are confined to this group (n = 112) and placebo (n = 107). Painful and paraesthetic symptoms were analysed separately: improvement in paraesthetic symptoms were seen at one year (p = 0.04), though painful symptoms improved on both placebo and active therapies. Significant improvement in both tibial and peroneal motor nerve conduction velocities were seen at 52 weeks. Tolrestat 200 mg once daily was significantly better than placebo in producing concordant improvements in both motor nerve conduction velocities and paraesthetic symptom scores at 24 weeks (p = 0.01), 42 weeks (p = 0.01) and 52 weeks (p = 0.02). Long-term benefit [concordant improvement at 24 weeks maintained until 52 weeks] was seen in 28% of treated patients compared to 5% on placebo (p = 0.001). It is concluded that some sustained improvement in symptomatic diabetic neuropathy may be obtained following aldose-reductase inhibition with tolrestat 200 mg once daily. There is reason to believe that diabetic neuropathy may be related to the accumulation of sorbitol in nerve tissue through an aldose reductase pathway from glucose. Short-term treatment with aldose reductase inhibitors improves nerve conduction in subjects with diabetes, but the effects of long-term treatment on the neuropathologic changes of diabetic neuropathy are unknown. To determine whether more prolonged aldose reductase inhibition reverses the underlying lesions that accompany symptomatic diabetic peripheral polyneuropathy, we performed a randomized, placebo-controlled, double-blind trial of the investigational aldose reductase inhibitor sorbinil (250 mg per day). Sural-nerve biopsy specimens obtained at base line and after one year from 16 diabetic patients with neuropathy were analyzed morphometrically in detail and compared with selected electrophysiologic and clinical indexes. In contrast to patients who received placebo, the 10 sorbinil-treated patients had a decrease of 41.8 +/- 8.0 percent in nerve sorbitol content (P less than 0.01) and a 3.8-fold increase in the percentage of regenerating myelinated nerve fibers (P less than 0.001), reflected by a 33 percent increase in the number of myelinated fibers per unit of cross-sectional area of nerve (P = 0.04). They also had quantitative improvement in terms of the degree of paranodal demyelination, segmental demyelination, and myelin wrinkling. The increase in the number of fibers was accompanied by electrophysiologic and clinical evidence of improved nerve function. We conclude that sorbinil, as a metabolic intervention targeted against a specific biochemical consequence of hyperglycemia, can improve the neuropathologic lesions of diabetic neuropathy. To evaluate the effects of the aldose reductase inhibitor Ponalrestat (Statil) on diabetic autonomic neuropathy, a double-blind placebo controlled trial was carried out on a group of 34 diabetic patients with documented cardiac autonomic neuropathy. After a 4-week, placebo run-in period, patients were randomised for treatment with 600 mg Statil or placebo for another 24 weeks. Moreover, the reliability of the autonomic nerve function tests was investigated by comparing the results at onset and at week 4. Fifteen patients treated with Statil and 12 with placebo completed the study. Neither symptom scores nor cardiovascular reflexes, pupil reflexes and skin vasomotor reflexes improved after Statil therapy, which led us to conclude that Statil is not effective in the treatment of diabetic autonomic neuropathy. Reliability coefficients for cardiovascular reflexes and pupil reflex showed high values, ranging from 60% to 80%. Therefore these methods are recommended in future therapy trials. Clinical and neurophysiological studies were undertaken, with particular reference to the arms, in 39 patients with diabetic neuropathy. The effects of an aldose reductase inhibitor, sorbinil, on neuropathy in these patients were studied in a 12 month double blind placebo controlled trial. Neurophysiological measurements, particularly of sensory amplitude, were considerably more sensitive than measurements of temperature and vibration sensation and remain of fundamental importance in measuring diabetic neuropathy at an early and potentially reversible stage. There was no significantly beneficial effect of sorbinil on clinical or neurophysiological measurements of nerve function in patients with established diabetic neuropathy. These results indicate that neurophysiological techniques are necessary, in conjunction with clinical measurements, for the assessment of 'early' diabetic neuropathy and that aldose reductase inhibitors are not effective in the treatment of established diabetic neuropathy. The effects of the aldose reductase inhibitor ponalrestat (600 mg day-1) on sensory, electrophysiological, and autonomic function were examined in 50 patients with chronic symptomatic, distal symmetrical diabetic neuropathy in a 52-week randomized, double-blind, parallel-group, placebo-controlled, single-centre study. In an endeavour to identify patients with a degree of neuropathy potentially amenable to pharmacological intervention, a minimum conduction velocity of 30 m s-1 was set for the peroneal motor nerve. At 52 weeks, no significant differences were observed between the ponalrestat and placebo groups in motor (ulnar, median, and peroneal) or sensory (ulnar and radial) nerve conduction velocities, vibration perception thresholds, adjectival symptom scores or tests of autonomic function (mean electrocardiographic R-R interval variability on deep breathing and orthostatic blood pressure response). Ponalrestat was clinically well tolerated and had no significant effect on glycaemic control. The lack of beneficial effects of ponalrestat may in part reflect the advanced stage of the neuropathic process in patients with established symptomatic disease, and the poor reproducibility of current neurophysiological techniques. Firmer knowledge of clinico-pathological correlates allied to improved non-invasive neurophysiological measurement techniques should facilitate the selection of patients for future therapeutic trials in diabetic neuropathy. A 2-year randomized placebo-controlled double-blind trial of 250 mg day-1 of the aldose reductase inhibitor Sorbinil in severe symptomatic chronic peripheral neuropathy was performed in 21 diabetic patients. Due to adverse reactions 8 patients completed the trial on Sorbinil and 6 patients on placebo. Despite differences in baseline neurophysiological parameters, duration of diabetes, and presence of retinopathy between the placebo and treatment groups, there were no initial differences in in vitro platelet aggregation, albumin excretion rate (AER) or muscle capillary basement membrane thickness. After 2 years the median deterioration in AER in the placebo group was 18.4 micrograms min-1 (range 2.6-64.8 micrograms min-1). This deterioration was significant (p less than 0.03). The change in AER in the Sorbinil group was +1.25 (-10.7 to +20.4) micrograms min-1, an insignificant change. In vitro platelet responsiveness to collagen and adenosine diphosphate (ADP) increased in the placebo group (median change max% collagen + 8 (+2 to +30)%; ADP +4.5 (0 to +20)% compared with a fall in the Sorbinil treated patients (median change; collagen -17.5 (-2 to -40)%, p less than 0.05; ADP, -4 (0 to -25)%, p less than 0.05). Muscle capillary basement membrane thickness was measured in only 3 patients in each group and did not alter significantly during the trial. All 12 neurophysiological measurements showed no significant changes between the treatment and placebo groups. The data suggest that aldose reductase inhibition has effects on platelet reactivity and microalbuminuria.