sorbinil and Diabetic-Neuropathies

Diabetic neuropathy is a major complication of poorly controlled diabetes mellitus. Aldose reductase, the first enzyme of the polyol pathway, is thought to play a role in initiating the metabolic damage to peripheral nerves during hyperglycemia. Aldose reductase inhibitors (ARIs) have been proposed to dampen the flux of glucose through the pathway during hyperglycemia; however, clinical trials in diabetic patients to demonstrate efficacy in the prevention or amelioration of diabetic neuropathy have failed thus far. Recent improved understanding of the pitfalls of past trials and some improved ARIs and clinical evaluation instruments show promise that success in the 20-plus year search for efficacious ARIs may soon be at hand.

Topics: Aldehyde Reductase; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Imidazolidines

Aldose reductase ([EC1.1.1.21]: AR) acts on the first step of the polyol metabolic pathway to catalyze the reduction of glucose to sorbitol with NADPH as a coenzyme. Hyperactivity of the pathway in individuals with high blood glucose level is closely related to the onset or progression of diabetic complications. AR inhibitors have therefore been noted as possible pharmacotherapeutic agents for the treatment of diabetic complications. One AR inhibitor has been on the market in Japan, while some potent inhibitors are in clinical trials. Reviewed are the physiological roles of AR, the chemical structures of AR inhibitors, interactions of AR inhibitors with AR using X-ray studies, and the following potencies of AR inhibitors: in vitro activities for AR, in vitro selectivities between AR and aldehyde reductase, their pharmacological effects in vivo, and their effectiveness in clinical trials. Also discussed are directions for the design of future AR inhibitors.

Topics: Aldehyde Reductase; Binding Sites; Clinical Trials as Topic; Crystallography, X-Ray; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Imidazoles; Imidazolidines; Naphthalenes; Quinazolines

Despite numerous attempts over 16 years, the results of aldose reductase inhibitor (ARI) trials for the treatment of diabetic neuropathy have not proven efficacy. This paper reviews each of the ARI trials, examines confounding factors, and proposes a future course. The confounding factors considered are pharmacokinetics (ARI penetration of human nerve), length of trial (in terms of the natural history of diabetic neuropathy), trial endpoints (reversibility or slowing of progression), reproducibility of clinical measurements (in terms of power calculations), standardization and quality control of endpoints, and clinically meaningful differences in endpoints. We conclude that ARIs are most likely to have a beneficial effect in the management of diabetic distal symmetrical polyneuropathy and autonomic neuropathy but that the clinical role of ARIs is to slow the progression of diabetic neuropathy rather than to reverse it. Future trials should be designed with adequate statistical power, with consideration of the variability of the endpoint measurements for long enough duration, and with rigorous quality control to definitively confirm the utility of ARIs in the treatment of diabetic distal symmetrical polyneuropathy and autonomic neuropathy.

Topics: Aldehyde Reductase; Autonomic Nervous System; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Imidazoles; Imidazolidines; Isoquinolines; Naphthalenes; Phthalazines; Time Factors

Recently, aldose reductase inhibitors (ARIs) have been registered in several countries for the improvement of glycaemic control. However, their efficacy is still controversial. ARIs inhibit the enhanced flux of glucose through the polyol pathway. As such, they can never be more effective than normoglycaemia, and so their potential benefits and limitations should be considered relative to the effects of prolonged euglycaemia. The clinical effects of ARIs can be put into perspective by assessing the effects of improved glycaemic control attained in randomised trials of intensive insulin treatment [such as the Diabetes Control and Complications Trial (DCCT)] and after pancreatic transplantation. Although direct comparison of these 3 interventions is hampered by differences in patient populations, duration and methods of follow-up and in the potency of ARIs, the effects of these 3 metabolic interventions and their course in time appear remarkably similar. For neuropathy, all 3 interventions induce an increase in average motor nerve conduction velocity of approximately 1 m/sec during the first months of treatment. At the same time, improvement of painful symptoms may occur. These changes probably largely represent a metabolic amelioration of the condition of the nerves. Around the second year of treatment with all 3 forms of metabolic improvement, an acceleration of nerve conduction of a similar magnitude occurs, with signs of structural nerve regeneration and some sensory recuperation. Experience with ARIs in nephropathy is still limited, but similar improvements in glomerular filtration rate and, less consistently, in urinary albumin excretion were found during short term normoglycaemia produced by all 3 forms of treatment. Comparison of a small number of studies, however, shows differences between intensive insulin regimens, pancreatic transplantation and ARIs in effects on retinopathy. Retinopathy often temporarily deteriorates in the early phases of improved glycaemic control, but this is not noted with ARIs. New microaneurysm formation was slightly reduced in a single long term study with the ARI sorbinil, but the preventive effects on the overall levels of retinopathy seemed less strong than in normoglycaemia trials of similar duration. However, the pharmacodynamic effects on inhibiting the polyol pathway differ among ARIs, and the half-life of the inhibiting effect of sorbinil may have been too short for a complete reduction of polyol pathway activity.

Topics: Adult; Aged; Aldehyde Reductase; Cross-Sectional Studies; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Imidazoles; Imidazolidines; Insulin; Islets of Langerhans Transplantation; Middle Aged; Naphthalenes; Pancreas Transplantation; Treatment Outcome

Topics: Aldehyde Reductase; Animals; Diabetic Neuropathies; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Naphthalenes; Nerve Regeneration; Sural Nerve

Topics: Aldehyde Reductase; Animals; Atrophy; Axons; Diabetic Neuropathies; Humans; Imidazoles; Imidazolidines; Neural Conduction; Structure-Activity Relationship; Sural Nerve

Topics: Aldehyde Reductase; Biopsy; Diabetic Neuropathies; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Neural Conduction; Peripheral Nerves; Phthalazines; Placebos; Vagus Nerve

Aldose reductase inhibitors impede flux of glucose through the sorbitol pathway in diabetes mellitus. They therefore reduce the accumulation of the pathway metabolites, sorbitol and fructose, reduce the impact of the flux on the cofactors used by the pathway and reduce other derived phenomena, such as osmotic stress and myo-inositol depletion. As drugs, their targets are the chronic complications of diabetes--neuropathy, retinopathy, nephropathy and vasculopathy. In experimental models there is proof of activity against biochemical, functional and structural defects in all of the involved tissues, but we await full clinical verification of this potential.

Topics: Aldehyde Reductase; Animals; Cataract; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Humans; Imidazoles; Imidazolidines

Topics: Aldehyde Reductase; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Humans; Imidazoles; Imidazolidines; L-Iditol 2-Dehydrogenase; Naphthalenes; Phthalazines; Sugar Alcohol Dehydrogenases

Neuropathy and retinopathy are two potentially serious late complications of diabetes. There is accumulating evidence that the development of these conditions is closely related to increased activity of the polyol pathway, which occurs in certain tissues as a consequence of long term hyperglycaemia. Symptomatic diabetic neuropathy may appear as one of many forms and is frequently accompanied by pain. Diabetic retinopathy is a progressive degeneration of the retina that represents one of the major causes of blindness in the developed world. A good prognosis for either of these conditions is believed to rely on early diagnosis and optimisation of glycaemic control as they become less reversible with progression of cellular damage. A new approach to the treatment of these and other late complications of diabetes may be offered by recently developed drugs, such as sorbinil, that inhibit the enzyme aldose reductase. In various animal models of late complications of diabetes sorbinil and other aldose reductase inhibitors have been shown to reverse some of the biochemical and physiological changes believed to underlie these complications. These include prevention or reversal of the accumulation of sorbitol and depletion of myo-inositol in nerve, lens and renal glomeruli. Sorbinil also counteracts the slowing of nerve conduction velocities, reverses the structural changes of Sipple stages I and II cataracts and prevents proteinuria in diabetic rats. Orally administered sorbinil is absorbed rapidly and reaches steady state plasma concentrations after 6 to 10 days' administration. Its elimination half-life is long (38-52 hours) and much greater than that of another aldose reductase inhibitor, tolrestat (10-12 hours). Within the dose range 50-250 mg about one-third of administered sorbinil appears in the urine as unchanged drug. In the small number of clinical studies of diabetic patients with neuropathies sorbinil has demonstrated limited therapeutic effects. There is now a requirement for studies of its prophylactic use and its therapeutic use in patients with diabetic neuropathy in the early stages of development.

Topics: Aldehyde Reductase; Diabetic Neuropathies; Diabetic Retinopathy; Drug Hypersensitivity; Humans; Imidazoles; Imidazolidines; Kinetics; Sugar Alcohol Dehydrogenases

Topics: Aldehyde Reductase; Animals; Binding Sites; Blood Glucose; Cataract; Chemical Phenomena; Chemistry; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Disease Models, Animal; Fluorenes; Galactose; Humans; Hydantoins; Imidazoles; Imidazolidines; Models, Molecular; Naphthalenes; Phthalazines; Rhodanine; Sorbitol; Structure-Activity Relationship; Substrate Specificity; Sugar Alcohol Dehydrogenases; Thiazolidines; Tissue Distribution

Topics: Adolescent; Adult; Aged; Animals; Calcium; Diabetic Neuropathies; Humans; Imidazoles; Imidazolidines; Inositol; Insulin; Ischemia; Middle Aged; Neural Conduction; Perception; Peripheral Nerves; Potassium; Vibration

Topics: Adolescent; Adult; Aldehyde Reductase; Clinical Trials as Topic; Diabetic Neuropathies; Diet; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Inositol; Middle Aged; Neural Conduction; Peripheral Nerves; Polymers; Random Allocation

Tissues of the eye affected by diabetes are the lens, cornea, and retina. The lens becomes cataractous through osmotic swelling of its cortical fibers. Sorbitol, formed in the presence of aldose reductase, accumulates in the lens during hyperglycemia. Dulcitol similarly accumulates in the presence of galactosemia. Cataractogenesis in both cases can be prevented by inhibitors of aldose reductase. The efficacy of synthetic inhibitors differs in various tissues and species, but they react with aldose reductase at a common structural site. The most promising inhibitor is sorbinil . Diabetic retinopathy is similarly related to sorbitol accumulation and may be prevented or reversed by inhibition of aldose reductase. Healing of corneal wounds in diabetes is facilitated by enzyme inhibition. Retinal vasculopathy of diabetes is due to selective loss of the intramural pericytes that normally form structural elements in the retinal capillary walls. The vulnerability of these cells is due to their aldose reductase content. Whether inhibition of aldose reductase will prevent retinopathy is being tested in a randomized trial conducted by the National Eye Institute.

Topics: Aldehyde Reductase; Animals; Axonal Transport; Cataract; Corneal Diseases; Diabetic Neuropathies; Diabetic Retinopathy; Disease Models, Animal; Galactosemias; Humans; Imidazoles; Imidazolidines; Lens, Crystalline; Osmolar Concentration; Peripheral Nerves; Rats; Sorbitol; Structure-Activity Relationship; Sugar Alcohol Dehydrogenases

Despite numerous attempts over 16 years, the results of aldose reductase inhibitor (ARI) trials for the treatment of diabetic neuropathy have not proven efficacy. This paper reviews each of the ARI trials, examines confounding factors, and proposes a future course. The confounding factors considered are pharmacokinetics (ARI penetration of human nerve), length of trial (in terms of the natural history of diabetic neuropathy), trial endpoints (reversibility or slowing of progression), reproducibility of clinical measurements (in terms of power calculations), standardization and quality control of endpoints, and clinically meaningful differences in endpoints. We conclude that ARIs are most likely to have a beneficial effect in the management of diabetic distal symmetrical polyneuropathy and autonomic neuropathy but that the clinical role of ARIs is to slow the progression of diabetic neuropathy rather than to reverse it. Future trials should be designed with adequate statistical power, with consideration of the variability of the endpoint measurements for long enough duration, and with rigorous quality control to definitively confirm the utility of ARIs in the treatment of diabetic distal symmetrical polyneuropathy and autonomic neuropathy.

Topics: Aldehyde Reductase; Autonomic Nervous System; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Imidazoles; Imidazolidines; Isoquinolines; Naphthalenes; Phthalazines; Time Factors

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.

Topics: Adult; Aldehyde Reductase; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Diabetic Retinopathy; Female; Follow-Up Studies; Humans; Imidazoles; Imidazolidines; Male; Median Nerve; Middle Aged; Neural Conduction; Patient Compliance; Peroneal Nerve

Topics: Aldehyde Reductase; Animals; Diabetic Neuropathies; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Naphthalenes; Nerve Regeneration; Sural Nerve

Topics: Aldehyde Reductase; Biopsy; Diabetic Neuropathies; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Neural Conduction; Peripheral Nerves; Phthalazines; Placebos; Vagus Nerve

Clinically overt diabetic neuropathy is characterized by neuroanatomical changes of the node of Ranvier and myelinated axons, and by decreased nerve conduction velocity. Sural nerve biopsies were obtained from 16 neuropathic diabetic patients participating in a 12-month randomized, placebo-controlled, double-blind clinical trial of the aldose reductase inhibitor sorbinil. One sural nerve biopsy was obtained at baseline and a second biopsy at the termination of the trial. Ten sorbinil-treated patients showed significant improvement in axo-glial dysjunction, a characteristic lesion of the node of Ranvier. Axonal atrophy assessed by three independent morphometric techniques also exhibited significant recovery in the sorbinil-treated patients. No change was demonstrated in any of these structural parameters in six placebo-treated patients. The improvement in sural nerve conduction velocity in sorbinil-treated patients correlated with the product of the quantitative improvements in axo-glial dysjunction and axonal atrophy. We conclude that the activated polyol-pathway plays a sustaining role in nerve fibre damage in diabetic neuropathy, and that structural lesions such as axo-glial dysjunction and axonal atrophy which are reversible following intervention with an aldose reductase inhibitor, constitute the morphological basis for nerve conduction slowing in overt diabetic neuropathy.

Topics: Adult; Aldehyde Reductase; Atrophy; Axons; Biopsy; Diabetic Neuropathies; Double-Blind Method; Follow-Up Studies; Humans; Imidazoles; Imidazolidines; Middle Aged; Myelin Sheath; Neural Conduction; Neuroglia; Sural Nerve

Aldose reductase inhibitors impede flux of glucose through the sorbitol pathway in diabetes mellitus. They therefore reduce the accumulation of the pathway metabolites, sorbitol and fructose, reduce the impact of the flux on the cofactors used by the pathway and reduce other derived phenomena, such as osmotic stress and myo-inositol depletion. As drugs, their targets are the chronic complications of diabetes--neuropathy, retinopathy, nephropathy and vasculopathy. In experimental models there is proof of activity against biochemical, functional and structural defects in all of the involved tissues, but we await full clinical verification of this potential.

Topics: Aldehyde Reductase; Animals; Cataract; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Humans; Imidazoles; Imidazolidines

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

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.

Topics: Aldehyde Reductase; Basement Membrane; Blood Pressure; Capillaries; Clinical Trials as Topic; Diabetic Angiopathies; Diabetic Neuropathies; Double-Blind Method; Female; Follow-Up Studies; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Muscles; Neural Conduction; Perception; Random Allocation; Regional Blood Flow; Sugar Alcohol Dehydrogenases

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.

Topics: Aldehyde Reductase; Blood Glucose; Clinical Trials as Topic; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Female; Heart Rate; Humans; Imidazoles; Imidazolidines; Male; Median Nerve; Middle Aged; Neural Conduction; Peroneal Nerve; Random Allocation; Sugar Alcohol Dehydrogenases; Valsalva Maneuver

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.

Topics: Action Potentials; Aldehyde Reductase; Biopsy; Clinical Trials as Topic; Demyelinating Diseases; Diabetic Neuropathies; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Nerve Fibers; Nerve Regeneration; Neural Conduction; Random Allocation; Sorbitol; Sugar Alcohol Dehydrogenases; Sural Nerve

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.

Topics: Adult; Arm; Autonomic Nervous System; Carpal Tunnel Syndrome; Clinical Trials as Topic; Diabetic Neuropathies; Evoked Potentials, Somatosensory; Female; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Sensory Thresholds; Thermosensing; Time Factors; Vibration

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.

Topics: Adult; Aldehyde Reductase; Autonomic Nervous System; Clinical Trials as Topic; Diabetic Neuropathies; Double-Blind Method; Female; Heart Rate; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Motor Neurons; Neurons, Afferent; Peripheral Nerves; Random Allocation; Sorbitol; Sugar Alcohol Dehydrogenases

Topics: Adult; Aldehyde Reductase; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Middle Aged; Neural Conduction; Random Allocation; Sugar Alcohol Dehydrogenases

Three clinical trials to evaluate the efficacy of the aldose reductase inhibitor sorbinil in improving or preventing diabetic neural function have either been completed or are currently in progress. In the first study from Seattle and Chicago, motor and sensory nerve conduction velocities (NCV) were evaluated in 39 insulin- and noninsulin-dependent, glycemic-stable diabetic patients in a randomized, double-blind, crossover trial. During the 9 weeks of treatment with 250 mg/d of sorbinil, there was a faster nerve conduction velocity of all 3 nerves tested when compared with the placebo period: peroneal motor NCV (+0.70 +/- 0.24 m/s; means +/- SEM; P less than 0.008), median motor NCV (+0.66 +/- 0.27 m/s; P less than 0.005), and median sensory NCV (+1.16 +/- 0.50 m/s; P less than 0.035). Conduction velocity for all 3 nerves declined significantly within 3 weeks following cessation of the drug. These effects of sorbinil were unrelated to glycemic control, which was constant during the study. Although the effects of sorbinil in improving nerve conduction velocity were small, the findings suggest that the polyol-pathway activity contributes to slowed nerve conduction velocity in diabetics. The second study is a seven-center, double-blind, randomized, 12-month trial of 210 to 280 diabetic patients with clinical signs, symptoms, and objective measurements of neuropathy. The trial has a common-core protocol with end-point evaluations of scored neural signs, symptoms, and neural measurements. Two unique neural tests were designed and validated for use in this trial: thermal and tactile perception thresholds of the fingers and toes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Neural Conduction; Neurons; Random Allocation

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)

Topics: Adult; Aldehyde Reductase; Autonomic Nervous System Diseases; Clinical Trials as Topic; Diabetic Neuropathies; Double-Blind Method; Evoked Potentials, Somatosensory; Female; Heart Rate; Humans; Imidazoles; Imidazolidines; Male; Neural Conduction; Peroneal Nerve; Random Allocation; Respiration; Sugar Alcohol Dehydrogenases

A considerable volume of animal pharmacologic data support the view that increased flux through the polyol pathway provides a unifying hypothesis for the major complications of diabetes. An extensive clinical program has been established to verify the extrapolation of the animal pharmacologic findings to man. Clinical data accumulated to date confirm the biochemical and electrophysiologic effects, and encouraging evidence of a drug effect in diabetic neuropathy and retinopathy has already been observed. In the large, controlled safety data base already available, the long-term clinical use of sorbinil is devoid of significant adverse effects in terms of both subjective side effects and laboratory parameters. The only clinically important adverse reaction reported to date has been a hypersensitivity reaction in the early weeks of therapy, which is similar to that seen with other hydantoins.

Topics: Aldehyde Reductase; Animals; Autonomic Nervous System Diseases; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Pain; Rats; Sorbitol; Sugar Alcohol Dehydrogenases

Extensive animal data now exist to indicate potential benefit of sorbinil in the treatment of the major complications of diabetes mellitus. A clinical programme has been constructed to explore this therapeutic potential and encouraging evidence of drug effect has already been observed in patients with neuropathy and retinopathy. Two small preliminary studies in patients with painful neuropathy have shown that clinically significant reduction of pain was more frequently achieved with sorbinil than with placebo. A 6-month study of patients with retinopathy, using vitreous fluorophotometry as the criterion of retinal damage, showed significant (p = 0.03) benefit for the sorbinil group compared with the placebo group. Drug evaluation in these areas is complex and difficult but it is anticipated that the accumulation of additional data will further substantiate the efficacy suggested by these early findings. The only clinically important adverse effect of sorbinil is the hypersensitivity reaction. This usually occurs during the initial weeks of therapy and is similar to that seen with phenytoin. The long term use of sorbinil is without significant adverse effects.

Topics: Aldehyde Reductase; Animals; Diabetic Neuropathies; Diabetic Retinopathy; Drug Hypersensitivity; Electrophysiology; Humans; Imidazoles; Imidazolidines; Sugar Alcohol Dehydrogenases

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.

Topics: Aldehyde Reductase; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Fibrinolysis; Glycoproteins; Humans; Imidazoles; Imidazolidines; Longitudinal Studies; Placebos; Plasminogen Inactivators; Research Design; Sugar Alcohol Dehydrogenases; Tissue Plasminogen Activator

A randomized placebo-controlled double-blind cross-over study was conducted in order to examine the effect of an aldose reductase inhibitor, sorbinil (100 mg daily for 4 weeks), on red cell sorbitol concentration and clinical and electrophysiological parameters of diabetic neuropathy. A total of 31 diabetic patients with either clinically or electrophysiologically verified diabetic neuropathy were studied. Red cell sorbitol levels decreased significantly to the levels reported in non-diabetic subjects, but there were no significant changes in symptoms, signs, vibration perception thresholds or nerve conduction variables. One patient had transient skin rash, fever, myalgia and leucopenia, but no other significant adverse effects were found.

Topics: Adult; Clinical Trials as Topic; Diabetic Neuropathies; Double-Blind Method; Erythrocytes; Female; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Neural Conduction; Peripheral Nerves; Random Allocation; 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

37 patients with diabetic neuropathy were randomized into 2 equal groups and given daily doses of 200 mg or 50 mg of Sorbinil - a potent aldose-reductase inhibitor - in a double-blind 4-week period between 2 periods on placebo. The purpose was to assess the role of the drug on various neurophysiological parameters and its clinical effect. No difference was shown either in the placebo periods compared to Sorbinil treatment or between the 2 groups on the neurophysiological parameters but there was a statistically significant effect on overall subjective well-being. The drug had no side-effects in the present study.

Topics: Aldehyde Reductase; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Female; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Sensory Thresholds; Sugar Alcohol Dehydrogenases; Touch; Visual Acuity

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.

Topics: Adult; Aged; Aldehyde Reductase; Autonomic Nervous System; Clinical Trials as Topic; Diabetic Neuropathies; Double-Blind Method; Heart Rate; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Neural Conduction; Sensory Thresholds; Skin Temperature

Topics: Adolescent; Adult; Aldehyde Reductase; Clinical Trials as Topic; Diabetic Neuropathies; Diet; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Inositol; Middle Aged; Neural Conduction; Peripheral Nerves; Polymers; Random Allocation

Topics: Aldehyde Reductase; Animals; Clinical Trials as Topic; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Erythrocytes, Abnormal; Humans; Imidazoles; Imidazolidines; Rats; Sorbitol; Sugar Alcohol Dehydrogenases

The effect of sorbinil (200 mg daily for 4 weeks) was examined in 13 patients, mean age 59.7 years (range 42-72 years), with symptomatic diabetic neuropathy of mean duration 6 year (range 1-18 years). 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 +/- 7.7 metres/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.

Topics: Adult; Aged; Aldehyde Reductase; Autonomic Nervous System; Clinical Trials as Topic; Diabetic Neuropathies; Double-Blind Method; Female; Heart Rate; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Motor Neurons; Muscles; Neural Conduction; Peripheral Nerves; Sensation; Sensory Thresholds; Sugar Alcohol Dehydrogenases

11 patients with severely painful diabetic neuropathy previously unresponsive to numerous drugs were treated with an aldose reductase inhibitor ('Sorbinil'--Pfizer CP 45, 634); 8 also received a placebo. Response was assessed according to a 0-20 graphic rating scale for pain and by tests for motor and sensory nerve conduction velocities (NCV) and cardiac autonomic nerve function. 8 patients had moderate to marked relief of symptoms, generally beginning on the 3rd or 4th day of medication, 2 had equivocal responses, and 1 had no change. Each of 4 patients with diabetic amyotrophy reported striking improvement in pain and mild to moderate improvement in proximal leg muscle strength; 2 of these noticed improved sensory perception in their feet. Objective evidence of improved muscle strength was obtained in each of these 4 patients and of improved sensation in 3. On stopping medication, pain worsened in 7 of 8 responders, although generally with some delay, suggesting a carry over effect. During the course of treatment autonomic nerve function improved significantly in 6 of 7 patients tested and across the group, and NCV improved in 4 of 7 tested. Both of these variables deteriorated after withdrawal of the drug. A correlation between NCV response and clinical response was apparent. Very little toxicity was observed. These observations suggest that aldose reductase inhibitors may be important in the treatment of symptomatic somatic and autonomic neuropathies complicating diabetes.

Topics: Adult; Aged; Aldehyde Reductase; Autonomic Nervous System; Clinical Trials as Topic; Diabetic Neuropathies; Female; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Neural Conduction; Pain; Peripheral Nerves; Placebos; Sugar Alcohol Dehydrogenases

Topics: Aldehyde Reductase; Clinical Trials as Topic; Diabetic Neuropathies; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Pain; Sugar Alcohol Dehydrogenases

A double-blind, randomized, placebo-controlled cross-over trial of the aldose reductase inhibitor sorbinil was undertaken in 15 patients (age 35-68 yr) with chronic painful diabetic neuropathy. Treatment was evaluated by subjective pain responses, clinical examination, vibration perception threshold, motor and sensory nerve electrophysiology, and cardiovascular reflex tests of autonomic nerve function. Among the many measurements, only pain, tendon reflex scores, and sural sensory potential amplitude improved significantly during sorbinil administration, while scores of clinical sensory examination deteriorated. Four patients experienced an idiosyncratic reaction that rapidly recovered on discontinuing the drug. This study suggests that aldose reductase inhibitor treatment with suggests that aldose reductase inhibitor treatment with sorbinil may have an effect on symptomatic diabetic neuropathy in man.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Diabetic Neuropathies; Double-Blind Method; Drug Eruptions; Erythema; Female; Humans; Imidazoles; Imidazolidines; Leukopenia; Lymphatic Diseases; Male; Middle Aged

To assess the potential role of polyol-pathway activity in diabetic neuropathy, we measured the effects of sorbinil--a potent inhibitor of the key polyol-pathway enzyme aldose reductase--on nerve conduction velocity in 39 stable diabetics in a randomized, double-blind, cross-over trial. During nine weeks of treatment with sorbinil (250 mg per day), nerve conduction velocity was greater than during a nine-week placebo period for all three nerves tested: the peroneal motor nerve (mean increase [+/- S.E.M.], 0.70 +/- 0.24 m per second, P less than 0.008), the median motor nerve (mean increase, 0.66 +/- 0.27, P less than 0.005), and the median sensory nerve (mean increase, 1.16 +/- 0.50, P less than 0.035). Conduction velocity for all three nerves declined significantly within three weeks after cessation of the drug. These effects of sorbinil were not related to glycemic control, which was constant during the study. Although the effect of sorbinil in improving nerve conduction velocity in diabetics was small, the findings suggest that polyol-pathway activity contributes to slowed nerve conduction in diabetics. The clinical applicability of these observations remains to be determined, but they encourage further exploration of this approach to the treatment or prevention of diabetic neuropathy.

Topics: Adult; Aged; Aldehyde Reductase; Diabetes Mellitus; Diabetic Neuropathies; Double-Blind Method; Drug Evaluation; Female; Glycated Hemoglobin; Humans; Imidazoles; Imidazolidines; Male; Median Nerve; Middle Aged; Motor Neurons; Neural Conduction; Peroneal Nerve; Random Allocation; Skin Temperature; Sugar Alcohol Dehydrogenases

Topics: Aldehyde Reductase; Clinical Trials as Topic; Diabetic Neuropathies; Double-Blind Method; Humans; Imidazoles; Imidazolidines; Neural Conduction; Sugar Alcohol Dehydrogenases

At least one of four diabetic patients is affected by distal symmetric polyneuropathy, which represents a major health problem, since it may present with partly excruciating neuropathic pain and is responsible for substantial morbidity, increased mortality, and impaired quality of life. Treatment is based on four cornerstones: 1) causal treatment aimed at (near)-normoglycemia, 2) treatment based on pathogenetic mechanisms, 3) symptomatic treatment, and 4) avoidance of risk factors and complications. Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. From the clinical point of view, it is important to note that, based on these pathogenetic mechanisms, therapeutic approaches could be derived, some of which are currently being evaluated in clinical trials. Among these agents, only alpha-lipoic acid is available for treatment in several countries and epalrestat in Japan. Although several novel analgesic drugs such as duloxetine and pregabalin have recently been introduced into clinical practice, the pharmacologic treatment of chronic painful diabetic neuropathy remains a challenge for the physician. Individual tolerability remains a major aspect in any treatment decision. Epidemiological data indicate that not only increased alcohol consumption but also the traditional cardiovascular risk factors such as hypertension, smoking, and cholesterol play a role in development and progression of diabetic neuropathy and hence need to be prevented or treated.

Topics: Aldehyde Reductase; Analgesics, Opioid; Clinical Trials as Topic; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Imidazolidines; Incidence; Inositol; Polyneuropathies; Sodium Channel Blockers; Sodium-Potassium-Exchanging ATPase

Pressure-induced vasodilation, a neurovascular mechanism relying on the interaction between mechanosensitive C-fibers and vessels, allows skin blood flow to increase in response to locally nonnociceptive applied pressure that in turn may protect against pressure ulcers. We expected that severe neuropathy would dramatically affect pressure-induced vasodilation in diabetic mice, and we aimed to determine whether pressure-induced vasodilation alteration could be reversed in 8-week diabetic mice. Control and diabetic mice received no treatment or sorbinil, an aldose reductase inhibitor, or alagebrium, an advanced glycation end product breaker, the last 2 weeks of diabetes. Laser Doppler flowmetry was used to evaluate pressure-induced vasodilation and endothelium-dependent vasodilation after iontophoretic delivery of acetylcholine (ACh). We assessed the nervous function with measurements of motor nerve conduction velocity (MNCV) as well as the C-fiber-mediated nociception threshold. Pressure-induced vasodilation, endothelial response, C-fiber threshold, and MNCV were all altered in 8-week diabetic mice. None of the treatments had a significant effect on MNCV. Although sorbinil and alagebrium both restored ACh-dependent vasodilation, sorbinil was the sole treatment to restore the C-fiber threshold as well as pressure-induced vasodilation development. Therefore, the inhibition of aldose reductase pathway by sorbinil improved vascular and C-fiber functions that allow pressure-induced vasodilation restoration that could limit neuropathic diabetic cutaneous pressure ulcers.

Topics: Acetylcholine; Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enzyme Inhibitors; Imidazolidines; Male; Mice; Nerve Fibers; Pressure Ulcer; Vasodilation

Topics: Aldehyde Reductase; Angiotensin-Converting Enzyme Inhibitors; Cross-Sectional Studies; Diabetic Neuropathies; Drug Therapy, Combination; Heart; Humans; Hypoglycemic Agents; Imidazoles; Imidazolidines; Risk Factors

Aldose reductase inhibitors (ARIs) prevent peripheral nerve dysfunction and morphological abnormalities in diabetic animal models. However, some experimental intervention studies and clinical trials of ARIs on diabetic neuropathy appeared disappointing because of either 1) their inadequate design and, in particular, insufficient correction of the sorbitol pathway activity or 2) the inability to reverse established functional and metabolic deficits of diabetic neuropathy by AR inhibition in general. We evaluated whether diabetes-induced changes in nerve function, metabolism, and antioxidative defense are corrected by the dose of ARI (sorbinil, 65 mg/kg/d in the diet), resulting in complete inhibition of increased sorbitol pathway activity. The groups included control rats and streptozotocin-diabetic rats treated with/without ARI for 2 weeks after 4 weeks of untreated diabetes. ARI treatment corrected diabetes-induced nerve functional changes; that is, decrease in endoneurial nutritive blood flow, motor and sensory nerve conduction velocities, and metabolic abnormalities (i.e., mitochondrial and cytosolic NAD+/NADH redox imbalances and energy deficiency). ARI restored nerve concentrations of two major non-enzymatic antioxidants, reduced glutathione (GSH) and ascorbate, and completely arrested diabetes-induced lipid peroxidation. In conclusion, treatment with adequate doses of ARIs (that is, doses that completely inhibit increased sorbitol pathway activity) is an effective approach for reversal of, at least, early diabetic neuropathy.

Topics: Aldehyde Reductase; Animals; Antioxidants; Cytosol; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enzyme Inhibitors; Imidazoles; Imidazolidines; Lipid Peroxidation; Mitochondria; Models, Biological; NAD; Neural Conduction; Oxidation-Reduction; Oxidative Stress; Peripheral Nerves; Rats

The activation of the polyol pathway through aldose reductase (AR) might be involved in diabetic neuropathy. A considerable structural similarity exists between AR and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) (both belonging to aldo-keto reductase superfamily); 3alpha-HSD forms 5alpha-reduced-3alpha-hydroxylated steroids, possibly possessing neurotrophic functions. Aim of these experiments was to test "in vitro" in rat sciatic nerves, whether glucose concentrations in the diabetic range might affect the capacity of 3alpha-HSD to transform dihydroprogesterone (DHP) into tetrahydroprogesterone (THP), a steroid proved to possess neurotrophic effects. The capability of AR inhibitors, drugs used to avoid diabetic complications, to decrease THP formation was also assessed. 3alpha-HSD activity was evaluated by the conversion of labelled DHP into THP (in a single case dihydrotestosterone was used as substrate, and the corresponding 3alpha-hydroxylated metabolite was evaluated). Freshly prepared rat sciatic nerve homogenates were used as source of the enzyme. Whole brain, liver and prostate served as "control" tissues. The results show that glucose added up to a concentration of 400 mg/dL (well above the euglycemic upper level) does not affect the 3alpha-HSD activity in the sciatic nerve and in the other tissues considered. Similarly, when the enzyme was challenged by two AR inhibitors, tolrestat and sorbinil, added in a concentration about 10 times higher than their IC50 for AR, no significant changes were observed. Analogous results were achieved when DHT was used in presence of glucose (400 mg/dL) and sorbinil. We conclude that hyperglycemia or the administration of the AR inhibitors do not affect 3alpha-HSD activity in peripheral nerves and therefore do not reduce the formation of steroid metabolites possibly endowed with neurotrophic action.

Topics: 20-alpha-Dihydroprogesterone; 3-Hydroxysteroid Dehydrogenases; Aldehyde Reductase; Animals; Diabetic Neuropathies; Dihydrotestosterone; Enzyme Inhibitors; Hyperglycemia; Imidazoles; Imidazolidines; Male; Naphthalenes; Rats; Rats, Sprague-Dawley; Sciatic Nerve

Nerve conduction velocity (NCV) increased with age in nondiabetic male Wistar rats for the first 26 weeks of life. The NCV of animals made hyperglycemic at age 6 weeks by administration of streptozotocin (STZ) also increases, but at a slower rate. Animals with 4 weeks of hyperglycemia and reduced NCV treated with an aldose reductase inhibitor (sorbinil) or a short-chain acyl-carnitine (acetyl-L-carnitine [ALC]) daily for 16 weeks showed an improvement in NCV. Morphometric studies of tibial nerves collected from animals after 20 weeks of hyperglycemia (age 26 weeks) showed a consistent reduction in the width of the myelin sheath and little change in axon area. The number of large myelinated fibers (>6.5 microns) found in nerves collected from hyperglycemic animals was less than the number found in nondiabetic animals. Treatment of hyperglycemic rats with either sorbinil or ALC was associated with increased NCV, myelin width, and large myelinated fibers. The apparent metabolic effect of these agents was similar for fatty acid metabolism, but different for polyol pathway activity. We conclude that in animals hyperglycemic long enough to slow NCV, sorbinil and/or ALC treatment reduces the functional, structural, and biochemical changes associated with hyperglycemia that occur in the myelin sheath.

Topics: Acetylcarnitine; Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enzyme Inhibitors; Fatty Acids; Hyperglycemia; Imidazoles; Imidazolidines; Male; Myelin Sheath; Neural Conduction; Nootropic Agents; Peripheral Nerves; Rats; Rats, Wistar; Time Factors

Acetyl-L-carnitine (ALC) has been shown to facilitate the repair of transected sciatic nerves. The effect of ALC (50 mg/kg/d) on the diminished nerve conduction velocity (NCV) of rats with streptozotocin (STZ)-induced hyperglycemia of 3 weeks' duration was evaluated. The aldose reductase inhibitor, sorbinil, which is reported to normalize the impaired NCV associated with experimental diabetes, was used as a positive control. Aldose reductase inhibitors are thought to have an effect by decreasing peripheral nerve sorbitol content and increasing nerve myo-inositol. Treatment of STZ-diabetic rats with either ALC or sorbinil resulted in normal NCV. Sorbinil treatment was associated with normalized sciatic nerve sorbitol and myo-inositol; ALC treatment did not reduce the elevated sorbitol levels, but sciatic nerve myo-inositol content was no different from nondiabetic levels. Both ALC and sorbinil treatment of STZ-diabetic rats were associated with a reduction in the elevated malondialdehyde (MDA) content of diabetic sciatic nerve, indicating reduced lipid peroxidation. The beneficial effects of sorbinil and ALC on the altered peripheral nerve function associated with diabetes were similar, but their effects on the polyol pathway (frequently implicated in the pathogenesis of peripheral neuropathy) were different.

Topics: Acetylcarnitine; Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Imidazoles; Imidazolidines; Male; Muscle, Skeletal; Neural Conduction; Rats; Rats, Wistar; Sciatic Nerve

To evaluate the role of excessive polyol pathway activity in the pathogenesis of nerve disorders in diabetes mellitus, nerve conduction velocity was measured in motor nerves of diabetic dogs given an aldose reductase inhibitor (Sorbinil) or placebo, and also in non-diabetic dogs made experimentally galactosaemic. The nerve conduction velocity slowly declined in the diabetic placebo group, becoming significantly less than normal by the fifth year of the study, and the decline was prevented by administration of the aldose reductase inhibitor. Non-diabetic dogs made galactosaemic by consuming a 30% galactose diet developed erythrocyte and nerve polyol concentrations many times greater than that of diabetic or normal animals, but the nerve conduction velocity remained normal throughout 5 years of study. These results in dogs suggest that aldose reductase inhibitors may prevent defective nerve conduction in long-term diabetes, and raise the possibility that excessive accumulation of polyol itself is not sufficient to produce the nerve defect in the absence of excessive polyol utilization.

Topics: Aldehyde Reductase; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dogs; Erythrocytes; Galactosemias; Glycated Hemoglobin; Glycosuria; Imidazoles; Imidazolidines; Neural Conduction; Time Factors; Ulnar Nerve

Diabetic neuropathy results from progressive nerve fibre damage with blunted nerve regeneration and repair and may be complicated by nerve hyperexcitability resulting in pain. The naturally occurring amino acid taurine functions as an osmolyte, inhibitory neurotransmitter, and modulator of pain perception. It is also known to have neurotrophic actions. The compatible osmolyte hypothesis proposes that levels of intracellular organic osmolytes including taurine and myo-inositol, respond co-ordinately in response to changes in intracellular sorbitol or external osmolality to maintain the intracellular milieu. We hypothesize that glucose-induced sorbitol accumulation in diabetes mellitus will result in taurine depletion in peripheral nerve which may potentially impair nerve regeneration and precipitate neuronal hyperexcitability and pain. This study explored the relationships of taurine, myo-inositol and sorbitol in the rat nerve and their effects on nerve conduction velocity. Osmolyte levels and nerve conduction velocity were determined in sciatic nerve from non-diabetic and streptozotocin-induced diabetic rats, with or without dietary taurine or myo-inositol supplementation. Taurine levels decreased by 31% (p < 0.01) and myo-inositol decreased by 37% (p < 0.05) in diabetic nerve as sorbitol accumulated. Taurine supplementation of diabetic animals did not affect nerve conduction velocity but further reduced nerve myo-inositol levels. Prevention of sorbitol accumulation with the aldose reductase inhibitor sorbinil increased nerve taurine levels by 22% (p < 0.05) when compared with untreated diabetic animals. Thus, we have demonstrated an interdependence of organic osmolytes within the nerve. Abnormal accumulation of one osmolyte results in reciprocal depletion of others. Diabetic neuropathy may be an example of maladaptive osmoregulation, nerve damage and instability being aggravated by taurine depletion.

Topics: Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Diet; Fructose; Glucose; Imidazoles; Imidazolidines; Inositol; Male; Neural Conduction; Osmolar Concentration; Rats; Rats, Wistar; Sciatic Nerve; Sorbitol; Taurine

L-Fucose is a monosaccharide that occurs in low concentrations in normal serum but has been shown to be increased in diabetic individuals. In cultured mammalian cells, L-fucose is a potent competitive inhibitor of myo-inositol transport. Abnormal myo-inositol metabolism has been proposed to be a factor in the development of diabetic complications. To test the hypothesis that myo-inositol deficiency may be responsible for the electrophysiological and biological defects in diabetic neuropathy, rats were fed a diet containing 10 or 20% L-fucose for a period of 6 wk. After 3 wk, the L-fucose diets in two groups of rats were supplemented with 1% myo-inositol. At the end of the study protocol, motor nerve conduction velocity, sciatic nerve tissue Na(+)-K(+)-ATPase activity, and myo-inositol content were determined. These results were compared with those of STZ-induced diabetic rats fed either a normal diet or a diet containing 1% myo-inositol or with those given 450 mg/kg body wt of sorbinil. Serum L-fucose levels were significantly increased in rats fed a diet containing 10 or 20% L-fucose. In comparison, the serum L-fucose levels in the diabetic rats were increased to a lesser extent. Motor nerve conduction velocity was significantly slower in rats fed a 10 or 20% L-fucose diet. Sciatic nerve composite and ouabain-sensitive Na(+)-K(+)-ATPase activity and myo-inositol content was also significantly decreased. Supplementation of 1% myo-inositol to the L-fucose-containing diet restored nerve myo-inositol levels and significantly improved Na(+)-K(+)-ATPase activity and motor nerve conduction velocity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biological Transport; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dietary Carbohydrates; Dose-Response Relationship, Drug; Fucose; Imidazoles; Imidazolidines; Inositol; Male; Motor Neurons; Neural Conduction; Ouabain; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase; Streptozocin; Time Factors

Sciatic nerve conduction velocity (NCV) is reduced in rats made hyperglycaemic with streptozotocin (STZ). This neurophysiological dysfunction has been associated with increased nerve sorbitol and reduced nerve inositol. Treatment of STZ diabetic rats with aldose reductase inhibitors (ARIs) which reduce sorbitol and increase inositol in the nerve results in normalization of NCVs. Male Wistar rats were made diabetic with 50 mg/kg of streptozotocin given intraperitoneally. Those animals with blood glucose > 300 mg/dl two weeks later were included in this study. The STZ-diabetic rats were treated with either the ARI sorbinil (40 mg/kg per day), or acetyl-L-carnitine (ALC) (300 mg/kg per day) or sterile 0.15% aqueous NaCl for 16 weeks after 4 or 8 weeks of untreated hyperglycaemia. A control group of non-diabetic rats received no treatment during the interval. Sciatic-nerve sorbitol was elevated (1.08 +/- 0.13 nanomol/mg wet weight vs. 0.19 +/- 0.03 nm/mg wet weight) and inositol was reduced (1.21 +/- 0.12 nm/mg ww vs. 2.02 +/- 0.08 nm/mg ww) in the STZ diabetic rats, which were untreated for 4 weeks. Treatment with sorbinil was associated with normalization of the tissue sorbitol (0.10 +/- 0.05 nm/mg ww), while ALC treatment also significantly reduced the nerve sorbitol but only to a level (0.34 +/- 0.08 nm/mg ww) more elevated than the normal level. The nerves of STZ animals treated with sorbinil or ALC had inositol levels no different from untreated diabetic rats. Thus, hyperglycaemic animals treated with either ALC or sorbinil had similar improvements in NCVs as the diabetic, even though the effect on nerve sorbitol was different and nerve inositol was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcarnitine; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Imidazoles; Imidazolidines; Male; Neural Conduction; Rats; Rats, Wistar; Sciatic Nerve

The effect of streptozotocin diabetes of 4-week duration on the adrenergic motor transmission and on the nonadrenergic, noncholinergic, inhibitory transmission in the rat anococcygeus was investigated by recording contractile and relaxant activity of isolated muscle preparations taken from diabetic and age-matched control animals. The neurogenic contractile responses to electrical field stimulation were significantly reduced in the preparations from diabetic rats. The inhibitory transmission remained unaffected in the diabetic rats. Concentration--response curves showed no change in sensitivity of the diabetic anococcygei to noradrenaline. The maximum tension generated was also similar in preparations from diabetic and nondiabetic animals. The contractile responses to electrical field stimulation were significantly greater in preparations from diabetic rats treated for 4 weeks with either sorbinil (20 mg.kg-1.day-1 orally) or myo-inositol (667 mg.kg-1.day-1 orally) when compared with the untreated diabetic controls; the sensitivity to noradrenaline was identical in all three groups. It is concluded that streptozotocin diabetes causes a significant reduction of adrenergic contractile responses of the anococcygeus to electrical field stimulation by a prejunctional mechanism, and the reduction can be prevented by treating the animals with the aldose reductase inhibitor sorbinil or with myo-inositol.

Topics: Aldehyde Reductase; Animals; Autonomic Nervous System Diseases; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electric Stimulation; Guanethidine; Imidazoles; Imidazolidines; In Vitro Techniques; Inositol; Male; Muscle Contraction; Muscle, Smooth; Neural Inhibition; Norepinephrine; Rats; Rats, Wistar; Synaptic Transmission

Topics: Alcohol Drinking; Animals; Diabetic Neuropathies; Energy Metabolism; Fructose; Glucose; Humans; Imidazoles; Imidazolidines; Inositol; Risk Factors; Smoking; Sodium-Potassium-Exchanging ATPase; Sorbitol

Previous studies indicate that experimental diabetic autonomic neuropathy can be largely prevented by initiating therapy at the onset of diabetes. More clinically relevant, however, is the ability of therapy to reverse established neuropathy produced by long-standing diabetes. We have examined the effect of selected therapies on established neuroaxonal dystrophy (NAD) in ileal mesenteric nerves, a rat model of diabetic autonomic neuropathy. Groups of 3-mo-old rats were made diabetic with streptozocin (STZ-D) and allowed to survive untreated for 5 mo, at which time they were begun on sorbinil, dietary myo-inositol, and daily insulin therapies or left untreated for an additional 2 or 4 mo. Ultrastructural evidence of NAD was demonstrated in ileal mesenteric nerves of rats with untreated 5-mo STZ-D and increased with the duration of diabetes. No lesions were demonstrated in control rats of any age. myo-Inositol or sorbinil administration failed to alter the severity of diabetes as measured by its metabolic indices. Institution of sorbinil or insulin treatment at 5 mo of diabetes prevented the increase in, but did not normalize, NAD at 7 or 9 mo. Dietary myo-inositol failed to significantly reverse established NAD or prevent its initial development. Morphometric examination of ileal mesenteric nerves demonstrated a decrease in the number of axons comprising each diabetic Schwann cell unit, suggestive of chronic cycles of axonal degeneration and regeneration. This parameter, clearly abnormal by 5 mo of diabetes, was not normalized by 2 or 4 mo of insulin, sorbinil, or myo-inositol treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Animals; Autonomic Nervous System; Axons; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Diet; Imidazoles; Imidazolidines; Inositol; Insulin; Male; Mesentery; Rats; Rats, Inbred Strains; Reference Values

Properties and efficacies of novel aldose reductase (AR) inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), were examined in vitro and in vivo, compared with known AR inhibitors, ONO-2235 and sorbinil. These four compounds inhibited partially purified aldose reductases from various origins, and the potencies of M16209 and M16287 were on the whole similar to ONO-2235, and were greater than that of sorbinil. The IC50 values of the four AR inhibitors did not substantially depend on the substrate used. Kinetic studies of inhibition of partially purified bovine lens (BLAR) revealed that M16209, M16287 and sorbinil were uncompetitive with glyceraldehyde and noncompetitive with nicotineamide adenine dinucleotide phosphate (NADPH), whereas ONO-2235 was noncompetitive with both glyceraldehyde and NADPH. Aldose reductase became less sensitive to the four inhibitors as enzyme purification progressed, although the susceptibility to inhibition was partially reversed by incubation with dithiothreitol. In addition, the four compounds slightly affected those enzymes of carbohydrate and glutathione metabolism which were tested. M16209 and M16287 prevented sorbitol accumulation in isolated rat tissues as potently as ONO-2235 and sorbinil. M16209 and M16287 were effective in the prevention of galactosemic cataracts and amelioration of diabetic neuropathy with almost the same potency, while ONO-2235 was effective only in neuropathy, and sorbinil was effective in galactosemic cataracts and diabetic neuropathy with a different potency. These results indicate that M16209 and M16287 are potent aldose reductase inhibitors, which could be applicable to treatment for diabetic complications.

Topics: Aldehyde Reductase; Animals; Benzofurans; Cataract; Cattle; Diabetic Neuropathies; Hydantoins; Imidazoles; Imidazolidines; In Vitro Techniques; Male; Rats; Rats, Inbred Strains; Rhodanine; Sorbitol; Thiazolidines

Endoneurial microvascular abnormalities have been invoked in the pathogenesis of diabetic distal symmetric polyneuropathy. Detailed morphometric analysis of the endoneurial microvasculature was correlated with previously published data on nerve fiber morphometry and teased fiber analysis obtained from the same sural nerve biopsies. Biopsy specimens from neuropathic diabetic patients were obtained before and after 12 mo of aldose reductase inhibitor (ARI) treatment and compared to 15 carefully age-matched control subjects. Diabetic microvessels showed basement membrane thickening and loss of endothelial cell tight junctions. Microvascular density and the frequency of microvessels closed by endothelial cells increased with age in diabetic and control nerves and were unaffected by diabetes. The density of microvessels showing patent lumina did not differ between control and diabetic subjects and was not related to age or diabetes. Closed microvessels were composed of postcapillary venules that were otherwise devoid of ultrastructural abnormalities. We suggest that microvascular closure by endothelial cells may be a physiological condition and is unlikely to have any pathogenetic significance in diabetic neuropathy. Based on the current limited biopsy material, we conclude that 12 mo of ARI treatment that induced significant fiber repair and regeneration had no detectable effect on endoneurial microvascular abnormalities. These data suggest that endoneurial vascular pathology is not a rate-limiting factor in fiber damage or repair at this stage of diabetic neuropathy.

Topics: Adult; Aldehyde Reductase; Biopsy; Capillaries; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Endothelium, Vascular; Female; Humans; Imidazoles; Imidazolidines; Male; Microcirculation; Microscopy, Electron; Middle Aged; Nerve Fibers; Sural Nerve

Biochemical and ultrastructural effects of the aldose reductase inhibitor sorbinil were examined in two experimental rat models of chronic diabetic neuropathy: rats with streptozocin-induced diabetes (STZ-D) and rats fed a galactose-enriched diet. The frequency of neuroaxonal dystrophy in the superior mesenteric sympathetic ganglia of rats with untreated 8-mo STZ-D increased sevenfold compared with that in age-matched controls. Animals chronically maintained on a diet containing 50% galactose, however, did not develop neuroaxonal dystrophy in excess of that found in untreated age-matched control rats. Institution of sorbinil therapy at the time of induction of STZ-D decreased, but did not completely normalize, the frequency of neuroaxonal dystrophy without altering the severity of diabetes; this finding is based on measurements of plasma glucose, body weight, food consumption, 24-h urine volume, and levels of glycosylated hemoglobin. Sorbitol levels in the superior cervical sympathetic ganglia (SCG) of untreated 8-mo-diabetic animals increased three- to fourfold compared with levels in controls. The increase in sorbitol content of diabetic SCG was completely prevented by early institution of dietary sorbinil therapy. The myo-inositol content of 8-mo-diabetic SCG was modestly decreased compared with controls. Sorbinil administration improved but did not completely normalize diabetic SCG myo-inositol. The sorbitol content of the SCG, superior mesenteric and celiac sympathetic ganglia, and a major trunk of the superior mesenteric nerve of short-term (2.5-mo)-diabetic rats increased comparably, but only the diabetic SCG showed a decrease in myo-inositol.

Topics: Aldehyde Reductase; Animals; Axons; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Galactose; Ganglia, Sympathetic; Imidazoles; Imidazolidines; Inositol; Male; Rats; Rats, Inbred Strains; Sorbitol; Sugar Alcohol Dehydrogenases

We measured the alcohol sugars in sural nerves from 11 controls, 21 conventionally treated patients with diabetes and neuropathy, and 4 diabetics without neuropathy. The results were related to metabolic control and to clinical, neuropathological, and morphometric abnormalities in the nerves. The mean endoneurial glucose, fructose, and sorbitol values were higher in diabetic patients than in controls. Linear regression analysis revealed that nerve sorbitol content in the diabetics was inversely related to the number of myelinated fibers (P = 0.003). Mean nerve levels of myo-inositol were not decreased in the diabetic patients, with or without neuropathy, and were not associated with any of the neuropathological end points of diabetes. Our results indicate that myo-inositol deficiency is not part of the pathogenesis of human diabetic neuropathy, as had been hypothesized. Other accumulated alcohol sugars, however, were increased in diabetes and were associated with the severity of neuropathy. On repeat biopsy, six diabetics, treated for a year with the aldose reductase inhibitor sorbinil, had decreased endoneurial levels of sorbitol (P less than 0.01) and fructose (0.05 less than P less than 0.1), but unchanged levels of myo-inositol.

Topics: Adolescent; Adult; Aged; Aldehyde Reductase; Diabetes Mellitus; Diabetic Neuropathies; Erythrocytes; Female; Fructose; Glucose; Humans; Imidazoles; Imidazolidines; Inositol; Male; Middle Aged; Myelin Sheath; Nerve Regeneration; Nerve Tissue; Sorbitol; Sural Nerve

The effects of the aldose reductase inhibitor (ARI) sorbinil (250 mg/day) were tested in an open-label pilot study over 1 year, in eight diabetics with peripheral neuropathy, seven of whom had symptomic autonomic neuropathy (AN). Autonomic function studies of the urinary bladder, stomach and cardiovascular system were performed at baseline, 6 and 12 months. Six patients reported improvement in symptoms of AN by 6 months which was maintained or further improved by 12 months. Bladder sensation, as measured by cystometrographic parameters, improved at 6 months (P less than 0.02- less than 0.04), but by 12 months had reverted to baseline. Residual urine volume decreased at 6 months (P less than 0.06) and 12 months (P less than 0.06). Vagally mediated gastric acid secretion improved at 6 months (P less than 0.06); the subgroup of patients with subnormal secretion showed improvement to the normal range at 6 months (P less than 0.03). Gastric emptying of solid food was normal in six of eight subjects and showed no significant change at 6 months. Both patients with delayed emptying normalized. No change in beat-to-beat variability in heart rate with respiration was noted. Resting minimum heart rate decreased at 12 months (P less than 0.05). Glycohemoglobin levels showed no statistically significant changes. No toxic reactions were observed. These data suggest a beneficial effect of ARI treatment on symptomatic and asymptomatic manifestations of diabetic autonomic neuropathy and indicate a need for large controlled trials.

Topics: Adult; Aged; Aldehyde Reductase; Autonomic Nervous System Diseases; Blood Pressure; Cardiovascular System; Diabetic Neuropathies; Female; Humans; Imidazoles; Imidazolidines; Male; Stomach; Sugar Alcohol Dehydrogenases; Urinary Bladder

Nerve conduction slowing, a hallmark of both experimental and human diabetic neuropathy, is improved or corrected by aldose reductase inhibitors such as sorbinil. Recent animal experiments attribute acutely reversible nerve conduction slowing in diabetes to a myo-inositol (MI)-related defect in the nerve Na-K-ATPase (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 MI-related abnormality in Na-K-ATPase function is currently viewed as a cyclic, metabolic defect involving sequential alteration of Na-dependent MI uptake, MI content, MI incorporation into membrane phospholipids, and phospholipid-dependent Na-K-ATPase function in peripheral nerve. Aldose reductase inhibitors have been shown to normalize both nerve MI content and nerve Na-K-ATPase activity. These observations suggest that the acute effects of aldose reductase inhibitors on nerve conduction in both diabetic animals and patients may be mediated by correction of an underlying MI-related nerve Na-K-ATPase defect. Furthermore, this sorbinil-corrected Na-K-ATPase defect in diabetic nerve may contribute to other biochemical, functional, and structural abnormalities present in patients with diabetic peripheral neuropathy.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Energy Metabolism; Humans; Imidazoles; Imidazolidines; Inositol; Ion Channels; Neural Conduction; Peripheral Nerves; Rats; Rats, Inbred BB; Sodium; Sodium-Potassium-Exchanging ATPase; Sorbitol

Deficits of axonal transport in short-term experimental diabetes may be a consequence of increased sorbitol pathway flux and may contribute to the development of degenerative neuropathies. Therefore, we studied the effect of the aldose reductase inhibitor sorbinil on the axonal transport of choline acetyltransferase (ChAT) in the cholinergic neurons of the sciatic nerve of rats with short-term streptozotocin diabetes. In addition, to examine the extent of axonal transport deficits, we studied the axonal transport of choline containing lipids in sensory neurons of the sciatic nerve of similarly diabetic rats and the effects of sorbinil thereon. In experimentally diabetic animals, sorbinil both prevented and reversed deficits of the axonal transport of ChAT and prevented a deficit in the axonal transport of choline containing lipids.

Topics: Animals; Axonal Transport; Blood Glucose; Choline O-Acetyltransferase; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Imidazoles; Imidazolidines; Inositol; Male; Phospholipids; Rats; Rats, Inbred Strains; Sciatic Nerve; Sorbitol

Studies of the effect of sorbinil, an aldose reductase inhibitor, in human diabetic neuropathy have shown improvements in motor and sensory nerve conduction velocity and somatosensory evoked potentials, and a reduction in neuropathic pain. Improvements in motor and sensory deficits have also been detected clinically. These effects occurred after the administration of sorbinil for relatively short periods. However, more prolonged treatment may be necessary to achieve a therapeutic response in some patients. The results of tests of cardiac autonomic (vagal) function improved with the administration of sorbinil for 6 weeks. The most notable finding was a reduction in resting heart rate. Improvements in both clinical and test measures, related to autonomic and somatic nerve function, have reversed on withdrawal of sorbinil and improved again on renewal of administration. Toxic manifestations of sorbinil were infrequent, almost invariably mild, and readily reversible.

Topics: Aldehyde Reductase; Diabetic Neuropathies; Double-Blind Method; Evoked Potentials, Somatosensory; Female; Heart; Humans; Imidazoles; Imidazolidines; Male; Neural Conduction; Palliative Care; Sugar Alcohol Dehydrogenases; Vagus Nerve

Decreased glutathione levels in the ocular lens have been invoked as a possible cause for the decreased lenticular Na+-K+-ATPase in diabetes because both are corrected by aldose reductase inhibitors, and the Na+-K+-ATPase is known to be susceptible to oxidation inactivation. Because an analogous Na+-K+-ATPase defect that is prevented by aldose reductase inhibitors has been described in diabetic peripheral nerve, we examined the effect of streptozocin (STZ) diabetes and aldose reductase inhibition on reduced (GSH) and oxidized (GSSG) glutathione levels in crude homogenates of rat sciatic nerve. Neither GSSG nor GSH levels were altered by 2 or 8 wk of untreated diabetes or by aldose reductase inhibition. Because the defect in Na+-K+-ATPase is fully expressed by 4 wk of STZ diabetes, we conclude that altered glutathione redox state plays no detectable role in the pathogenesis of this defect in diabetic peripheral nerve.

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Glutathione; Imidazoles; Imidazolidines; Inositol; Lens, Crystalline; Male; Oxidation-Reduction; Rats; Rats, Inbred Strains; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase; Sugar Alcohol Dehydrogenases

Topics: Aldehyde Reductase; Body Water; Cataract; Collagen; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Hand; Humans; Imidazoles; Imidazolidines; Joint Diseases; Models, Biological

Topics: Aldehyde Reductase; Animals; Axons; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Imidazoles; Imidazolidines; Inositol; Motor Neurons; Neural Conduction; Rats; Sorbitol

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

The resistance of the action potential to ischemic inactivation observed in diabetic patients has been reproduced in vivo in rat rendered diabetic with streptozotocin and, acutely, in normal rats given p.o. a load of glucose. The resistance phenomenon was not detected in galactosemic rats. The preservation of the action potential was reversed by the administration of insulin, but not by treatment with an aldose reductase (AR) inhibitor. The ischemic resistance is attributed to the metabolic availability of excess glucose to the nerve. AR does not appear to be involved in the phenomenon.

Topics: Action Potentials; Aldehyde Reductase; Animals; Blood Glucose; Body Temperature; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Galactosemias; Glucose; Imidazoles; Imidazolidines; Insulin; Ischemia; Neural Conduction; Rats; Rats, Inbred Strains

The small, but statistically significant, improvement in nerve conduction after treatment of diabetic patients with the aldose reductase inhibitor, sorbinil, suggests that increased polyol (sorbitol) pathway activity may contribute to diabetic nerve conduction slowing. Although classically viewed solely in terms of sorbitol-induced osmotic swelling, polyol pathway inhibition is now speculated to influence a concomitant myo-inositol-mediated alteration in nerve sodium-potassium ATPase activity in diabetic nerve. Therefore, we directly examined the effect of sorbinil treatment on sodium-potassium ATPase activity in crude homogenates of sciatic nerve from streptozotocin-diabetic and non-diabetic rats. We demonstrate that sorbinil treatment, which preserves normal nerve myo-inositol content, prevents the fall in nerve sodium-potassium ATPase activity that has been linked to conduction slowing in the diabetic rat.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Imidazoles; Imidazolidines; Inositol; Male; Neural Conduction; Ouabain; Rats; Rats, Inbred Strains; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase

This investigation was designed to determine whether the aldose reductase inhibitor Sorbinil prevented the development of or reversed defects of nerve conduction and axonal transport in streptozotocin-diabetic rats. Untreated diabetes of either 3 or 6 wk duration caused a fall in sciatic motor nerve conduction velocity (MNCV) of 6-9 m/s (P less than 0.001) and significantly reduced the accumulation of axonally transported choline acetyltransferase activity against a 24-h sciatic nerve crush. These functional defects were associated with accumulation of sorbitol and depletion of myo-inositol in the sciatic nerve. Treatment with Sorbinil (25 mg/kg/day, p.o.) throughout the period of diabetes prevented the development of all these abnormalities in both 3- and 6-wk diabetic groups. In a second study, three groups of rats were subject to 3 wk untreated diabetes followed by Sorbinil treatment (as above) for 1, 2, or 3 wk to determine whether the abnormalities expected from 3 wk of untreated diabetes could be reversed. One week of treatment significantly elevated both MNCV and choline acetyltransferase accumulation (P less than 0.05). The longer treatments progressively ameliorated these defects such that the group that received Sorbinil for the second 3 wk of a 6-wk diabetic period gave values that were similar to controls and to diabetic rats that had been given Sorbinil throughout their diabetes. Sorbitol accumulation was markedly reduced by only 1 wk of Sorbinil treatment, but the normalization of myo-inositol levels required 2 wk of treatment. These findings indicate that Sorbinil treatment in diabetic rats prevented and reversed both Sorbitol accumulation and depletion of nerve myo-inositol in the sciatic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Animals; Axonal Transport; Choline O-Acetyltransferase; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Imidazoles; Imidazolidines; Inositol; Male; Neural Conduction; Rats; Rats, Inbred Strains; Sciatic Nerve; Sorbitol

Topics: Diabetic Neuropathies; Humans; Imidazoles; Imidazolidines; Prognosis

Sorbitol, resulting from glucose metabolism through aldose reductase, may play a role in diabetic complications such as cataracts, neuropathy, and vasculopathy. Sulindac (Clinoril) and sorbinil, two inhibitors of aldose reductase, decreased sorbitol formation in cataract or nerve tissue incubated in high glucose TC-199 media. Sulindac, a widely used anti-rheumatic drug, may have clinical applications in preventing diabetic complications.

Topics: Aldehyde Reductase; Animals; Diabetic Neuropathies; Diabetic Retinopathy; Imidazoles; Imidazolidines; Indenes; Lens, Crystalline; Rabbits; Rats; Sciatic Nerve; Sorbitol; Sugar Alcohol Dehydrogenases; Sulindac

Two major metabolic perturbations, increased polyol (sorbitol) pathway activity and reduced tissue myo-inositol content, are induced in peripheral nerve by hyperglycemia. Although they are commonly invoked as alternative biochemical pathogenetic mechanisms for diabetic neuropathy, their possible interrelationship has never been adequately explored. Therefore, we studied the effect of polyol pathway blockade with sorbinil, a specific inhibitor of aldose reductase, on nerve myo-inositol content in acutely streptozotocin-diabetic rats. Sorbinil administration completely prevented the fall in nerve myo-inositol, thereby implicating increased polyol pathway activity as a likely factor in the fall in nerve myo-inositol content in experimental diabetes.

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Fructose; Glucose; Imidazoles; Imidazolidines; Inositol; Male; Rats; Rats, Inbred Strains; Sciatic Nerve; Sorbitol; Sugar Alcohols

Topics: Animals; Axons; Diabetes Mellitus; Diabetic Neuropathies; Fructose; Humans; Imidazoles; Imidazolidines; Neural Conduction; Rabbits; Schwann Cells; Sorbitol

Topics: Diabetic Neuropathies; Humans; Imidazoles; Imidazolidines; Neural Conduction; Skin Temperature

This study examined the effects of an aldose reductase inhibitor (CP 45634, Sorbinil, Pfizer, New York, New York) on the neuropathy of streptozotocin-induced diabetic rats. Sorbinil treatment for 4 wk reduced sciatic nerve sorbitol concentration and improved motor nerve conduction velocity in diabetes of 2-9 mo duration. It remains to be determined whether Sorbinil can prevent chronic diabetic neuropathy.

Topics: Aldehyde Reductase; Animals; Diabetic Neuropathies; Female; Imidazoles; Imidazolidines; Motor Neurons; Neural Conduction; Rats; Rats, Inbred Strains; Sciatic Nerve; Sorbitol; Sugar Alcohol Dehydrogenases; Time Factors