sorbinil and Diabetes-Mellitus--Type-1

Topics: Adult; Aldehyde Reductase; Aneurysm; Capillaries; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Edema; Humans; Imidazoles; Imidazolidines; Laser Therapy; Neovascularization, Pathologic; Retinal Diseases; Retinal Vessels; Sorbitol; Vitrectomy

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

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

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

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

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

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

Erythrocytes from diabetic patients before and after treatment with the aldose reductase inhibitor, sorbinil, were analyzed by a capillary gas chromatographic method for sorbitol and myo-inositol. The mean erythrocyte sorbitol level in the diabetic patients was significantly higher than in the control subjects (13.1 +/- 0.9 and 5.2 +/- 0.3 nmol/ml erythrocytes, respectively, mean +/- SEM, p less than 0.001). The mean erythrocyte myo-inositol level in diabetic patients was not different from that in control subjects (43.2 +/- 2.9 and 40.5 +/- 1.9 nmol/ml erythrocytes, respectively). Sorbinil treatment reduced the elevated sorbitol levels in the diabetic patients to normal or slightly below normal, but did not affect the erythrocyte myo-inositol concentration. It is concluded that the erythrocyte is not a suitable model to monitor a possible effect of sorbinil on myo-inositol concentration in less accessible tissues.

Topics: Adult; Aldehyde Reductase; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Erythrocytes; Female; Gas Chromatography-Mass Spectrometry; Humans; Imidazoles; Imidazolidines; Inositol; Male; Middle Aged; Sorbitol; Sugar Alcohol Dehydrogenases

In a double-blind crossover study of 15 diabetic patients, elevated red blood cell (RBC) sorbitol levels were reduced by oral doses of the potent aldose reductase inhibitor, sorbinil (250 mg o.d.), to near-normal ranges. In diabetic rats with severe hyperglycemia, oral sorbinil (5 mg/kg) dramatically reduced (80-90%) sorbitol levels in tissues without affecting blood glucose; the RBC dose-response curve was similar to that in lens and sciatic nerve. In streptozotocin-treated rats with varying degrees of diabetes sorbitol levels in the lens, sciatic nerve, and RBC were elevated in proportion to the degree of hyperglycemia. RBC sorbitol levels in these animals were positively correlated with the levels in lens and sciatic nerve. These results establish that orally administered sorbinil is effective in lowering elevated sorbitol levels, and strongly suggest that the reduction seen in RBC sorbitol levels in human diabetic subjects is likely to reflect comparable effects of the drug in less accessible tissues associated with the long-term complications of diabetes.

Topics: Administration, Oral; Adolescent; Adult; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Erythrocytes; Hemoglobin A; Humans; Imidazoles; Imidazolidines; Male; Polymers; Rats; Rats, Inbred Strains; Sorbitol

In many ophthalmologic studies, progression of diseases such as diabetic retinopathy, age-related maculopathy, cataract, and glaucoma is only noted when each eye is examined at intervals that commonly vary between subjects. Such data are often analysed using continuous time survival methods with observed progression assumed to occur at the end of the interval. Tied times of progression can lead to substantial bias in estimation of the association between progression in right and left eyes. We describe a multiple imputation strategy to create multiple data sets without ties, based on drawing interval-censored progression times from a parametric gamma frailty model that accounts for continuous and discrete covariates. We illustrate the method with data from 478 patients with insulin-dependent diabetes mellitus who were followed for progression of diabetic retinopathy in the Sorbinil Retinopathy Trial. Resolution of tied failure times allows for valid estimation of the hazard of progression in one eye given the progression status of the other eye. A simulation study suggests that the method performs well. Results highlight the advantage of multiple imputation that data imputed under one model can be analysed under several alternative models.

Topics: Adolescent; Adult; Computer Simulation; Data Interpretation, Statistical; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Disease Progression; Enzyme Inhibitors; Eye Diseases; Humans; Imidazolidines; Middle Aged; Models, Statistical; Randomized Controlled Trials as Topic

The authors compared, in the context of diabetic retinopathy, alternative methods of quantifying the extent to which disease progression in one eye increases the risk of subsequent progression in the other eye. Data were gathered on 478 US patients with insulin-dependent diabetes mellitus who participated in the 1983-1988 Sorbinil Retinopathy Trial and were followed up for a median of 41 months. During that time, diabetic retinopathy progressed in 93 right eyes and 77 left eyes. Crude incidence rates of progression for right eyes were 7.7 times higher after the left eye had progressed and, for left eyes, were 4.4 times higher after the right eye had progressed. In eye-specific proportional hazards models that adjusted for increasing rates of progression over time and for baseline risk factors, the comparable relative risks associated with progression in the other eye were 2.6 (95% confidence interval (CI): 1.5, 4.7) for right eyes and 1.4 (95% CI: 0.72, 2.9) for left eyes. Two alternative proportional hazards models that included data on both eyes and accounted for their correlation produced estimated relative risks of 1.9 (95% CI: 1.2, 2.9) and 2.7 (95% CI: 1.8, 3.5), respectively. The more complex models for joint survival integrate information on both eyes and provide more stable estimates than do separate analyses of right or left eyes.

Topics: Adult; Aldehyde Reductase; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Disease Progression; Female; Follow-Up Studies; Humans; Imidazoles; Imidazolidines; Incidence; Male; Models, Statistical; Multivariate Analysis; Proportional Hazards Models; Reproducibility of Results; Risk Factors; Survival Analysis; Time Factors; United States

To determine the risk factors for retinopathy progression in type 1 (insulin-dependent) diabetes mellitus in a prospective cohort study.. Subjects were 485 participants in the Sorbinil Retinopathy Trial, a randomized trial of aldose reductase inhibition among patients aged 18 to 56 years with type 1 diabetes mellitus (duration of 1 to 15 years) and no or only mild retinopathy. Retinopathy progression, assessed by seven-field stereoscopic fundus photography, was defined as worsening by two or more levels on a standardized grading scale at the end of follow-up (median, 41 months).. The relative risks for retinopathy progression according to successively greater quintiles of total glycosylated hemoglobin level at baseline, after adjusting for age, diabetes duration, sorbinil assignment, and other variables, were 1.0, 2.0, 1.6, 3.7, and 4.4 (P trend <0.0001). Risk increased with greater baseline diastolic blood pressure: 1.0 for <70 mm Hg, 1.2 for 70 to 79 mm Hg, and 1.8 for > or =80 mm Hg (P for trend = 0.04). Diastolic blood pressure was a significant risk factor for progression in participants with mild baseline retinopathy (P for trend <0.02) but not in those without retinopathy at entry. Systolic blood pressure, by comparison, was not associated with progression. Baseline total cholesterol level was a marginally significant predictor of retinopathy progression when examined as a categorical variable (relative risks for increasing quartiles; 1.0, 1.6, 1.8, 1.9; P for trend = 0.03) but not when it was examined as a continuous variable or when hypercholesterolemic patients were compared with those with normal levels. Furthermore, when cholesterol levels were updated in subsequent visits, it was not a significant predictor of progression, and low density lipoprotein (LDL) cholesterol levels did not predict progression no matter how analyzed. Smoking was not associated with progression of retinopathy.. Levels of hyperglycemia and diastolic blood pressure predicted progression of retinopathy in type 1 diabetes mellitus. We found only a suggestion of an association between total cholesterol level (but not of LDL cholesterol level) and progression of retinopathy; resolution of this issue will require additional studies with larger sample sizes and longer follow-up.

Topics: Adult; Aldehyde Reductase; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Disease Progression; Enzyme Inhibitors; Female; Humans; Imidazoles; Imidazolidines; Lipids; Male; Middle Aged; Prospective Studies; Randomized Controlled Trials as Topic; Risk; Risk Factors; Smoking

Diabetic nephropathy leading to kidney failure is a major complication of type I (insulin-dependent) diabetes mellitus and is associated with progressive proteinuria. In the present 6-month study, effects of two structurally dissimilar aldose reductase inhibitors (sorbinil and ponalrestat or Statil) were examined on prevention of proteinuria in insulin-dependent spontaneously diabetic BB rats and compared with age-matched BB resistant controls. Prior to aldose reductase inhibitor treatment, all diabetic BB rats exhibited hyperglycemia (> 300 mg/dl), glycosuria (> 2,000 mg/dl) and 24-hour urinary protein excretion ranging from 5.01 to 11.23 mg/day. After daily administration of ponalrestat (20 mg/kg) for 3 months, 24-hour urinary protein excretion was 11.53 +/- 1.76 mg/day in ponalrestat-treated rats, despite persistence of hyperglycemia (444 +/- 31 mg/dl) and glycosuria (> 2,000 mg/dl); by contrast, urinary protein excretion was 17.76 +/- 2.59 mg/day in the control group of untreated BB diabetic rats. Ponalrestat initially protected against excretion of an array of urinary proteins having molecular weights between 30,000 and 100,000 daltons. These effects sustained throughout the 4th month of treatment, tended to change toward valves in control rats by the 5th month. At the end of 6 months, ponalrestat-treated diabetic rats excreted 18.73 +/- 3.20 mg/day of protein, similar to valves in untreated BB diabetic rats; both demonstrated a 4-fold increase in urinary protein excretion when compared to age-matched BB resistant controls. Proteinuria was attributed to an increase in albumin and an array of proteins having molecular weights between 30,000 and 100,000 daltons.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Imidazoles; Imidazolidines; Male; Phthalazines; Proteinuria; Rats; Rats, Inbred BB

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

Nephropathy is a serious complication of Type I or insulin-dependent diabetes mellitus (IDDM) with a poor prognosis after the onset of proteinuria. Since aldose reductase may be implicated in the pathogenesis of proteinuria, onset and reversal studies were performed with sorbinil at a dose of 20 mg/kg to determine whether inhibition of this enzyme promoted either diminution or reversal of the appearance of urinary proteins. In the onset study, age-matched control, streptozotocin-diabetic, and sorbinil-treated diabetic rats were maintained for ten weeks; their 24-hour urine samples were analyzed weekly for volume, glucose, ketones, total protein, and individual protein components with molecular weights between 15,000 and 120,000 daltons. These last were examined by polyacrylamide gel electrophoresis and quantitated by laser densitometric analysis. Results indicated that sorbinil administered daily for ten weeks effectively diminished total protein excretion throughout this period primarily by protecting against appearance of abnormal urinary proteins that characterized the untreated diabetic state; the latter exhibited albuminuria, numerous newly detected proteins between 30,000 and 65,000 daltons, and an additional 4 to 5 proteins between 70,000 and 120,000 daltons. These findings closely resembled protein patterns exhibited by 54-week spontaneously diabetic BB rats, another model for IDDM. In the reversal study, age-matched control and streptozotocin-induced diabetic rats were maintained for four weeks, and weekly 24-hour urine analyses were performed as previously described.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Animals; Cataract; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Electrophoresis, Polyacrylamide Gel; Humans; Imidazoles; Imidazolidines; L-Iditol 2-Dehydrogenase; Proteinuria; Rats; Rats, Inbred BB

Erythrocyte deformability was studied in a total of 83 poorly controlled diabetics (mean blood glucose 12.2 mmol/l) who were divided into three groups, each with matched healthy controls. There was no appreciable difference between diabetics and matched controls regarding the filtration of erythrocytes through 3 micron diameter straight channel pores (25 diabetics) or tortuous channel pores (28 diabetics), or for the measurement of erythrocyte elongation over a range of osmolalities in the Ektacytometer (30 diabetics). When erythrocytes from 17 additional diabetics and 17 healthy controls were incubated for two hours at 37 degrees C in hyperglycaemic (50 mmol glucose/l) buffer, however, there was a considerable reduction in erythrocyte filterability for both diabetics and controls in parallel with an increase in erythrocyte sorbitol concentration. This loss of filterability was prevented by the addition of an aldose reductase inhibitor (Sorbinil). High glucose concentrations (congruent to 50 mmol/l) impair the filterability of erythrocytes through 3 micron pores, and the intracellular accumulation of sorbitol in poorly controlled outpatients is therefore unlikely to have a major adverse effect on erythrocyte rheology in diabetes mellitus.

Topics: Adult; Aged; Aldehyde Reductase; Blood Glucose; Diabetes Mellitus, Type 1; Erythrocyte Deformability; Female; Glucose; Humans; Imidazoles; Imidazolidines; In Vitro Techniques; Male; Middle Aged; Osmolar Concentration; Sorbitol