rhodanine and Diabetic-Retinopathy

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

The long-term efficacy of epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to epalrestat treatment.. Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor-Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity > or = 40 m/s and with glycated haemoglobin (HbA(1c)) < or = 9.0%. Longitudinal data on HbA(1c) and subjective symptoms of the patients for 3 years were analysed (epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted.. Stratified subgroup analyses revealed significantly better efficacy of epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA(1c) < or = 7.0%).. Our results suggest that epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients.

Topics: Administration, Oral; Aged; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diabetic Retinopathy; Enzyme Inhibitors; Female; Glycated Hemoglobin; Humans; Long-Term Care; Male; Middle Aged; Patient Selection; Proteinuria; Rhodanine; Thiazolidines; Treatment Outcome

To evaluate the effect of ranirestat, a new aldose reductase inhibitor (ARI), on diabetic retinopathy (DR) in Spontaneously Diabetic Torii (SDT) rats.. The animals were divided into six groups, normal Sprague-Dawley rats (n = 8), untreated SDT rats (n = 9), ranirestat-treated SDT rats (0.1, 1.0, and 10 mg/kg/day, n = 7, 8, and 6, resp.), and epalrestat-treated SDT rats (100 mg/kg/day, n = 7). Treated rats received oral ranirestat or epalrestat once daily for 40 weeks after the onset of diabetes. After the eyes were enucleated, the retinal thickness and the area of stained glial fibrillary acidic protein (GFAP) were measured.. The retinas in the untreated group were significantly thicker than those in the normal and ranirestat-treated (0.1, 1.0, and 10 mg/kg/day) groups. The immunostained area of GFAP in the untreated group was significantly larger than that in the normal and ranirestat-treated (1.0 and 10 mg/kg/day) groups. There were no significant differences between the untreated group and epalrestat-treated group in the retinal thickness and the area of stained GFAP.. Ranirestat reduced the retinal thickness and the area of stained GFAP in SDT rats and might suppress DR and have a neuroprotective effect on diabetic retinas.

Topics: Administration, Oral; Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetic Retinopathy; Disease Models, Animal; Drug Administration Schedule; Enzyme Inhibitors; Glial Fibrillary Acidic Protein; Glycated Hemoglobin; Male; Neuroprotective Agents; Pyrazines; Rats; Rats, Sprague-Dawley; Retina; Rhodanine; Spiro Compounds; Thiazolidines; Time Factors

The goal of the study was to evaluate the efficacy of epalrestat, an aldose reductase inhibitor, on diabetic retinopathy and diabetic nephropathy, based on analysis of the results of the Aldose Reductase Inhibitor-Diabetes Complications Trial, a 3-year multicentre comparative clinical trial of conventional therapy (control group) and epalrestat therapy (epalrestat group) in Japanese patients with mild diabetic neuropathy.. The subjects of the study were patients enrolled in the Aldose Reductase Inhibitor-Diabetes Complications Trial for whom data for major patient characteristics, severity of diabetic neuropathy at the end of the study and time-courses of diabetic retinopathy and diabetic nephropathy were available (57 and 52 patients from the control and epalrestat groups, respectively). Progression of diabetic retinopathy/nephropathy (a primary endpoint) in relation to major patient characteristics, severity of diabetic neuropathy at the end of the study (assessed from the mean of z-scores in four neurological function tests) and epalrestat treatment were analysed using univariate analysis and multiple logistic regression analysis.. Progression of diabetic retinopathy/nephropathy was significantly inhibited in the epalrestat group compared with the control group (odds ratio = 0.323, P = 0.014) and was dependent on the severity of diabetic neuropathy at the end of the study (odds ratio = 2.131, P = 0.025).. Epalrestat prevented progression of diabetic neuropathy and retinopathy/nephropathy. The effect on diabetic retinopathy/nephropathy may have occurred indirectly because of the prevention of progression of diabetic neuropathy, in addition to the inhibitory action of epalrestat on aldose reductase.

Topics: Aged; Aged, 80 and over; Aldehyde Reductase; Asian People; Blood Glucose; Cost-Benefit Analysis; Diabetic Neuropathies; Diabetic Retinopathy; Disease Progression; Enzyme Inhibitors; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Multivariate Analysis; Neural Conduction; Rhodanine; Severity of Illness Index; Thiazolidines; Time Factors; Treatment Outcome

To clarify the role of the polyol pathway in the intracellular formation of advanced glycation end products in human tissues, we examined the effects of epalrestat, an aldose reductase inhibitor, on the level of Nepsilon-(carboxymethyl)lysine (CML) along with 3-deoxyglucosone (3-DG) and triosephosphates in erythrocytes from diabetic patients. Plasma thiobarbituric acid-reactive substances (TBARS) were also determined as indicators of oxidative stress.. Blood samples were collected from 12 nondiabetic volunteers, 38 untreated type 2 diabetic patients, and 16 type 2 diabetic patients who had been treated with 150 mg epalrestat/day. Blood samples were also collected from 14 of the untreated type 2 diabetic patients before and after the administration of epalrestat for 2 months. The amount of erythrocyte CML was determined by a competitive enzyme-linked immunosorbent assay, and 3-DG was measured by high-performance liquid chromatography. In diabetic patients not treated with epalrestat, the erythrocyte CML level was significantly elevated above levels seen in nondiabetic individuals (49.9 +/- 5.0 vs. 31.0 +/- 5.2 U/g protein, P < 0.05) and was significantly lower in patients receiving epalrestat (33.1 +/- 3.8 U/g protein, P < 0.05). Similar results were observed with 3-DG. The treatment of patients with epalrestat for 2 months significantly lowered the level of erythrocyte CML (46.2 +/- 5.6 at baseline vs. 34.4 +/- 5.0 U/g protein, P < 0.01) along with erythrocyte 3-DG (P < 0.05), triosephosphates (P < 0.05), fructose (P < 0.05), sorbitol (P < 0.05), and plasma TBARS (P < 0.05) without changes in plasma glucose and HbA(1c) levels. A positive correlation was evident between the erythrocyte CML and sorbitol (r = 0.49, P < 0.01) or fructose (r = 0.40, P < 0.05) levels in diabetic patients.. The results indicate that epalrestat administration lowers CML and associated variables and that polyol metabolites are correlated with CML in the erythrocytes of diabetic patients. The observed results suggest that aldose reductase activity may play a substantial role in the intracellular formation of CML in the mediation of reactive intermediate metabolites and oxidative stress.

Topics: Aldehyde Reductase; Blood Glucose; Blood Proteins; Deoxyglucose; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diabetic Retinopathy; Enzyme Inhibitors; Erythrocytes; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Lysine; Male; Middle Aged; Reference Values; Rhodanine; Thiazolidines

Topics: Adolescent; Adult; Aged; Aldehyde Reductase; Blood Glucose; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Enzyme Inhibitors; Erythrocytes; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Regression Analysis; Reproducibility of Results; Rhodanine; Sorbitol; Spectrophotometry; Thiazolidines

The effect of concomitant administration of galactose and the aldose reductase inhibitor(ARI) Epalrestat (Kinedak) on corneal barrier function was examined in dogs. Six-month-old male beagles were rendered aphakic in one eye and then divided into four groups as follows: 1) a control group fed on 30% cellulose, 2) a galactosemic group fed on 30% galactose, 3) a 30% galactose-fed group treated with low dose (20 mg/kg) ARI and 4) a 30% galactose-fed group treated with high dose (50 mg/kg) ARI. Forty-one months after the start of these diets, corneal autofluorescence and the corneal barrier function were measured in each dog using anterior fluorophotometry (FL-500). When barrier function was analyzed in non-operated eyes, fluorescence data were significantly higher in the galactosemic group compared to the control group. In non-operated eyes, fluorescent data in high-dose ARI treated group were significantly lower than those in the galactosemic group. However, in operated eyes, no significant difference was observed between the galactosemic group and the ARI treated groups. Similar trends were observed when corneal autofluorescence of each group was compared. Long-term galactose feeding appeared to damage corneal epithelial barrier function. This damage was not observed in the high-dose ARI treated group suggesting that this damage may be linked to the polyol pathway.

Topics: Aldehyde Reductase; Animals; Diabetic Retinopathy; Diet; Dogs; Enzyme Inhibitors; Epithelium, Corneal; Fluorescence; Galactose; Male; Reference Values; Rhodanine; Thiazolidines

Topics: Animals; Diabetic Retinopathy; Electroretinography; Humans; Male; Middle Aged; Polymers; Rats; Rats, Inbred Strains; Retina; Rhodanine; Thiazolidines

Topics: Adult; Age Factors; Aged; Blood Glucose; Diabetic Retinopathy; Diet Therapy; Exercise Therapy; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Polymers; Rhodanine; Sex Factors; Thiazolidines

Topics: Aldehyde Reductase; Animals; Diabetic Retinopathy; Male; Rats; Rats, Inbred Strains; Rhodanine; Sugar Alcohol Dehydrogenases; Thiazoles; Thiazolidines