epalrestat and Diabetic-Neuropathies

Epalrestat is the only aldose reductase inhibitor that is currently available for diabetic peripheral neuropathy. Oxidative stress impairs endothelial cells, thereby leading to numerous pathological conditions. Increasing antioxidative ability is important to prevent cellular toxicity induced by reactive oxygen species. Epalrestat increases antioxidant defense factors such as glutathione and γ-glutamylcysteine ligase in vascular endothelial cells through activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This increases suppression of oxidative stress-induced cellular toxicity. Cadmium is an industrial and environmental pollutant that targets the vascular endothelium. The vascular system is critically affected by cadmium toxicity. Therapeutic treatment against cadmium toxicity is chelation therapy that promotes metal excretion; however, cadmium chelators can cause renal toxicity. Therefore, safe and efficient therapeutic agents are required. Epalrestat suppresses cadmium-induced cytotoxicity in vascular endothelial cells through activation of Nrf2. In addition, epalrestat affects the intracellular levels of cadmium, cadmium transporter Zrt-Irt-like protein 8 (ZIP8), and metallothionein (MT). The upregulation of ZIP8 and MT may be involved in the suppression of cadmium-induced cytotoxicity by epalrestat. Drug repurposing is a new strategy for drug discovery in which the pharmacological action of existing medicines whose safety and pharmacokinetics have already been confirmed clinically and whose use has been approved is examined comprehensively at the molecular level. The results can be applied to the development of existing drugs for use as medicines for the treatment of other diseases. This review provides useful findings for future expansion of indications as research leading to drug repurposing of epalrestat.

Topics: Aldehyde Reductase; Antioxidants; Cadmium; Chelating Agents; Diabetes Mellitus; Diabetic Neuropathies; Endothelial Cells; Environmental Pollutants; Glutathione; Humans; Ligases; Metallothionein; NF-E2-Related Factor 2; Reactive Oxygen Species; Rhodanine; Thiazolidines

Objective To compare the clinical effectiveness of lipoic acid combined with epalrestat versus lipoic acid in treating diabetic peripheral neuropathy(DPN). Methods Randomized controlled trials(RCTs) and clinical controlled trials on lipoic acid versus epalrestat for DPN before February 2016 were searched through five databases:CNKI,CBM,VIP,Wanfang,and PubMed. The quality of the included trials were assessed using Cochrane software and Jadad scores. Data were analyzed with Review Manager 5.3 software. Results Nine studies were included in the analysis. Meta analysis showed that the lipoic aid monotherapy was significantly inferior to lipoic acid-epalerestat combination therapy [RR=0.58,95%Cl(0.47,0.71),P<0.00001]. Inferiority of the lipoic acid monotherapy was also shown in nerve conduction velocity with WMDs of-4.94 [95%Cl(-7.41,-2.46),P<0.0001] for median motor nerve conduction velocity(MNCV),-5.08 [95%Cl(-7.68,-2.49),P=0.0001] for peroneal MNCV,-4.24 [95%Cl(-6.20,-2.29),P<0.0001] for median sensory nerve conduction velocity(SNCV),and-3.66 [95%Cl(-5.02,-2.31),P<0.00001] for peroneal SNCV. Sensitivity analysis showed that the results were robust. However,the included trials were limited by simple design,few subjective indicators,and short follow-up time. Conclusions Lipoic acid combined with epalrestat is better than lipoic acid alone in the treatment of DPN,as well as the MNCV and SNCV of median or peroneal nerve. Due to the low quality of the included studies,high-quality RCTs are warranted to validate the results.. 目的 比较硫辛酸联合依帕司他与硫辛酸治疗糖尿病周围神经病变(DPN)患者的临床疗效。方法 收集2016年2月以前CNKI、CBM、维普、万方、PubMed等数据库中硫辛酸联合依帕司他对比硫辛酸治疗DPN的临床试验资料,采用Cochrane系统及Jadad评分对文章进行质量评估,RevMan5.3软件对多项研究结果的总体效应进行Meta分析。结果 共纳入9项研究。Meta分析结果显示:硫辛酸显效率明显低于硫辛酸联合依帕司他[RR=0.58,95% CI(0.47,0.71),P<0.00001],正中运动神经传导速度[WMD=-4.94,95% CI(-7.41,-2.46),P<0.0001]、腓总运动神经传导速度[WMD=-5.08,95% CI(-7.68,-2.49),P=0.0001]、正中感觉神经传导速度[WMD=-4.24,95% CI(-6.20,-2.29),P<0.0001]和腓总感觉神经传导速度[WMD=-3.66,95% CI(-5.02,-2.31),P<0.00001]也明显低于联合用药。敏感性分析显示结果稳健。但纳入研究存在设计报道简单、主观指标少、随访时间短等问题。结论 硫辛酸联合依帕司他可提高显效率,增加正中或腓总神经的运动神经传导速度和感觉神经传导速度。由于目前纳入文献质量普遍不高,需谨慎考虑此结论,希望有更多高质量的随机对照试验支持。.

Topics: Diabetic Neuropathies; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Rhodanine; Thiazolidines; Thioctic Acid

Topics: Achilles Tendon; Aldehyde Reductase; Animals; Antidepressive Agents, Tricyclic; Atrophy; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Hypoglycemic Agents; Leg; Muscle, Skeletal; Pain Measurement; Reflex; Rhodanine; Skin; Thiazolidines; Vibration

Diabetic neuropathy is one of the most common long-term complications in patients with diabetes mellitus, with a prevalence of 60-70% in the United States. Treatment options include antidepressants, anticonvulsants, tramadol, and capsaicin. These agents are modestly effective for symptomatic relief, but they do not affect the underlying pathology nor do they slow progression of the disease. Epalrestat is an aldose reductase inhibitor that is approved in Japan for the improvement of subjective neuropathy symptoms, abnormality of vibration sense, and abnormal changes in heart beat associated with diabetic peripheral neuropathy. Unlike the current treatment options for diabetic neuropathy, epalrestat may affect or delay progression of the underlying disease process. Data from experimental studies indicate that epalrestat reduces sorbitol accumulation in the sciatic nerve, erythrocytes, and ocular tissues in animals, and in erythrocytes in humans. Data from six clinical trials were evaluated, and it was determined that epalrestat 50 mg 3 times/day may improve motor and sensory nerve conduction velocity and subjective neuropathy symptoms as compared with baseline and placebo. Epalrestat is well tolerated, and the most frequently reported adverse effects include elevations in liver enzyme levels and gastrointestinal-related events such as nausea and vomiting. Epalrestat may serve as a new therapeutic option to prevent or slow the progression of diabetic neuropathy. Long-term, comparative studies in diverse patient populations are needed for clinical application.

Topics: Aldehyde Reductase; Animals; Clinical Trials as Topic; Diabetic Neuropathies; Humans; Rhodanine; Thiazolidines

Topics: Aldehyde Reductase; Animals; Capillaries; Capillary Permeability; Diabetic Neuropathies; Enzyme Inhibitors; Genetic Therapy; Hepatocyte Growth Factor; Humans; Ischemia; Oxidative Stress; Peripheral Nerves; Regional Blood Flow; Reperfusion Injury; Rhodanine; Thiazolidines; Vascular Endothelial Growth Factor A

Topics: Aldehyde Reductase; Antioxidants; C-Peptide; Diabetic Neuropathies; Drug Design; Enzyme Inhibitors; Genetic Therapy; Glycation End Products, Advanced; Hedgehog Proteins; Humans; Indoles; Maleimides; Nerve Growth Factor; Oxidative Stress; Polymers; Protein Kinase C; Rhodanine; Thiadiazoles; Thiamine; Thiazoles; Thiazolidines; Trans-Activators; Vascular Endothelial Growth Factor A

Topics: Aldehyde Reductase; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Chronic Disease; Diabetic Neuropathies; Enzyme Inhibitors; gamma-Linolenic Acid; Glycation End Products, Advanced; Guanidines; Humans; Insulin; Oxidative Stress; Rhodanine; Thiazolidines

Topics: Aldehyde Reductase; Blood Glucose; Clinical Trials as Topic; Depression, Chemical; Diabetic Neuropathies; Enzyme Inhibitors; Free Radicals; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Multicenter Studies as Topic; Protein Precursors; Rhodanine; Thiazolidines

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

In order to study a long-term effect along with adverse action of epalrestat, an aldose reductase inhibitor, a randomized, prospective study was conducted over the period of 3 years at 112 facilities. Six hundred and three diabetic patients with median motor conduction velocity (MCV)>40 m/s, HbA1c<9% were randomly allocated to epalrestat (50 mg/day p.o. ac, t.i.d.) group (E group: n=289, age: 61+/-9.8 y.o.) and a control group (C group: n=305, age: 61+/-9.1 y.o.). MCV was measured once a year for 3 years. MCV (m/s, M+/-S.D.) on baseline, 1 year and 3 years, was 52.0+/-4.5, 52.2+/-4.9, 52.1+/-4.6 in E group and 53.3+/-4.4, 52.4+/-4.2, 52.0+/-4.6 in C group, respectively. After 3 years, difference from the baseline was significant (p<0.0001, E versus C). Among the subjects with HbA1c<7.0%, C group showed marked deterioration of MCV while in E group, there was no significant deterioration (p<0.001). Although, the subjects with pre-proliferative or proliferative retinopathy, there was no difference between E and C groups for 3 years, in subjects with background retinopathy or without retinopathy, deterioration rate of E group was significantly less than that of C group (p<0.0001). Epalrestat was found to prevent deterioration of MCV especially in well-controlled patients without advanced complications. No remarkable side effects serious enough to discontinue the study was observed.

Topics: Age of Onset; Aged; Aldehyde Reductase; Body Mass Index; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Enzyme Inhibitors; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Motor Neurons; Neural Conduction; Prospective Studies; Rhodanine; Thiazolidines

In diabetic nerves, activation of the polyol pathway via an aldose reductase and the resulting impairment of the Na(+)-K(+) pump would lead to a decreased transaxonal Na+ gradient and thereby reduced nodal Na+ currents.. To investigate whether the aldose reductase inhibitor (ARI) epalrestat improves nodal Na+ currents and nerve conduction in human diabetic neuropathy.. The authors conducted a 6-month, open clinical trial with an ARI, epalrestat, in 30 patients with mild-to-moderate diabetic neuropathy. The latent addition technique and measurements of the strength-duration time constant were used to estimate nodal persistent Na+ currents in median motor axons. Excitability testing and extensive nerve conduction studies including F-wave analyses were performed before and 1 and 6 months after the initiation of treatment with oral epalrestat.. Within a month of the start of treatment, there was a significant improvement in nerve conduction, particularly in conduction times across the carpal tunnel and F-wave latencies. The results of latent addition (p < 0.05) and strength-duration time constant (p = 0.06) suggested increased nodal persistent Na+ currents. At 6 months, nerve conduction continued to improve.. Aldose reductase pathway inhibition could rapidly increase nodal Na+ currents and thereby improve the slowing of nerve conduction, presumably because of a restoration of the membranous Na+ gradient.

Topics: Adult; Aged; Aged, 80 and over; Aldehyde Reductase; Carpal Tunnel Syndrome; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Ion Transport; Male; Median Nerve; Middle Aged; Neural Conduction; Reaction Time; Rhodanine; Sodium; Sodium Channels; Thiazolidines

Topics: Action Potentials; Aldehyde Reductase; Diabetes Mellitus; Diabetic Neuropathies; Double-Blind Method; Electric Stimulation; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neural Conduction; Reaction Time; Rhodanine; Thiazolidines

We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy.. Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) >or=40 m/s, and HbA(1c)

Topics: Adult; Aged; Aldehyde Reductase; Blood Glucose; Diabetic Angiopathies; Diabetic Neuropathies; Enzyme Inhibitors; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Neural Conduction; Rhodanine; Thiazolidines

The present study was conducted to investigate the effect of an aldose reductase inhibitor, epalrestat, on autonomic and somatic neuropathy at an early stage in type 2 diabetic patients by assessing the pupillary light reflex and minimum latency of the F-wave.. A total of 30 diabetic patients with subclinical or mild diabetic neuropathy were randomly allocated to a control group (n = 15) and epalrestat (150 mg/day) group (n = 15). After 24 weeks, the pupillary light reflex test, cardiovascular autonomic function tests, and nerve conduction study were performed.. The beneficial effect of epalrestat on the pupillary light reflex was observed in the minimum diameter after light stimuli (P = 0.044), constriction ratio (P = 0.014), and maximum velocity of constriction (P = 0.008). Among cardiovascular autonomic nerve functions, the ratio of the longest expiratory R-R interval to the shortest inspiratory R-R interval during deep breathing was significantly improved by epalrestat (P = 0.037). Minimum latencies of F-wave of median and tibial motor nerves were significantly shortened by epalrestat (P = 0.002 and P = 0.001, respectively); however, no significant effects were observed in motor or sensory nerve conduction velocity.. These observations suggest that epalrestat may have therapeutic value at the early stage of diabetic neuropathy and that the pupillary light reflex and minimum latency of F-wave may be useful indicators of diabetic neuropathy.

Topics: Aldehyde Reductase; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diet, Diabetic; Electrocardiography; Enzyme Inhibitors; Female; Heart Rate; Humans; Hypoglycemic Agents; Insulin; Light; Male; Median Nerve; Middle Aged; Neural Conduction; Reaction Time; Reflex, Pupillary; Respiratory Mechanics; Rhodanine; Thiazolidines; Tibial Nerve

To evaluate the effect of long-term administration of an aldose reductase inhibitor on diabetic cardiovascular autonomic neuropathy, 22 subjects with non-insulin dependent diabetes mellitus (NIDDM, 11 men and 11 women, mean age; 64.8 +/- 7.8 years, duration of diabetes; 18.3 +/- 5.6 years) were administered epalrestat, one type of aldose reductase inhibitor, for 36 months. The changes in the coefficient of variation of the R-R interval (CV(R R)) during rest and the QTc interval were compared with 43 age-matched NIDDM (controls). During the study, the CV(R R) value gradually decreased in the controls, while it slightly increased in subjects treated with epalrestat. After 36 months, the CV(R R) value (2.31 +/- 1.09%) in subjects treated with epalrestat was significantly (P < 0.05) higher than that (1.84 +/- 0.75%) in the controls. There were no significant differences in QTc intervals in both groups. These results suggest that long-term administration of an aldose reductase inhibitor may be available for cardiac autonomic neuropathy in even relatively older diabetic subjects with long duration.

Topics: Aged; Aged, 80 and over; Aldehyde Reductase; Autonomic Nervous System Diseases; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Electrocardiography; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Rhodanine; Statistics, Nonparametric; Thiazolidines

The clinical efficacy of epalrestat (150 mg/day, 50 mg tid, po; A group), an aldose reductase inhibitor, was evaluated in 196 patients with diabetic neuropathy by a double-blind study using placebo (9 mg/day, 3 mg tid, po; P group) as a control for 12 weeks. The disappearance rates of upper limb spontaneous pain were 42.9% and 12.0% in the A and P groups, respectively, and those of lower limb spontaneous pain 48.6% and 22.6%, thus being significantly higher in the A group (p < 0.05, logrank-test). The motor nerve conduction velocity of the peroneal nerve significantly increased only in the A group (delta 1.6 +/- 0.6 m/sec, p < 0.01, paired t-test), and the extent of increase in that of the median nerve was significantly greater in the A group than in the P group (p < 0.05). Thresholds of vibratory sensation and autonomic nerve function were also significantly improved in the A group (p < 0.05). The data were reanalyzed by dividing patients into two groups according to their HbA1c values. The improvement ratings of subjective symptoms and of nerve function tests for cases with HbA1c > or = 7.5% were both significantly different between the A and P groups, with the improvement rate being higher in the A group, and also higher as compared to the analysis for cases with HbA1c < 7.5%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aldehyde Reductase; Arm; Blood Glucose; Diabetic Neuropathies; Double-Blind Method; Enzyme Inhibitors; Female; Heart Rate; Humans; Male; Middle Aged; Neural Conduction; Pain; Rhodanine; Sensory Thresholds; Thiazolidines; Vibration

Topics: Adult; Aldehyde Reductase; Diabetic Neuropathies; Double-Blind Method; Glycated Hemoglobin; Humans; Median Nerve; Middle Aged; Neural Conduction; Peroneal Nerve; Placebos; Rhodanine; Thiazolidines

Diabetic peripheral neuropathy is the most common complication of diabetes mellitus. Epalrestat, an aldose reductase inhibitor, has been approved for clinical therapy for diabetic peripheral neuropathic pain. In the present study, solid lipid-based nanoparticles are used for oral administration of epalrestat (E-SLN) and evaluated against diabetic neuropathic pain in a rat model.. Experimental diabetes in rats was induced by a single dose of streptozotocin (STZ) administration. The therapeutic efficiency of Epalrestat nanoparticles (0.25, 0.50, 1, and 5 mg/kg) in diabetic rats was studied. STZinduced diabetic rats were treated with different doses of E-SLN for 8 weeks. The nanoparticles were orally administered at a single dose in rats, and the various parameters related to peripheral neuropathy were evaluated and compared with the bare drug. The blood glucose level was estimated by standard glucometer, HbA1c, triglycerides, total cholesterol, and liver function test (ALT and AST) were analyzed by blood samples collected from retro-orbital plexus. Oxidative stress markers and Na+K+ATPase, TNF-α, and IL-1β levels were measured in the homogenate of sciatic nerves. Behavioral tests were also performed by the hot plate method and tail-flick method.. E-SLN synthesized by the micro-emulsification method was 281 ± 60 nm in size, and encapsulation efficacy was found to be 88 ± 2%. Optimized E-SLN were characterized and found to be optimum in size, spherical shape, decent encapsulation efficiency, stable at acidic gastric pH, and suitable for oral delivery. E-SLNs did not significantly reverse the STZ-induced elevated blood glucose level (FBS and PPBS), HbA1c, triglycerides, and total cholesterol but significantly improved TNF-α, IL-1β, and increased Na+K+ATPase levels, oxidative stress marker and ALT, AST in the treated rat group as compared with the diabetic group. Doses of E-SLN, i.e. 0.5, 1.0, 2.5, and 5 mg/kg, significantly increased the tail-flick latency time and hot plate response time in a dose-dependent manner compared with the diabetic group.. Thus, it is suggested that E-SLN were equally effective and less hepatotoxic compared with the standard treatment of epalrestat. To the best of our knowledge, we, for the first time, propose the orally deliverable E-SLN that ameliorates STZ-induced diabetes neuropathic pain effectively as compared with conventional epalrestat.

Topics: Adenosine Triphosphatases; Aldehyde Reductase; Animals; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Glycated Hemoglobin; Lipids; Neuralgia; Rats; Streptozocin; Triglycerides; Tumor Necrosis Factor-alpha

Epalrestat is the only effective aldose reductase (ALR2) inhibitor available in the market for the treatment of diabetic neuropathy. Clinical effectiveness of epalrestat in diabetic neuropathy encouraged us to develop some more ALR2 inhibitors with a better therapeutic profile. Herein, we utilized the pharmacophoric features of epalrestat to search some novel ALR2 inhibitors from an InterBioScreen database of natural compounds. ADME and PAINS filters were applied to provide drug-likeness and to remove toxicophores from the screened hits. The pharmacophoric features of 4-hydroxy-2-nonenal (HNE), a well-known substrate of ALR1, were also explored to identify selective ALR2 inhibitors. The structure-based analysis was then adopted to find out the molecules showing interactions with ALR2 which are crucial for their therapeutic activity. These interaction patterns and binding modes were compared with that of epalrestat. Molecular dynamics (MD) analysis was also carried out to get more insight into the interactions of screened hits in the catalytic domain of ALR2. Additionally, the top hits were docked and simulated with aldehyde reductase (ALR1) to determine their selectivity for ALR2 over ALR1. Overall, five hits including

Topics: Biological Products; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Rhodanine; Thiazolidines

Herein, a quantum mechanics/molecular mechanics (QM/MM) based biotransformation study was performed on synthetically feasible mutual-prodrugs of epalrestat which have been identified from an in-house database developed by us. These prodrugs were submitted to quantum polarized ligand docking (QPLD) with the CES1 enzyme followed by MM-GBSA calculation. Electronic aspects of transition state of these prodrugs were also considered to study the catalytic process through density functional theory (DFT). ADMET analysis of prodrugs was then carried out to assess the drug-likeness. On the basis of in-silico results, the best five prodrugs were synthesized and further evaluated for their neuroprotective and nephroprotective potential in high-fat diet-streptozotocin (HFD-STZ) induced diabetes in rat model. Clinically relevant molecular manifestations of diabetic complications (DC) including aldose reductase (ALR2) activity and oxidative stress markers such as reduced glutathione (GSH), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) were determined in blood plasma as well as tissues of the brain and kidneys. The histopathological examination of these organs was also carried out to see the improvement in structural deformities caused due to neuropathy and nephropathy. Finally, in-vivo pharmacokinetic study was performed for the best two prodrugs to assess the improvement in biopharmaceutical attributes of parent drugs. Overall, EP-G-MFA and EP-MFA have significantly reduced the hyperglycemia-induced ALR2 activity, levels of oxidative stress markers, and manifested about a two-fold increase in the biological half-life (T

Topics: Animals; Density Functional Theory; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Hypoglycemic Agents; Male; Molecular Structure; Prodrugs; Rats; Rats, Wistar; Rhodanine; Streptozocin; Structure-Activity Relationship; Thiazolidines

Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation and affects over 1000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. To identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multispecies drug repurposing screen using a novel worm model of PMM2-CDG, followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the worm-based phenotypic screen, 12 were plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations. We demonstrate that epalrestat is the first small molecule activator of PMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.

Topics: Aldehyde Reductase; Animals; Cells, Cultured; Congenital Disorders of Glycosylation; Diabetic Neuropathies; Disease Models, Animal; Drug Repositioning; Endoplasmic Reticulum Stress; Fibroblasts; Glycosylation; Humans; Nematoda; Phosphotransferases (Phosphomutases); Polyphenols; Rhodanine; Thiazolidines

Diabetic peripheral neuropathy (DPN) is a common long-term complication of diabetes mellitus, affecting patients in the world. Epalrestat combined with α-lipoic acid (ALA) is the most frequent combine therapy used in the DPN researches. We aim to assess the effectiveness and safety of epalrestat combined with ALA in patients with DPN, compare with epalrestat alone.. We will search Cochrane Library, PubMed, Wanfang Data, China National Knowledge Infrastructure, VIP Chinese Science and Technology Journals Database, and Chinese Biomedical Database from inception until October 31th, 2017. Inclusion the randomized controlled trials and clinical control trials of combine therapy which evaluate clinical efficacy and side effect in people with DPN. Data extraction and risk of bias assessments will be independently conducted by 2 reviewers. The primary outcome measures will be total effective rate, motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), Toronto clinical scoring system (TCSS), and total symptom score (TSS). All statistical analyses will be performed using RevMan V.5.3 software.. This review will evaluate the total effective rate, nerve conduction velocity, TCSS, TSS, and safety of ALA combined with epalrestat for patients with DPN, compare with epalrestat alone.. Our study will provide evidence to assess whether epalrestat combined with ALA is an optional treatment for patients with DPN.

Topics: Antioxidants; Diabetic Neuropathies; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Research Design; Rhodanine; Thiazolidines; Thioctic Acid; Treatment Outcome

Type-2 diabetes mellitus (DM) is associated with cognitive impairment. Increasing evidence establishes that neuro-inflammatory and oxidative stress condition plays a main role in the development of neurodegeneration. Epalrestat, an aldose reductase inhibitor is commonly prescribed for the treatment of diabetic peripheral neuropathy. Its beneficial effects for antioxidant, anti-inflammatory potential and being rhodanine structure containing compound suggests possible role for treatment of DM associated with cognitive dysfunction.. In the present study, we evaluated the effect of epalrestat (54, 27, 13.5 mg/kg, p.o.) and donepezil (1 mg/kg, p.o.) on Tau protein levels, oxidative stress and inflammatory markers in high fat diet (HFD) and Streptozotocin (STZ; 35 mg/kg, i.p.) induced cognitive impairment in diabetic rats.. The epalrestat - 54, 27 mg/kg p.o. and donepezil treatment significantly increased CAT (p < 0.001, p < 0.01, p < 0.001) and GSH (p < 0.001, p < 0.01, p < 0.001) activities respectively as compared to diabetic control rats. In addition, similar dose of epalrestat treatment indicated considerably lowered TAU protein levels (p < 0.001, p < 0.05) while no significant effect was noted with donepezil. These treatments significantly decreased gene expression of TNF-α (1.6, 1.6, 1.7 fold change) and IL-6 (2.5, 1.9, 1.7 fold change). Histopathological examination indicated that epalrestat could attenuate apoptosis of neurons, vacuolations and clumped processes, disorganization and thinning of all the layers.. Our findings suggest that diabetic rats treated with epalrestat could ameliorate the cognition deficits and might act as a beneficial agent for prevention and treatment of cognitive impairment in diabetes.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Cognition Disorders; Cytokines; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Diet, High-Fat; Hippocampus; Inflammation; Male; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Rhodanine; tau Proteins; Thiazolidines

Epalrestat (EPS) is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Recently, we found that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH) in rat Schwann cells. GSH plays a crucial role in protecting endothelial cells from oxidative stress, thereby preventing vascular diseases. Here we show that EPS increases GSH levels in not only Schwann cells but also endothelial cells. Treatment of bovine aortic endothelial cells (BAECs), an in vitro model of the vascular endothelium, with EPS caused a dramatic increase in intracellular GSH levels. This was concomitant with the up-regulation of glutamate cysteine ligase, an enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Moreover, EPS stimulated the expression of thioredoxin and heme oxygenase-1, which have important redox regulatory functions in endothelial cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the expression of antioxidant genes. EPS increased nuclear Nrf2 levels in BAECs. Nrf2 knockdown by siRNA suppressed the EPS-induced glutamate cysteine ligase, thioredoxin-1, and heme oxygenase-1 expression. Interestingly, LY294002, an inhibitor of phosphatidylinositol 3-kinase, abolished the EPS-stimulated GSH synthesis, suggesting that the kinase is associated with Nrf2 activation induced by EPS. Furthermore, EPS reduced the cytotoxicity induced by H2O2 and tert-butylhydroperoxide, indicating that EPS plays a role in protecting cells from oxidative stress. Taken together, the results provide evidence that EPS exerts new beneficial effects on endothelial cells by increasing GSH, thioredoxin, and heme oxygenase-1 levels through the activation of Nrf2. We suggest that EPS has the potential to prevent several vascular diseases caused by oxidative stress.

Topics: Animals; Cattle; Chromones; Diabetic Neuropathies; Endothelial Cells; Gene Expression Regulation; Glutathione; Heme Oxygenase-1; Humans; Morpholines; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rhodanine; Thiazolidines; Thioredoxins

Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that de-differentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitamin D3, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination, and all conditions were significantly rescued by aldose reductase inhibitor or vitamin D3 administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition.

Topics: Aldehyde Reductase; Animals; Calcitriol; Cell Dedifferentiation; Cells, Cultured; Demyelinating Diseases; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Down-Regulation; Enzyme Inhibitors; Glucose; Hyperglycemia; In Vitro Techniques; Insulin-Like Growth Factor I; Mice; Mice, Inbred C57BL; Models, Neurological; Rats; Rhodanine; Schwann Cells; Sciatic Nerve; Sorbitol; Thiazolidines; Vitamin D

Autonomic neuropathy, one of the serious complications of diabetes, decreases quality of life. Aldose reductase inhibitor (ARI) blocks sorbitol production, and results in prevention of damage of nerve fibers. Beneficial effects of ARI have usually been confirmed through nerve conduction velocity tests in motor and sensory nerves. On the other hand, few reports have dealt with the effects of ARI on the small fiber activity such as sympathetic nerve one. In the present study, we administered eparlestat, ARI orally for 3weeks, to streptozotocin-induced diabetic (STZ+ARI) rats, and then recorded peripheral sympathetic nervous signal detected with microneurographic technique. Action potentials (APs) and bursts of APs were detected from the recorded signal, and their rates and incidences (=rates/heart rate) were compared with those in non-diabetic control (normal) and ARI-untreated streptozotocin-induced diabetic (STZ) rats. While streptozotocin and/or epalrestat did not influence burst parameters in all the three groups, AP parameters in the STZ+ARI and normal groups were higher than those in the STZ group. However, response of AP parameters to the intravenous glucose administration (IVGA) was not large in the STZ+ARI group, similar to that of the STZ group and different from that of the normal group in which AP parameters increased after IVGA. The results suggest that epalrestat may prevent sympathetic nerve activity (SNA) from reduction under hyperglycemic and insulin-depleted conditions, that enhancement of SNA was not induced after IVGA under that condition, and that AP parameters might be useful to assess the degree of neuropathy.

Topics: Action Potentials; Aldehyde Reductase; Animals; Blood Glucose; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enzyme Inhibitors; Heart Rate; Insulin; Male; Neuroprotective Agents; Rats, Wistar; Rhodanine; Sciatic Nerve; Sympathetic Nervous System; Thiazolidines

To conclude, effective management of hyperglycaemia, symptom control, and prevention of foot ulcers and infection through screening and surveillance remain mainstays of diabetic neuropathy management. Traditional and rational diabetic neuropathy treatments will be supplemented by novel cell based therapy and targeted drug delivery systems in the future.

Topics: Antidepressive Agents, Tricyclic; Diabetic Foot; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Hyperglycemia; Oxidative Stress; Rhodanine; Thiazolidines

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

Topics: Anticonvulsants; Antidepressive Agents; Blood Glucose; Diabetic Neuropathies; Disease Progression; Humans; Pain; Rhodanine; Sensation Disorders; Thiazolidines

Epalrestat (Kinedak) is an aldose reductase inhibitor (ARI) for diabetic peripheral neuropathy. In 41 diabetics, we conducted a questionnaire survey to evaluate symptoms of peripheral neuropathy and select appropriate drug therapy. We investigated 27 patients who participated in the first and second questionnaire surveys. We reviewed questionnaire items, and examined the correlation between the therapeutic effects and responses to the questionnaire. Concerning the usefulness of the questionnaire items, some questions were correlated with the effects. Treatment was effective for somatic neuropathy, but not for autonomic neuropathy. The questionnaire regarding diabetic peripheral neuropathy was useful for somatic neuropathy screening, but it was difficult to detect autonomic neuropathy.

Topics: Aged; Aldehyde Reductase; Diabetic Neuropathies; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Peripheral Nervous System Diseases; Regression Analysis; Rhodanine; Surveys and Questionnaires; Thiazolidines

During chronic hyperglycaemia, elevated vascular glucose level causes increased flux through the polyol pathway, which induces functional and morphological changes associated with secondary diabetic complications. Inhibitors of aldose reductase (ARIs) have been widely investigated as potential therapeutic agents, but to date only epalrestat is successfully marketed for treatment of diabetic neuropathy, in Japan. Promising compounds during in vitro studies or in trials with animal models have failed to proceed beyond clinical trials and to everyday use, due to a lack of efficacy or adverse side effects attributed to lack of inhibitor specificity and likely inhibition of the related aldehyde reductase (ALR1). Knowledge of the catalytic mechanism and structures of the current inhibitors complexed with ALR2 are means by which more specific and tightly bound inhibitors can be discovered. This review will provide an overview of the proposed catalytic mechanism and the current state of structure-based drug design.

Topics: Aldehyde Reductase; Animals; Databases, Factual; Diabetic Neuropathies; Drug Design; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Mutagenesis, Site-Directed; Protein Conformation; Rhodanine; Thiazolidines

Diabetic patients with severe autonomic nervous disorder show delayed gastric emptying accompanied by diabetic gastroparesis, which decreases the electric activity of the stomach associated with gastric motility. It is reported that epalrestat, an aldose reductase inhibitor, is useful for treating diabetic neuropathy. Therefore, we evaluated whether this drug improves the decreased gastric motility in diabetic patients.. The present study evaluated the electrogastrograms (EGG) and autonomic nervous activity in 15 healthy volunteers (N group), and in 15 diabetic patients before and after the administration of epalrestat (DM group). Autonomic nervous activity was evaluated by spectral analysis of heart rate variability. The EGGs were recorded before and after oral administration of epalrestat (3 months or more) in the DM group.. The dominant frequency of EGG was 3 cycles/min (cpm) in the N group. However, these 3 cpm waves disappeared with bradygastria, and postprandial increases in the peak powers of EGG were not observed in the DM group. Both the amplitude of 3 cpm waves and the postprandial peak powers were significantly increased after the administration of epalrestat. The parameters of autonomic nervous activities (LF power, HF power, and the LF/HF ratio) were significantly lower in the DM group before the administration of epalrestat than in the N group. However, these parameters were improved after the administration of epalrestat.. Since gastroparesis is a form of diabetic dysautonomia, complication by gastroparesis may influence blood sugar control and the absorbance of oral antidiabetics. Epalrestat significantly increased the amplitude of 3 cpm waves on EGG and improved the spectral analytical parameters of heart rate variability. These findings suggest that epalrestat is useful for the treatment of diabetic gastroparesis.

Topics: Aged; Aldehyde Reductase; Autonomic Nervous System; Diabetic Neuropathies; Electrodiagnosis; Enzyme Inhibitors; Female; Gastrointestinal Motility; Gastroparesis; Glycated Hemoglobin; Heart Rate; Humans; Male; Middle Aged; Rhodanine; Thiazolidines

Topics: Aldehyde Reductase; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Nerve Fibers; Rhodanine; Skin; Thiazolidines

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

I-123 metaiodobenzylguanidine (MIBG) scintigraphy is a new method to evaluate cardiac sympathetic nerve disturbance in patients with diabetes mellitus. Epalrestat specifically inhibits aldose reductase and improves diabetic neuropathy. The authors report a case of improvement in cardiac sympathetic dysfunction using MIBG scintigraphy with epalrestat therapy. In this case, epalrestat effectively reversed diabetic neuropathy, and MIBG scintigraphy was useful to evaluate the effect of epalrestat.

Topics: 3-Iodobenzylguanidine; Adult; Aldehyde Reductase; Autonomic Nervous System Diseases; Diabetic Neuropathies; Enzyme Inhibitors; Heart; Humans; Male; Radionuclide Imaging; Radiopharmaceuticals; 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

We investigated alterations in nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF) contents during treatment with epalrestat, an aldose reductase inhibitor (ARI), on streptozotocin (STZ)-induced diabetic neuropathy in rats. Diabetic rats showed a statistically significant reduction in H-wave-related sensory nerve conduction velocity (HSNCV) and in NGF content in sciatic nerves during the experiment of 8 weeks. No reduction in the CNTF content in sciatic nerves was seen in the diabetic rats. The epalrestat treatment, which started 4 weeks after STZ injection, resulted in a significantly greater NGF content and faster HSNCV than those in untreated diabetic rats. But no statistically significant alterations of motor nerve conduction velocity (MNCV) or CNTF content were seen during the treatment. ARI showed the stimulating effect for NGF synthesis/secretion in rat Schwann cell culture in vitro. These findings suggest that decreased levels of NGF in diabetic sciatic nerves may be involved in the pathogenesis of diabetic neuropathy in these rats and further show that epalrestat treatment can be useful for the treatment of diabetic neuropathy through NGF-induction in Schwann cells and/or inhibition of the polyol pathway.

Topics: Aldehyde Reductase; Animals; Catechols; Cells, Cultured; Ciliary Neurotrophic Factor; Diabetic Neuropathies; Electrophysiology; Enzyme Inhibitors; Male; Nerve Growth Factors; Nerve Tissue Proteins; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Rhodanine; Schwann Cells; Sciatic Nerve; Thiazolidines

The effects of the aldose reductase inhibitor epalrestat (150 mg/day) on electrophysiological function were examined in 22 NIDDM patients with diabetic polyneuropathy for 6 months. Although no significant differences were observed in sensory (the sural nerve) or motor (the posterior tibial nerve) conduction velocities and amplitude, only F wave conduction velocities were significantly improved at 3 and 6 months after the treatment. There were no significant changes in CV-RR, vibration threshold and laboratory data. No serious side effects were observed during the therapeutic trial. This study suggests F wave is appropriate for the assessment of diabetic neuropathy and for therapeutic trials.

Topics: Aldehyde Reductase; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Neural Conduction; Rhodanine; Thiazolidines

This study was undertaken to examine the effects of aldose reductase inhibitor (ARI) and vitamin B12 (VB12) on myocardial uptake of iodine-123 metaiodobenzylguanidine (MIBG) in patients with diabetic autonomic disorder. Myocardial scintigraphy using 123I-MIBG was performed on 20 healthy volunteers (controls) and 56 patients with non-insulin-dependent diabetes mellitus (NIDDM), in order to obtain the heart/mediastinum ratio in the initial (HMi) and the delayed images (HMd), and the washout rate (%WR). Thirty-four of the 56 NIDDM patients could be diagnosed as having diabetic autonomic disorder by evaluating their scintigraphic findings in comparison with the controls. Seventeen of these 34 patients received 150 mg/day of doses before meals, and the other 17 received 1.5 mg/day of mecobalamin (VB12 group) in three divided doses after meals, for 3-5 months. According to the presence or absence of clinical symptoms of autonomic or peripheral somatic nerve disorder, the patients were subclassified into four groups. group 1=patients, with autonomic symptoms or somatosensory disorder in the ARI group; group 2=patients without autonomic symptoms or somatosensory disorder in the ARI group; group 3=patients with autonomic symptoms or somatosensory disorder in the VB12 group; and group 4=patients without autonomic symptoms or somatosensory disorder in the VB12 group. After completion of the treatment, myocardial scintigraphy was performed again. Comparing the results obtained before and after the treatment, it was seen that ARI improved only the HMi in group 1 (P=0.046), whereas VB12 significantly improved HMi in the group 3 (P=0.018) and HMi, HMd and %WR in group 4 (P=0.043, P=0.018 and P=0.043, respectively). We conclude that VB12 is more efficacious than ARI in the treatment of diabetic cardiovascular autonomic disorder.

Topics: 3-Iodobenzylguanidine; Adult; Aged; Aged, 80 and over; Aldehyde Reductase; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Enzyme Inhibitors; Female; Heart; Heart Diseases; Humans; Male; Middle Aged; Radionuclide Imaging; Radiopharmaceuticals; Rhodanine; Thiazolidines; Vitamin B 12

We present a diabetic patient with long-standing constipation complicated by paralytic ileus and septic shock. She successfully recovered from a critical condition, and her diabetes was well controlled. However, the constipation did not improve even after the administration of conventional medications. Epalrestat, an aldose reductase inhibitor (ARI), improved her bowel motility and autonomic cardiovascular dysfunction, as evident from her heart rate and blood pressure response. Gastroenteropathy is a major diabetic complication which may cause disturbed bowel motility leading to serious enterobacterial infections, thus, its amelioration is important. ARI may be beneficial in the treatment of diabetic gastroenteropathy refractory to conventional therapies.

Topics: Aldehyde Reductase; Autonomic Nervous System Diseases; Cardiovascular Diseases; Constipation; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Enzyme Inhibitors; Female; Gastrointestinal Motility; Hemodynamics; Humans; Intestinal Pseudo-Obstruction; Middle Aged; Rhodanine; Shock, Septic; Thiazolidines

Cardiac autonomic neuropathy can be a cause of sudden death in patients with diabetes mellitus. Clinical evaluation methods for diabetic cardiac sympathetic neuropathy have not been established. Using 125I-metaiodobenzylguanidine (MIBG) and streptozotocin (STZ)-induced diabetic rats, we evaluated cardiac sympathetic neuropathy and the effects of aldose reductase inhibitor (ARI).. Myocardial MIBG uptake was measured 4 hr after injection in the following groups: control rats, rats treated with insulin or ARI (epalrestat, 100 mg/kg/day) from immediately to 4 wk after STZ injection and rats treated with insulin or ARI from 4-8 wk. Myocardial MIBG distribution and norepinephrine content were evaluated in the control and diabetic rats with or without ARI therapy started immediately after STZ injection.. Myocardial MIBG uptake was significantly lower in diabetic rats than in control rats; the reduction was marked in the subendocardial myocardium. Myocardial norepinephrine content was increased significantly in diabetic rats compared with control rats. Decreased MIBG uptake and increased norepinephrine content in diabetic myocardium were completely prevented by insulin therapy started immediately after STZ injection and partially, but significantly, by ARI administered from immediately after STZ injection. Heterogeneous MIBG distribution also disappeared with the ARI therapy. In contrast, diabetic rats treated with insulin or ARI therapy started 4 wk after STZ injection showed no improvement in MIBG uptake.. These results suggest that MIBG abnormalities observed in diabetic rats may reflect diabetic cardiac sympathetic neuropathy independently of cardiomyopathy, nephropathy or coronary heart disease secondary to diabetes and that MIBG imaging may be useful for clinical assessment of cardiac sympathetic neuropathy.

Topics: 3-Iodobenzylguanidine; Aldehyde Reductase; Animals; Autonomic Nervous System Diseases; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enzyme Inhibitors; Heart; Insulin; Iodine Radioisotopes; Male; Myocardium; Norepinephrine; Radionuclide Imaging; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rhodanine; Thiazolidines

The effects of a stable prostacyclin analog, Iloprost, and aldose reductase inhibitors (ONO-2235 and isoliquiritigenin) were studied to elucidate the role of cAMP in diabetic neuropathy in relation to polyol metabolism. In in vivo experiments, the cAMP and myoinositol contents in sciatic nerves and motor nerve conduction velocity were significantly reduced in diabetic rats. Iloprost significantly restored the reduced cAMP content in sciatic nerves and improved motor nerve conduction velocity in diabetic rats. However, the contents of sorbitol or myoinositol in sciatic nerves were not affected by Iloprost in diabetic rats. On the other hand, aldose reductase inhibitors significantly reduced the sorbitol content and increased the cAMP and myoinositol contents in the sciatic nerves of diabetic rats. The motor nerve conduction velocity was also slightly but significantly improved by treatment with aldose reductase inhibitors. There was a negative correlation between cAMP and sorbitol in the sciatic nerves of diabetic rats treated with aldose reductase inhibitors and a positive correlation between cAMP and motor nerve conduction velocity. In in vitro experiments, Iloprost significantly increased cAMP, but did not affect the sorbitol content in sciatic nerves. Aldose reductase inhibitors inhibited sorbitol accumulation and increased cAMP in sciatic nerves. Our data suggest that polyol pathway activation somehow results in cAMP reduction in sciatic nerves and that the reduction of cAMP in peripheral nerves may be closely related to the pathogenesis of diabetic neuropathy.

Topics: Aldehyde Reductase; Animals; Blood Glucose; Chalcone; Chalcones; Cyclic AMP; Cyclic GMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Iloprost; Inositol; Male; Neural Conduction; Rats; Rats, Inbred WKY; Rhodanine; Sciatic Nerve; Sorbitol; Thiazolidines

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

Topics: Aldehyde Reductase; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetic Nephropathies; Diabetic Neuropathies; Glycosylation; Humans; Inositol; Proteins; Rhodanine; Sorbitol; Thiazolidines

The effect of a newly developed oral agent, prostaglandin E1 (PGE1) analogue TFC 612, on diabetic neuropathy was studied by giving it for 6 wk to streptozocin-induced diabetic rats that had been diabetic for 3 mo and was compared with the effects of aldose reductase inhibitor ONO 2235. Although both compounds improved decreased motor nerve conduction velocity, the effect of TFC 612 continued during the 6 wk of treatment, whereas that of ONO 2235 became weaker from wk 4. The abnormality in sciatic nerve sorbitol and myo-inositol levels was reversed with ONO 2235, whereas it was unchanged with TFC 612. With the laser Doppler flowmetry technique, a decrease in the sciatic nerve blood flow in diabetic rats was shown to improve with both compounds, but TFC 612 had a greater effect than ONO 2235, and the increased lactate level of the diabetic nerve was corrected with both compounds, suggesting that both may be associated with the amelioration of ischemia in the diabetic endoneurium. Both TFC 612 and ONO 2235 partially but significantly normalized decreased fiber size in diabetic rats. On the other hand, TFC 612 completely normalized the dilated lumen area in diabetic rats, whereas ONO 2235 did not. These results suggest that the PGE1 analogue TFC 612 has a significant effect on diabetic neuropathy, possibly via vasotropic action, and may be a potent compound for the treatment of diabetic neuropathy.

Topics: Adenosine Triphosphate; Aldehyde Reductase; Alprostadil; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electrophysiology; Inositol; Lactates; Male; Myelin Sheath; Nerve Fibers; Phosphocreatine; Rats; Rats, Inbred Strains; Rhodanine; Sciatic Nerve; Sorbitol; Streptozocin; Sugar Alcohol Dehydrogenases; Thiazoles; Thiazolidines

To test the hypothesis that inhibitors of aldose reductase, a key enzyme for polyol synthesis, prevent the decrease of sympathetic nervous system (SNS) activity and improve motor nerve conduction velocity (MNCV) through the reduction of sorbitol accumulation in streptozocin (STZ)-induced diabetic rats, norepinephrine (NE) turnover (reliable indicator of SNS activity in the interscapular brown adipose tissue (IBAT), heart, and pancreas), and MNCV were measured in untreated STZ-induced diabetic rats, STZ-induced diabetic rats treated with an aldose reductase inhibitor (ARI) (ONO 2235, 50 mg X kg-1 X day-1, orally), STZ-induced diabetic rats treated with insulin therapy, control rats, and control rats treated with ARI. As expected, results from studies with the inhibition of NE biosynthesis with alpha-methyl-p-tyrosine or radiolabeled NE to measure NE turnover demonstrated significant reductions in SNS activity in IBAT, heart, and pancreas of untreated STZ-induced diabetic rats, compared with those in control rats. MNCV determined with the tail nerve was significantly reduced in untreated STZ-induced diabetic rats, compared with that of the controls. Both daily ARI treatment and insulin therapy in STZ-induced diabetic rats prevented partially but significantly the decrease of NE turnover in IBAT, heart, and pancreas, ameliorated MNCV, and reduced sorbitol accumulation in the nerve tissue and red blood cells. ARI treatment in control rats had no effect on NE turnover, MNCV, or sorbitol content. These results suggest that STZ-induced diabetic rats had not only motor neuropathy but also sympathetic nervous dysfunction and that ARI treatment might prevent these as well as insulin therapy does through the reduction of sorbitol accumulation.

Topics: Aldehyde Reductase; alpha-Methyltyrosine; Animals; Autonomic Nervous System Diseases; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Erythrocytes; Female; Methyltyrosines; Neural Conduction; Norepinephrine; Peripheral Nervous System Diseases; Rats; Rats, Inbred Strains; Rhodanine; Sciatic Nerve; Sorbitol; Streptozocin; Sugar Alcohol Dehydrogenases; Sympathetic Nervous System; Thiazoles; Thiazolidines; Triiodothyronine

Topics: Action Potentials; Adolescent; Adult; Aldehyde Reductase; Arm; Child; Diabetic Neuropathies; Female; Humans; Ischemia; Male; Middle Aged; Peripheral Nerves; Rhodanine; Sugar Alcohol Dehydrogenases; Thiazoles; Thiazolidines

Streptozotocin-diabetic rats were maintained on a 72% fructose diet for 4 weeks and some were treated with an aldose reductase inhibitor (either alrestatin: 0.9 g . kg-1 . day-1 or ONO-2235: 50 mg . kg-1 . day-1). Fructose feeding significantly influenced the development of impaired motor nerve conduction velocity in the diabetic rats and this effect was positively correlated with sorbitol accumulation in the sciatic nerve of diabetic rats maintained on a fructose-rich diet. Treatment with ONO-2235, a new aldose reductase inhibitor, prevented both slowing of motor nerve conduction velocity and elevation of nerve sorbitol concentration. On the other hand, erythrocyte sorbitol levels were significantly correlated to those of the sciatic nerve (r = 0.86, p less than 0.001) and the retina (r = 0.91, p less than 0.001) in these animals. Thus, our findings suggest that increased polyol pathway activity may be related to the pathogenesis of diabetic neuropathy and erythrocyte sorbitol concentrations may prove a useful indicator for the presence of diabetic complications.

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dietary Carbohydrates; Erythrocytes; Fructose; Male; Motor Neurons; Neural Conduction; Rats; Retina; Rhodanine; Sciatic Nerve; Sorbitol; Sugar Alcohol Dehydrogenases; Thiazoles; Thiazolidines

A potent inhibitor of aldose reductase, (E)-3-carboxy-methyl-5-[(2E)-methyl-3-phenylpropenylidene]rhodanin e (ONO-2235), was orally administered at a dose of 20 mg X kg-1 X d-1 for 2 weeks to streptozotocin-diabetic rats from the beginning of the diabetic state, ie, 24 hours after streptozotocin injection. The impairment of motor nerve conduction velocity (MNCV) of the tail nerve found in nontreated diabetic rats was apparently prevented by the treatment with the aldose reductase inhibitor (24.5 +/- 0.4 v 29.0 +/- 1.4 m/s on day 14, P less than 0.005). Those diabetic rats treated with the compound actually showed an age-dependent increase in MNCV similar to that of normal control rats (25.5 +/- 1.5 v 26.4 +/- 1.0 m/s on day 7, 29.0 +/- 1.4 v 29.4 +/- 1.3 m/s on day 14, treated v normal, not statistically significant on both days). The sorbitol content of the sciatic nerve excised from ONO-2235-treated diabetic rats (0.067 +/- 0.018 nmol/g wet weight) was significantly lower than that of the nontreated diabetic rats (1.309 +/- 0.080 nmol/g wet weight, P less than 0.001) but significantly higher than that of normal control rats (0.229 +/- 0.015 nmol/g wet weight, P less than 0.001). These results suggest that the reduction in MNCV noted in the experimental diabetic animals is not the result of retarded maturation of peripheral nerves but of metabolic derangement caused by the diabetic state, which can be prevented by suppressing sorbitol accumulation in nerve tissue. It also appears that there may be a threshold level of sorbitol accumulation that causes the impairment of nerve conduction velocity.

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Male; Motor Neurons; Neural Conduction; Rats; Rats, Inbred Strains; Rhodanine; Sciatic Nerve; Sorbitol; Sugar Alcohol Dehydrogenases; Thiazoles; Thiazolidines

A new aldose reductase inhibitor, (E)-3-carboxymethyl-5-[(2E-methyl-3-phenylpropenylidene]rhodanine (ONO-2235) was administered orally to streptozotocin-diabetic rats (60 mg/kg IV) for 14 days and its effect on motor nerve conduction velocity studied. The compound significantly improved motor nerve conduction velocity of diabetic rats at a minimal dose of 10 mg . kg-1 . day-1 (treated 28.8 +/- 0.5 versus untreated 23.2 +/- 4.7 m/s, p less than 0.01). The sorbitol content of the sciatic nerve and red blood cells measured after 2 weeks was concomitantly reduced in ONO-2235-treated rats (sciatic nerve: 120 +/- 13 versus 595 +/- 146 nmol/g wet weight; red blood cell: 91 +/- 21 versus 165 +/- 39 nmol/g haemoglobin; p less than 0.01 in both 20 mg . kg-1 . day-1-treated versus untreated animals). These results suggest that sorbitol accumulation might contribute to the development of peripheral nerve dysfunction in acutely diabetic animals and the new aldose reductase inhibitor could be a potential drug for therapy of diabetic neuropathy.

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Erythrocytes; Insulin; Male; Neural Conduction; Rats; Rats, Inbred Strains; Rhodanine; Sciatic Nerve; Sorbitol; Sugar Alcohol Dehydrogenases; Thiazoles; Thiazolidines