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Yukio Shigeta - One of the best experts on this subject based on the ideXlab platform.
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long term clinical effects of epalrestat an Aldose Reductase Inhibitor on progression of diabetic neuropathy and other microvascular complications multivariate epidemiological analysis based on patient background factors and severity of diabetic neur
Diabetic Medicine, 2012Co-Authors: Nigishi Hotta, Ryuzo Kawamori, M Fukuda, Yukio ShigetaAbstract:Aims 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.
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stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long term treatment with an Aldose Reductase Inhibitor epalrestat
Diabetic Medicine, 2008Co-Authors: N Hotta, Hitoshi Yasuda, Jiro Nakamura, Ryuzo Kawamori, Yoshihito Atsumi, M Baba, H Kishikawa, Shinichi Oikawa, Nobuhiro Yamada, Yukio ShigetaAbstract:Aims 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. Methods 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 ≥ 40 m/s and with glycated haemoglobin (HbA1c) ≤ 9.0%. Longitudinal data on HbA1c 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. Results 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 HbA1c ≤ 7.0%). Conclusion 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.
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original article complications stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long term treatment with an Aldose Reductase Inhibitor epalrestat
2008Co-Authors: N Hotta, Hitoshi Yasuda, Jiro Nakamura, Ryuzo Kawamori, Yoshihito Atsumi, M Baba, H Kishikawa, Shinichi Oikawa, Nobuhiro Yamada, Yukio ShigetaAbstract:Aims 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. Methods 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 ≥ 40 m/s and with glycated haemoglobin (HbA 1c ) ≤ 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. Results 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 ≤ 7.0%). Conclusion 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.
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clinical investigation of epalrestat an Aldose Reductase Inhibitor on diabetic neuropathy in japan multicenter study
Journal of Diabetes and Its Complications, 1996Co-Authors: Nigishi Hotta, Ryuichi Kikkawa, Nobuo Sakamoto, Yukio Shigeta, Yoshio GotoAbstract:A number of diabetic patients with diabetic neuropathy were treated with epalrestat, an Aldose Reductase Inhibitor, since this drug was launched into the market in Japan. More than 5000 patients with diabetic neuropathy who were treated with epalrestat for 3-12 months were treated to analyze the efficacy and the adverse reactions of the drug in this study. The improvement rates of subjective symptoms (i.e., spontaneous pain, numbness, coldness, and hypoesthesia) was 75% (slightly improved or better) and those of nerve function tests (i.e., motor nerve conduction velocity, sensory nerve-conduction velocity, and vibration threshold) 36%. Adverse drug reactions were encountered in 129 cases (2.5%) out of 5249 patients, none of which were severe ones. Although data are limited, they strongly suggest that epalrestat is a highly effective and safe agent for the treatment of diabetic neuropathy.
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the effect of an Aldose Reductase Inhibitor epalrestat on diabetic nephropathy in rats
Diabetes Research and Clinical Practice, 1994Co-Authors: Iori Itagaki, Ryuichi Kikkawa, Masakazu Haneda, Kiyoshi Shimizu, Yoshihisa Kamanaka, Kazuhiko Ebata, Yukio ShigetaAbstract:In order to clarify the possible contribution of the abnormal polyol pathway to the development of diabetic nephropathy, the effect of Aldose Reductase Inhibitor on renal function and morphology was examined in streptozotocin (STZ)-induced diabetic rats. Six months after STZ injection, glomerular filtration rate and renal plasma flow showed marked decline with significant increase in nuclear-free mesangial area (MA) and relative mesangial area (RMA; MA per glomerular area) in diabetic rats. Oral administration of an Aldose Reductase Inhibitor, Epalrestat, prevented renal hypofunction and mesangial expansion in diabetic rats without influencing the levels of blood glucose. These results suggest that the abnormal polyol pathway in diabetic rats is closely related to the development of mesangial expansion, a morphologic representative of diabetic glomerulopathy, and renal hypofunction.
Boas Gonen - One of the best experts on this subject based on the ideXlab platform.
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withdrawal of the Aldose Reductase Inhibitor tolrestat in patients with diabetic neuropathy effect on nerve function
Journal of Diabetes and Its Complications, 1993Co-Authors: Julio V Santiago, Jay G Graepel, Wieslaw J Bochenek, Andrew Macleod, Peter H. Sönksen, Andrew J M Boulton, Boas GonenAbstract:Abstract A double-blind, placebo-controlled clinical trial was conducted to study the effects of discontinuing tolrestat, an Aldose Reductase Inhibitor, on peripheral sensorimotor diabetic neuropathy. After an average of 4.2 years of continuous tolrestat use, 372 patients were randomly assigned to either placebo or continued tolrestat therapy and were followed for 52 weeks. After 3 months, patients who perceived worsening of symptoms of neuropathy were allowed to switch once to the alternate treatment group while maintaining the double-blind. Patients assigned to placebo had significant deterioration in motor nerve conduction velocity (MNCV) while those maintained on tolrestat did not ( p p p
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effect of hyperglycemia and the Aldose Reductase Inhibitor tolrestat on sural nerve biochemistry and morphometry in advanced diabetic peripheral polyneuropathy
Journal of Diabetes and Its Complications, 1993Co-Authors: Anders A F Sima, T. C. Hohman, Jay G Graepel, Wieslaw J Bochenek, David Hicks, Douglas A. Greene, Morton B. Brown, Boas GonenAbstract:Abstract Tolrestat is a well tolerated nonhydantoin Aldose Reductase Inhibitor that has been reported to improve nerve conduction in diabetic animals and humans. Its effects on nerve biochemistry and structure have not been studied in patients with diabetic neuropathy. Patients with advanced diabetic neuropathy treated with long-term open-label tolrestat were randomly assigned to continuation on drug treatment or to placebo-controlled drug withdrawal for 12 months. At the end of this period, sural nerve biopsies were obtained for measurement of glucose, sorbitol, and fructose content, and for detailed morphometric analysis. Tolrestat ameliorated the glucose-mediated increase in sorbitol and fructose in sural nerve tissue. No statistically significant differences in nerve morphometry emerged between the two groups; however, both treatment groups exhibited increased nerve-fiber regeneration and normalization of axo-glial dysjunction and segmental demyelination following long-term tolrestat treatment. These findings are similar to those previously reported in a placebo-controlled sequential nerve biopsy study with the Aldose Reductase Inhibitor sorbinil. Thus tolrestat is a biochemically effective Aldose Reductase Inhibitor in human diabetic nerve with potential therapeutic efficacy for diabetic neuropathy.
Nigishi Hotta - One of the best experts on this subject based on the ideXlab platform.
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Long-Term Clinical Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy The 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial
2015Co-Authors: Nigishi Hotta, Yasuo Akanuma, Ryuzo Kawamori, Kempei Matsuoka, Motoaki Shichiri, Mitsuyoshi Nakashima, Isao YoshimuraAbstract:OBJECTIVE — We sought to evaluate the long-term efficacy and safety of epalrestat, an Aldose Reductase Inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN ANDMETHODS — Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) 40 m/s, and HbA1c 9 % were enrolled in this open-label, multicenter study and randomized to 150 mg/day epalrestat or a control group. After excluding the withdrawals, 289 (epalrestat group) and 305 (control group) patients were in-cluded in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception thresh-old [VPT]), cardiovascular autonomic nerve function, and subjective symptoms. RESULTS — Over the 3-year period, epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s (P 0.001). Although a benefit with epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, an
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long term clinical effects of epalrestat an Aldose Reductase Inhibitor on progression of diabetic neuropathy and other microvascular complications multivariate epidemiological analysis based on patient background factors and severity of diabetic neur
Diabetic Medicine, 2012Co-Authors: Nigishi Hotta, Ryuzo Kawamori, M Fukuda, Yukio ShigetaAbstract:Aims 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.
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long term clinical effects of epalrestat an Aldose Reductase Inhibitor on diabetic peripheral neuropathy the 3 year multicenter comparative Aldose Reductase Inhibitor diabetes complications trial
Diabetes Care, 2006Co-Authors: Nigishi Hotta, Yasuo Akanuma, Ryuzo Kawamori, Kempei Matsuoka, Yoshitomo Oka, Motoaki Shichiri, Takayoshi Toyota, Mitsuyoshi Nakashima, Isao Yoshimura, Nobuo SakamotoAbstract:OBJECTIVE —We sought to evaluate the long-term efficacy and safety of epalrestat, an Aldose Reductase Inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS —Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) ≥40 m/s, and HbA1c ≤9% were enrolled in this open-label, multicenter study and randomized to 150 mg/day epalrestat or a control group. After excluding the withdrawals, 289 (epalrestat group) and 305 (control group) patients were included in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception threshold [VPT]), cardiovascular autonomic nerve function, and subjective symptoms. RESULTS —Over the 3-year period, epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s ( P < 0.001). Although a benefit with epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, and cramping improved significantly with epalrestat versus the control group. The effects of epalrestat on median MNCV were most evident in subjects with better glycemic control and with no or mild microangiopathies. CONCLUSIONS —Long-term treatment with epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited microangiopathy.
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clinical investigation of epalrestat an Aldose Reductase Inhibitor on diabetic neuropathy in japan multicenter study
Journal of Diabetes and Its Complications, 1996Co-Authors: Nigishi Hotta, Ryuichi Kikkawa, Nobuo Sakamoto, Yukio Shigeta, Yoshio GotoAbstract:A number of diabetic patients with diabetic neuropathy were treated with epalrestat, an Aldose Reductase Inhibitor, since this drug was launched into the market in Japan. More than 5000 patients with diabetic neuropathy who were treated with epalrestat for 3-12 months were treated to analyze the efficacy and the adverse reactions of the drug in this study. The improvement rates of subjective symptoms (i.e., spontaneous pain, numbness, coldness, and hypoesthesia) was 75% (slightly improved or better) and those of nerve function tests (i.e., motor nerve conduction velocity, sensory nerve-conduction velocity, and vibration threshold) 36%. Adverse drug reactions were encountered in 129 cases (2.5%) out of 5249 patients, none of which were severe ones. Although data are limited, they strongly suggest that epalrestat is a highly effective and safe agent for the treatment of diabetic neuropathy.
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In vitro retinal and erythrocyte polyol pathway regulation by hormones and an Aldose Reductase Inhibitor.
Diabetes Research and Clinical Practice, 1991Co-Authors: Nigishi Hotta, Naoki Koh, Hironobu Kakuta, Hideo Fukasawa, T. Yasuma, S. Awaya, Nobuo SakamotoAbstract:Abstract The effects of a high-glucose medium, insulin, and an Aldose Reductase Inhibitor (ONO-2235) on sorbitol accumulation were compared in the human erythrocyte and the rabbit retina, while the effects of epinephrine on in vitro sorbitol accumulation were investigated in the human and rabit retina. In both erythrocytes and the retina, linear increments of sorbitol accumulation were observed in a dose-dependent manner with 5 to 50 mM glucose. These increments were markedly inhibited by 100 μM ONO-2235 but not by insulin (400 μU/ml). In the presence of 5 mM glucose, a dose-dependent increase of the sorbitol content of the rabbit retina was seen following epinephrine stimulation (0.4–4.0 μM and this was markedly reduced by 100 μM ONO-2235. Moreover, both 50 mM glucose and 4.0 μM epinephrine increased the sorbitol content of the retina from a diabetic patient, and the glucose-induced increment in sorbitol was significantly reduced by 100 μM ONO-2235. Our data suggested that Aldose Reductase Inhibitors might be useful for the treatment of diabetic retinopathy, since the polyol pathway appears to be an important factor in its pathogenesis, and that catecholamines might have some role in the activation of the retinal polyol pathway.
T. C. Hohman - One of the best experts on this subject based on the ideXlab platform.
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correction of nerve conduction and endoneurial blood flow deficits by the Aldose Reductase Inhibitor tolrestat in diabetic rats
Journal of The Peripheral Nervous System, 1998Co-Authors: Murray A Cotter, Norman E Cameron, T. C. HohmanAbstract:Increased activation of the first half of the polyol pathway, the conversion of glucose to sorbitol by Aldose Reductase, has been implicated in Aldose Reductase Inhibitor-preventable neurochemical changes that may contribute to the aetiology of diabetic neuropathy. Tolrestat has been used as a standard Aldose Reductase Inhibitor to dissect out polyol pathway-dependent mechanisms in many experimental studies; however, doubt has been cast upon its ability to prevent nerve conduction velocity deficits in diabetic rats. Nerve dysfunction has also been linked to abnormal endoneurial blood flow and oxygenation via increased vasa nervorum polyol pathway flux. The aim of this study was to test whether tolrestat could correct sciatic conduction velocity and perfusion defects in diabetic rats. Sciatic motor conduction velocity, 21% reduced by 1 month of streptozotocin-induced diabetes, was corrected by 23% and 84% with 1 month of tolrestat treatment at doses of 7 and 35 mg/kg/day respectively. Endoneurial blood flow, 44-52% reduced by untreated diabetes, was within the nondiabetic range with high-dose tolrestat treatment and the flow deficit was 39% corrected by the low dose. Sciatic sorbitol and fructose concentrations were approximately 13-fold and approximately 4-fold elevated by untreated diabetes. This was 32-50% attenuated by low-dose tolrestat and sorbitol and fructose content was suppressed below the nondiabetic level by high dose treatment. A 58% nerve myo-inositol deficit was partially (32%) corrected by high-dose tolrestat treatment. We conclude that tolrestat restores defective conduction and blood flow in diabetic rats and is a good pharmacological tool for studies on polyol pathway effects in peripheral nerve.
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effect of hyperglycemia and the Aldose Reductase Inhibitor tolrestat on sural nerve biochemistry and morphometry in advanced diabetic peripheral polyneuropathy
Journal of Diabetes and Its Complications, 1993Co-Authors: Anders A F Sima, T. C. Hohman, Jay G Graepel, Wieslaw J Bochenek, David Hicks, Douglas A. Greene, Morton B. Brown, Boas GonenAbstract:Abstract Tolrestat is a well tolerated nonhydantoin Aldose Reductase Inhibitor that has been reported to improve nerve conduction in diabetic animals and humans. Its effects on nerve biochemistry and structure have not been studied in patients with diabetic neuropathy. Patients with advanced diabetic neuropathy treated with long-term open-label tolrestat were randomly assigned to continuation on drug treatment or to placebo-controlled drug withdrawal for 12 months. At the end of this period, sural nerve biopsies were obtained for measurement of glucose, sorbitol, and fructose content, and for detailed morphometric analysis. Tolrestat ameliorated the glucose-mediated increase in sorbitol and fructose in sural nerve tissue. No statistically significant differences in nerve morphometry emerged between the two groups; however, both treatment groups exhibited increased nerve-fiber regeneration and normalization of axo-glial dysjunction and segmental demyelination following long-term tolrestat treatment. These findings are similar to those previously reported in a placebo-controlled sequential nerve biopsy study with the Aldose Reductase Inhibitor sorbinil. Thus tolrestat is a biochemically effective Aldose Reductase Inhibitor in human diabetic nerve with potential therapeutic efficacy for diabetic neuropathy.
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Intervention with the Aldose Reductase Inhibitor, tolrestat, in renal and retinal lesions of streptozotocin-diabetic rats
Diabetologia, 1991Co-Authors: Michael L Mccaleb, T. C. Hohman, Nicholas Laver, Mar-lee Mckean, W. Gerald RobisonAbstract:The progressive increase in urinary albumin excretion, which precedes the development of diabetic nephropathy, can be prevented in diabetic rats if the Aldose Reductase Inhibitor, tolrestat, is administered at the initiation and throughout the duration of hyperglycaemia. We therefore determined the ability of tolrestat to intervene in the further progression of already established urinary albumin excretion of streptozotocin-diabetic female Wistar rats. Two months after streptozotocin injection, diabetic rats were grouped as low-urinary albumin excretion (0.2–1.0 mg albumin/day) or high-urinary albumin excretion (1.9–5.9 mg albumin/day), at which time tolrestat intervention (25 mg/kg per day) was begun for half of the diabetic rats in each urinary albumin excretion group. After six months of treatment tolrestat caused a significant reduction in the urinary albumin excretion rate of the low-urinary albumin excretion group only. The diabetes-induced rise of total urinary protein in both groups was significantly reduced by tolrestat. Furthermore, the diabetes-induced increase (49%) in the thickness of the basement membranes of retinal capillaries from the outer plexiform layer was significantly diminished by tolrestat administration. In conclusion, intervention therapy with the Aldose Reductase Inhibitor, tolrestat, can reduce the progression of urinary albumin excretion and retinal basement membrane thickening in long-term diabetic rats.
Paul J. Thornalley - One of the best experts on this subject based on the ideXlab platform.
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modification of the glyoxalase system in streptozotocin induced diabetic rats effect of the Aldose Reductase Inhibitor statil
Biochemical Pharmacology, 1993Co-Authors: Susan A Phillips, Donald Mirrlees, Paul J. ThornalleyAbstract:The glyoxalase system was characterized in tissue (liver, skeletal muscle, kidney cortex and medulla, lens and sciatic nerve) and blood from streptozotocin-induced diabetic rats and normal controls. The effect of the Aldose Reductase Inhibitor, Statil [3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazine-1-yl-acetic acid; ICI 128 436], was also investigated. Glyoxalase I and glyoxalase II activities were decreased in the liver and increased in skeletal muscle of diabetic rats and of Statil-treated diabetic rats, relative to normal controls. The concentration of non-protein sulphydryl (NPSH) was decreased in the liver and lens of diabetic rats, relative to normal controls; Statil prevented these effects. The concentrations of methylglyoxal in the kidney cortex and medulla, lens and blood were increased in diabetic rats, relative to normal controls. Statil prevented these increases except in the kidney cortex. The concentration of D-lactate was increased in the lens and blood of diabetic rats, relative to normal controls, which was partially prevented in blood but not in the lens by Statil. These data suggest that the glyoxalase system is modified in tissues and blood of streptozotocin-induced diabetic rats and some of the modifications may be prevented by Statil. The increased concentrations of methylglyoxal in the kidney, lens and blood, and the decreased concentration of NPSH in the lens may be related to the development of diabetic complications.
