Effects of an aldose reductase inhibitor, epalrestat, on diabetic neuropathy. Clinical benefit and indication for the drug assessed from the results of a placebo-controlled double-blind study

doi:10.1016/0753-3322(96)82642-4

Biomedicine & Pharmacotherapy

Volume 49, Issue 6, 1995, Pages 269-277

https://doi.org/10.1016/0753-3322(96)82642-4 Get rights and content

Summary

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 (Δ 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 HbA_1c. values. The improvement ratings of subjective symptoms and of nerve function tests for cases with HbA_1c. ≧ 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 HbA_1c < 7.5%. This reanalysis also revealed that the effects of epalrestat were marked in patients receiving the drug as early after the onset of diabetic neuropathy as possible (3 yrs ≧) and were more marked in patients with mild or moderate neuropathy than in those with severe neuropathy. Our findings suggest that epalrestat is a highly effective agent for the treatment of diabetic neuropathy.

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Cited by (73)

Moving toward a new horizon for the aldose reductase inhibitor epalrestat to treat drug-resistant cancer
2022, European Journal of Pharmacology
Epalrestat (EPA) is a potent inhibitor of aldose reductases AKR1B1 and AKR1B10, used for decades in Japan for the treatment of diabetic peripheral neuropathy. This orally-active, brain-permeable small molecule, with a relatively rare and essential 2-thioxo-4-thiazolidinone motif, functions as a regulator intracellular carbonyl species. The repurposing of EPA for the treatment of pediatric rare diseases, brain disorders and cancer has been proposed. A detailed analysis of the mechanism of action, and the benefit of EPA to combat advanced malignancies is offered here. EPA has revealed marked anticancer activities, alone and in combination with cytotoxic chemotherapy and targeted therapeutics, in experimental models of liver, colon, and breast cancers. Through inhibition of AKR1B1 and/or AKR1B10 and blockade of the epithelial-mesenchymal transition, EPA largely enhances the sensitivity of cancer cells to drugs like doxorubicin and sorafenib. EPA has revealed a major anticancer effect in an experimental model of basal-like breast cancer and clinical trials have been developed in patients with triple-negative breast cancer. The repurposing of the drug to treat chemo-resistant solid tumors seems promising, but more studies are needed to define the best trajectory for the positioning of EPA in oncology.
Mechanistic approach towards diabetic neuropathy screening techniques and future challenges: A review
2022, Biomedicine and Pharmacotherapy
Citation Excerpt :
The aldose reductase enzyme converts glucose to sorbitol, is inhibited by these inhibitors, resulting in a rise in osmotic stress [138]. In a three-year randomized trial [139], ARI, like Epalrestat, improves prodromal neuropathy with a considerable safety profile. One of the most difficult tasks has now become delivering adequate treatment for neuropathic patients.
Diabetic neuropathy, also called peripheral diabetic neuropathy (PDN), is among the most significant diabetes health consequences, alongside diabetic nephropathy, diabetic cardiomyopathy and diabetic retinopathy. Diabetic neuropathy is the existence of signs and indications of peripheral nerve damage in patients with diabetes after other causes have been governed out. Diabetic neuropathy is a painful and severe complication of diabetes that affects roughly 20% of people. The development of diabetic neuropathy is regulated by blood arteries that nourish the peripheral nerves and metabolic problems such as increased stimulation of polyol pathway, loss of myo-inositol and enhanced non-enzymatic glycation. It's divided into four types based on where neurons are most affected: autonomic, peripheral, proximal, and focal, with each kind presenting different symptoms like numbing, gastrointestinal disorders, and heart concerns. Pharmacotherapy for neuropathic pain is complex and for many patients, effective treatment is lacking; as a result, scientific proof recommendations are crucial. As a result, the current demand is to give the most vital medications or combinations of drugs that work directly on the nerves to help diabetic neuropathy patients feel less pain without causing any adverse effects. In diabetic neuropathy research, animal models are ubiquitous, with rats and mice being the most typically chosen for various reasons. This review covers the epidemiology, clinical features, pathology, clinical symptom, mechanism of diabetic neuropathy development, diagnosis, screening models of animals, diabetic neuropathy pharmacotherapy.
Development of coumarin-thiosemicarbazone hybrids as aldose reductase inhibitors: Biological assays, molecular docking, simulation studies and ADME evaluation
2021, Bioorganic Chemistry
The over expression of aldose reductase (ALR2) in the state of hyperglycemia causes the conversion of glucose into sorbitol and initiates polyol pathway. Accumulation of sorbitol in insulin insensitive tissue like peripheral nerves, glomerulus and eyes, induces diabetic complications like neuropathy, nephropathy and retinopathy. For the treatment of diabetic complications, the inhibition of aldose reductase (ALR2) is a promising approach. A series of coumarin-based thiosemicarbazone derivatives was synthesized as potential inhibitor of aldose reductase. Compound N-(2-fluorophenyl)-2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)hydrazinecarbiothioamide (3n) was found to be the most promising inhibitor of ALR2 with an IC₅₀ in micromolar range (2.07 µM) and high selectivity, relative to ALR1. The crystal structure of ALR2 complexed with 3n explored the types of interaction pattern which further demonstrated its high affinity. Compound 3n has excellent lead-likeness, underlined by its physicochemical parameters, and can be considered as a likely prospect for further structural optimization to get a drugable molecule.
Study on degradation kinetics of epalrestat in aqueous solutions and characterization of its major degradation products under stress degradation conditions by UHPLC-PDA-MS/MS
2019, Journal of Pharmaceutical Analysis
Citation Excerpt :
Modern pharmaco-studies have indicated that epalrestat reduces sorbitol accumulation in the sciatic nerve, erythrocytes, and ocular tissues in animals, and erythrocytes in humans [11,12]. Epalrestat is increasingly applied in the clinic as it is presently the only aldose reductase inhibitor with less severe side effects [13–18]. Numerous reports have been published investigating related substances, the content assay by RP-HPLC [19,20].
Drug stability is closely related to drug safety and needs to be considered in the process of drug production, package and storage. To investigate the stability of epalrestat, a carboxylic acid derivative, a reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed in this study and applied to analyzing the degradation kinetics of epalrestat in aqueous solutions in various conditions, such as different pH, temperatures, ionic strengths, oxidation and irradiation. The calibration curve was A = 1.6 × 10⁵C–1.3 × 10³ (r = 0.999) with the liner range of 0.5–24 μg/mL, the intra-day and inter-day precision was less than 2.0%, as was the repeatibility. The average accuracy for different concentrations was more than 98.5%, indicating that perfect recoveries were achieved. Degradation kinetic parameters such as degradation rate constants (k), activation energy (Ea) and shelf life (t_0.9) under different conditions were calculated and discussed. The results indicated that the degradation behavior of epalrestat was pH-dependent and the stability of epalrestat decreased with the rised irradiation and ionic strength; however, it was more stable in neutral and alkaline conditions as well as lower temperatures. The results showed that the degradation kinetics of epalrestat followed first-order reaction kinetics. Furthermore, the degradation products of epalrestat under stress conditions were identified by UHPLC-PDA-MS/MS, with seven degradation products being detected and four of them being tentatively identified.
hCES1 and hCES2 mediated activation of epalrestat-antioxidant mutual prodrugs: Unwinding the hydrolytic mechanism using in silico approaches
2019, Journal of Molecular Graphics and Modelling
Herein, we report four series of mutual prodrugs of epalrestat by combining it with different antioxidants using glycine, beta-alanine, and phenylalanine as a linker and by directly linking them through an ester linkage. The designed prodrugs were subjected to pharmacophore and docking-based virtual screening to determine the susceptibility of these prodrugs to be hydrolyzed by human carboxylesterases (hCES1 and hCES2). Five best prodrugs from each series were further submitted to detailed mechanistic study of hCES1 and hCES2 based hydrolytic activation using quantum mechanics and molecular dynamics approach. Additionally, Verloop'ssterimol parameters (B1-B5, L) were calculated in order to investigate the steric constraint of prodrugs to the catalytic sites of hCES1 and hCES2 enzymes. Our results indicated that, among these prodrugs, EP-D4, EP-E13, EP-F5, and EP-F14 are best substrates for hCES1 while EP-G3 and EP-G15 are potential substrates for hCES2. On the other hand, EP-D19 serves as good substrates for both enzymes.
Quinazolinone-based rhodanine-3-acetic acids as potent aldose reductase inhibitors: Synthesis, functional evaluation and molecular modeling study
2017, Bioorganic and Medicinal Chemistry Letters
A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors.

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Dossier “Diabetes II”Effects of an aldose reductase inhibitor, epalrestat, on diabetic neuropathy. Clinical benefit and indication for the drug assessed from the results of a placebo-controlled double-blind study

Summary

Lancet

Metabolism

The sorbitol pathway and the complications of diabetes

N Engl J Med

Glucose-induced alterations in nerve metabolism: current perspective on the pathogenesis of diabetic neuropathy and future directions for research and therapy

Diabetes Care

Altered myoinositol metabolism in diabetic nerve

Aldose reductase inhibitors

Effect of blood sugar control on the accumulation of sorbitol and fructose in nervous tissues

Diabetes

Clinical effect of aldose reductase inhibitor (Epalrestat, ONO 2235) on diabetic neuropathy. Multi-institutional studies

Aldose reductase inhibition improves nerve conduction velocity in diabetic patient

N Engl J Med

A placebo-controlled double-blind study of epalrestat (ONO-2235) in patients with diabetic neuropathy

J Clin Exp Med (Igaku No Ayumi)

Myoinositol and sorbitol metabolism in relation to peripheral nerve function in experimental diabetes in the rat: the effect of aldose reductase inhibitor

Diabetologia

Dossier “Diabetes II”
Effects of an aldose reductase inhibitor, epalrestat, on diabetic neuropathy. Clinical benefit and indication for the drug assessed from the results of a placebo-controlled double-blind study