| Reference | [1]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2019 Jan;35(1):79-84. doi: 10.12047/j.cjap.5735.2019.019.<br />
[Interventional effect of epalrestat on renal interstitial fibrosis in unilateral ureteral obstruction rats and its mechanism].<br />
Gao YX(1), Tang J(2), Zhang Q(2), Jiang LL(2), Li XW(3).<br />
Author information: (1)Departments of Medical Microbiology and Immunology, Wannan Medical College, Wuhu 241002. (2)Department of Pharmacology, Wannan Medical College. (3)Department of Pharmacology, Wannan Medical College; Anhui Provincial Engineering Technology Research Center for Polysaccharide Drugs, Wuhu 241002, China.<br />
OBJECTIVE: To observe the protective effects of epalrestat (EPS) on interstitial fibrosis in unilateral ureteral obstruction (UUO) rats and its mechanism. METHODS: Rats were randomly divided into four groups: sham group, UUO group, UUO + epalrestat (50 or 100 mg/kg), 8 rats in each group.Rats in UUO and UUO + epalrestat group were obstructed left ureter.In the sham group, rats had their left ureters exposed and manipulated without ligation.Animals for epalrestat treatment received daily drug via gavage for 3 weeks, the rats of sham and UUO groups received equal amount of sodium carboxymethyl cellulose with the same regimen.Renal tissues pathological changes and collagen deposition were observed by HE and Masson's staining.The aldose reductase(AR) expression in renal tissues was measured by immunohistochemisty.The expression levels of collagen I, collagen III, alpha-smooth muscle actin (α-SMA), fibroblast-specific protein1 (FSP-1), fibronectin (FN), epithelial cadherin (E-cadherin), transforming growth factor-β1 (TGF-β1) and AR from kidney tissues were measured by real-time RT-PCR or Western blot. RESULTS: Compared with the sham group, the renal tissues of the UUO group showed significant fibrosis, including renal tubular epithelial cell atrophy and vacuolated degeneration, collagen deposition, fibroblasts and myofibroblasts proliferation and inflammatory cell infiltration, and concomitantly with the expressions of collagen I, collagen III, TGF-β1, AR, α-SMA, FSP-1 and FN were remarkably up-regulated, but E-cadherin was significantly reduced in UUO group.Compared with the UUO group, after 3 weeks epalrestat administration, the level of renal interstitial fibrosis was obviously ameliorated and the expressions of collagen I, collagen III, TGF-β1, AR, α-SMA, FSP-1 and FN were remarkably down-regulated, but E-cadherin was significantly increased in rats of epalrestat groups. CONCLUSION: These results suggest that epalrestat attenuates renal interstitial fibrosis possibly through inhibition of EMT via inhibiting TGF-β1 and AR expression.<br />
DOI: 10.12047/j.cjap.5735.2019.019 PMID: 31245958<br />
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[2]. Int J Impot Res. 2019 Mar;31(2):97-104. doi: 10.1038/s41443-018-0075-x. Epub 2018 Sep 13.<br />
Epalrestat, an Aldose Reductase Inhibitor, Restores Erectile Function in Streptozocin-induced Diabetic Rats.<br />
Yang BB(1), Hong ZW(2), Zhang Z(1), Yu W(1), Song T(1), Zhu LL(1), Jiang HS(1), Chen GT(1), Chen Y(3), Dai YT(4).<br />
Author information: (1)Department of Andrology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210000, China. (2)Department of Urology, Fujian Provincial Hospital, Fuzhou, 350000, China. (3)Department of Andrology, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, 210000, China. [email protected]. (4)Department of Andrology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210000, China. [email protected].<br />
Erratum inInt J Impot Res. 2019 Feb 4;:<br />
Epalrestat, an aldose reductase inhibitor (ARI), was adopted to improve the function of peripheral nerves in diabetic patients. The aim of this study was to investigate whether epalrestat could restore the erectile function of diabetic erectile dysfunction using a rat model. From June 2016, 24 rats were given streptozocin (STZ) to induce the diabetic rat model, and epalrestat was administered to ten diabetic erectile dysfunction (DED) rats. Intracavernous pressure (ICP) and mean systemic arterial pressure (MAP), levels of aldose reductase (AR), nerve growth factor (NGF), neuronal nitric oxide synthase (nNOS), α-smooth muscle antigen (α-SMA), and von Willebrand factor (vWF) in the corpus cavernosum were analyzed. We discovered that epalrestat acted on cavernous tissue and partly restored erectile function. NGF and nNOS levels in the corpora were increased after treatment with epalrestat. We also found that the content of α-SMA-positive smooth muscle cells and vWF-positive endothelial cells in the corpora cavernosum were declined. Accordingly, epalrestat might improve erectile function by increasing the upregulation of NGF and nNOS to restore the function of the dorsal nerve of the penis.<br />
DOI: 10.1038/s41443-018-0075-x PMCID: PMC6462873 PMID: 30214006<br />
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[3]. Drugs Aging. 1993 Nov-Dec;3(6):532-55. doi: 10.2165/00002512-199303060-00007.<br />
Epalrestat. A review of its pharmacology, and therapeutic potential in late-onset complications of diabetes mellitus.<br />
Steele JW(1), Faulds D, Goa KL.<br />
Author information: (1)Adis International Limited, Auckland, New Zealand.<br />
Epalrestat is a carboxylic acid derivative which inhibits aldose reductase, an enzyme of the sorbitol (polyol) pathway. Under hyperglycaemic conditions epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat 150 mg/day for 12 weeks improved motor and sensory nerve conduction velocity, and vibration threshold compared with baseline and placebo in patients with diabetic neuropathy. Subjective symptoms including pain, numbness, hyperaesthesia, coldness in the extremities, muscular weakness, dizziness, and orthostatic fainting were also improved. Similar benefits were seen in a comparison with historical controls. Epalrestat 300 mg/day for 1 or 3 years was also significantly superior to placebo or no treatment in improving electroretinogram parameters and photo stress recovery time in patients with diabetic retinopathy. Improvements were also documented by funduscopy and fluorescein angiography. Epalrestat appeared most effective in patients with less severe diabetes mellitus and more recent development of late-onset complications. Epalrestat is apparently well tolerated with predominantly minor adverse events reported in clinical trials. Liver enzyme elevations were most commonly reported but generally resolved spontaneously on dose reduction or discontinuation. The effects of age and renal impairment on the efficacy and tolerability of epalrestat require clarification, and data on its use in other late-onset complications of diabetes such as nephropathy are also lacking. Comparisons with other aldose reductase inhibitors are also required to fully determine the role of epalrestat. The suggested ability of epalrestat to prevent the onset of diabetic complications should also be investigated. Thus, available data suggest epalrestat produces some improvement in the late-onset neuropathy and retinopathy associated with diabetes mellitus, although additional trials are required to determine whether ongoing therapy is necessary to maintain the improvements achieved and to confirm tolerability in the long term. Nevertheless, preliminary results suggest that epalrestat may be a useful drug in an area where there is a need for effective therapy.<br />
DOI: 10.2165/00002512-199303060-00007 PMID: 8312678<br />
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[4]. Pharmacotherapy. 2008 May;28(5):646-55. doi: 10.1592/phco.28.5.646.<br />
Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy.<br />
Ramirez MA(1), Borja NL.<br />
Author information: (1)Department of Pharmacy Practice, Nova Southeastern University College of Pharmacy, Fort Lauderdale, Florida, USA.<br />
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.<br />
DOI: 10.1592/phco.28.5.646 PMID: 18447661<br />
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[5]. Nihon Rinsho. 1997 Nov;55 Suppl:204-11. [Epalrestat].<br />
Hotta N(1).<br />
Author information: (1)Third Department of Internal Medicine, Nagoya University School of Medicine.<br />
PMID: 9434468
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