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Article(id=1193674744143773986, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1193674740352119804, articleNumber=1001-2494(2025)06-0553-06, orderNo=null, doi=10.11669/cpj.2025.06.001, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1726070400000, receivedDateStr=2024-09-12, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1762523836407, onlineDateStr=2025-11-07, pubDate=1742572800000, pubDateStr=2025-03-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762523836407, onlineIssueDateStr=2025-11-07, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762523836407, creator=13701087609, updateTime=1762523836407, updator=13701087609, issue=Issue{id=1193674740352119804, tenantId=1146029695717560320, journalId=1190317699101192196, year='2025', volume='60', issue='6', pageStart='553', pageEnd='662', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1762523835503, creator=13701087609, updateTime=1762524041683, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1193675605205025683, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1193674740352119804, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1193675605205025684, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1193674740352119804, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=553, endPage=558, ext={EN=ArticleExt(id=1193674744349294885, articleId=1193674744143773986, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Progress in Clinical Trials of Aldose Reductase Inhibitors in the Treatment of Diabetic Peripheral Neuropathy, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

Diabetic peripheral neuropathy is one of the most common complications of diabetes. Aldose reductase is a key enzyme in the pathogenesis of diabetic complications. This review systematically reviews the efficacy and safety of five kinds of aldose reductase inhibitors in the treatment of diabetic peripheral nerves. Epalrestat is the only aldose reductase inhibitor in clinical application so far. A number of clinical trials have shown that epalrestat has a certain therapeutic effect on diabetic peripheral neuropathy and has sufficient safety, but long-term studies have shown that its therapeutic effect is not better than mecobalamine. Torrestat, zoporestat, ponastat, and fedastat were all withheld from the market or withdrawn from the market due to efficacy or safety concerns, which was inferred to be related to the structural characteristics of the drugs. Development of more effective and safer aldose reductase inhibitors from the perspective of drug structure will become one of the future research focuses on diabetic peripheral neuropathy.

, correspAuthors=Lianhua FANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Jian ZHOU, Lianhua FANG, Yang LÜ, Guanhua DU), CN=ArticleExt(id=1193674825588769157, articleId=1193674744143773986, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=醛糖还原酶抑制剂治疗糖尿病周围神经病变的临床试验研究进展, columnId=1190352408384471863, journalTitle=中国药学杂志, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

糖尿病周围神经病变是糖尿病最常见的并发症之一,醛糖还原酶是糖尿病周围神经病变等多种糖尿病并发症发病机制中的关键酶。笔者系统综述了5种醛糖还原酶抑制剂用于治疗糖尿病周围神经病变临床试验的有效性与安全性研究进展。依帕司他是至今唯一在临床应用的醛糖还原酶抑制剂,多项临床试验表明其对于糖尿病周围神经病变具有一定的治疗作用且具有足够的安全性,但是长期研究表明其治疗效果不优于甲钴胺。托瑞司他、唑泊司他、泊那司他及非达司他均由于有效性或安全性问题未能上市或被撤市,可能与药物的结构特征有关。从药物结构出发,研究和开发更为有效和安全的醛糖还原酶抑制剂治疗糖尿病周围神经病变将成为未来的研究重点之一。

, correspAuthors=方莲花, authorNote=null, correspAuthorsNote=
*方莲花,女,博士,研究员,博士生导师 研究方向:心脑血管药理学与新药发现 Tel:(010)63165313
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周健,男,博士研究生 研究方向:心脑血管药理学与新药发现

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周健,男,博士研究生 研究方向:心脑血管药理学与新药发现

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J Clin Pharmacol, 1994, 34(7): 760-766., articleTitle=Pharmacokinetics of the aldose reductase inhibitor, zopolrestat, in humans, refAbstract=null), Reference(id=1193712783930913309, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=2015, volume=37, issue=4, pageStart=1537, pageEnd=1546, url=null, language=null, rfNumber=[39], rfOrder=38, authorNames=BOUGUERRA G, BISSINGER R, ABBÈS S, journalName=Cell Physiol Biochem, refType=null, unstructuredReference=BOUGUERRA G, BISSINGER R, ABBÈS S, et al. Zopolrestat induced suicidal death of human erythrocytes[J]. Cell Physiol Biochem, 2015, 37(4): 1537-1546., articleTitle=Zopolrestat induced suicidal death of human erythrocytes, refAbstract=null), Reference(id=1193712783989633566, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=1990, volume=39, issue=2, pageStart=337, pageEnd=346, url=null, language=null, rfNumber=[40], rfOrder=39, authorNames=WARD W H, SENNITT C M, ROSS H, journalName=Biochem Pharmacol, refType=null, unstructuredReference=WARD W H, SENNITT C M, ROSS H, et al. Ponalrestat: a potent and specific inhibitor of aldose reductase[J]. Biochem Pharmacol, 1990, 39(2): 337-346., articleTitle=Ponalrestat: a potent and specific inhibitor of aldose reductase, refAbstract=null), Reference(id=1193712784065131039, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=1991, volume=14, issue=1, pageStart=63, pageEnd=73, url=null, language=null, rfNumber=[41], rfOrder=40, authorNames=ZIEGLER D, MAYER P, RATHMANN W, journalName=Diabetes Res Clin Pract, refType=null, unstructuredReference=ZIEGLER D, MAYER P, RATHMANN W, et al. One-year treatment with the aldose reductase inhibitor, ponalrestat, in diabetic neuropathy[J]. Diabetes Res Clin Pract, 1991, 14(1): 63-73., articleTitle=One-year treatment with the aldose reductase inhibitor, ponalrestat, in diabetic neuropathy, refAbstract=null), Reference(id=1193712784157405728, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=1992, volume=6, issue=2, pageStart=123, pageEnd=130, url=null, language=null, rfNumber=[42], rfOrder=41, authorNames=SUNDKVIST G, ARMSTRONG F M, BRADBURY J E, journalName=J Diabetes Complicat, refType=null, unstructuredReference=SUNDKVIST G, ARMSTRONG F M, BRADBURY J E, et al. Peripheral and autonomic nerve function in 259 diabetic patients with peripheral neuropathy treated with ponalrestat (an aldose reductase inhibitor) or placebo for 18 months. United Kingdom/Scandinavian ponalrestat trial[J]. J Diabetes Complicat, 1992, 6(2): 123-130., articleTitle=Peripheral and autonomic nerve function in 259 diabetic patients with peripheral neuropathy treated with ponalrestat (an aldose reductase inhibitor) or placebo for 18 months. United Kingdom/Scandinavian ponalrestat trial, refAbstract=null), Reference(id=1193712784228708897, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=1999, volume=13, issue=3, pageStart=141, pageEnd=150, url=null, language=null, rfNumber=[43], rfOrder=42, authorNames=MIZUNO K, KATO N, MAKINO M, journalName=J Diabetes Complicat, refType=null, unstructuredReference=MIZUNO K, KATO N, MAKINO M, et al. Continuous inhibition of excessive polyol pathway flux in peripheral nerves by aldose reductase inhibitor fidarestat leads to improvement of diabetic neuropathy[J]. J Diabetes Complicat, 1999, 13(3): 141-150., articleTitle=Continuous inhibition of excessive polyol pathway flux in peripheral nerves by aldose reductase inhibitor fidarestat leads to improvement of diabetic neuropathy, refAbstract=null), Reference(id=1193712784312594978, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=2002, volume=16, issue=2, pageStart=133, pageEnd=138, url=null, language=null, rfNumber=[44], rfOrder=43, authorNames=ASANO T, SAITO Y, KAWAKAMI M, journalName=J Diabetes Complicat, refType=null, unstructuredReference=ASANO T, SAITO Y, KAWAKAMI M, et al. Fidarestat (SNK-860), a potent aldose reductase inhibitor, normalizes the elevated sorbitol accumulation in erythrocytes of diabetic patients[J]. J Diabetes Complicat, 2002, 16(2): 133-138., articleTitle=Fidarestat (SNK-860), a potent aldose reductase inhibitor, normalizes the elevated sorbitol accumulation in erythrocytes of diabetic patients, refAbstract=null), Reference(id=1193712785382142499, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=2004, volume=18, issue=6, pageStart=336, pageEnd=342, url=null, language=null, rfNumber=[45], rfOrder=44, authorNames=ASANO T, SAITO Y, KAWAKAMI M, journalName=J Diabetes Complicat, refType=null, unstructuredReference=ASANO T, SAITO Y, KAWAKAMI M, et al. Erythrocytic sorbitol contents in diabetic patients correlate with blood aldose reductase protein contents and plasma glucose levels, and are normalized by the potent aldose reductase inhibitor fidarestat (SNK-860)[J]. J Diabetes Complicat, 2004, 18(6): 336-342., articleTitle=Erythrocytic sorbitol contents in diabetic patients correlate with blood aldose reductase protein contents and plasma glucose levels, and are normalized by the potent aldose reductase inhibitor fidarestat (SNK-860), refAbstract=null), Reference(id=1193712785453445668, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=2001, volume=24, issue=10, pageStart=1776, pageEnd=1782, url=null, language=null, rfNumber=[46], rfOrder=45, authorNames=HOTTA N, TOYOTA T, MATSUOKA K, journalName=Diabetes Care, refType=null, unstructuredReference=HOTTA N, TOYOTA T, MATSUOKA K, et al. Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study[J]. Diabetes Care, 2001, 24(10): 1776-1782., articleTitle=Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study, refAbstract=null), Reference(id=1193712785507971621, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=2020, volume=26, issue=12, pageStart=1117, pageEnd=1129, url=null, language=null, rfNumber=[47], rfOrder=46, authorNames=SAWANGJIT R, THONGPHUI S, CHAICHOMPU W, journalName=J Altern Complement Med, refType=null, unstructuredReference=SAWANGJIT R, THONGPHUI S, CHAICHOMPU W, et al. Efficacy and safety of mecobalamin on peripheral neuropathy: a systematic review and meta-analysis of randomized controlled trials[J]. J Altern Complement Med, 2020, 26(12): 1117-1129., articleTitle=Efficacy and safety of mecobalamin on peripheral neuropathy: a systematic review and meta-analysis of randomized controlled trials, refAbstract=null), Reference(id=1193712785562497574, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=2022, volume=49, issue=null, pageStart=101657, pageEnd=null, url=null, language=null, rfNumber=[48], rfOrder=47, authorNames=LEE C W, JIN J S, KWON S, journalName=Complement Ther Clin Pract, refType=null, unstructuredReference=LEE C W, JIN J S, KWON S, et al. Are herbal medicines alone or in combination for diabetic peripheral neuropathy more effective than methylcobalamin alone? A systematic review and meta-analysis[J]. Complement Ther Clin Pract, 2022, 49: 101657. DOI:10.1016/j.ctcp.2022.101657., articleTitle=Are herbal medicines alone or in combination for diabetic peripheral neuropathy more effective than methylcobalamin alone? A systematic review and meta-analysis, refAbstract=null), Reference(id=1193712785621217831, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=2024, volume=38, issue=2, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[49], rfOrder=48, authorNames=RAN G L, LI Y P, LU L C, journalName=J Diabetes Complicat, refType=null, unstructuredReference=RAN G L, LI Y P, LU L C, et al. Disease-modifying therapies for diabetic peripheral neuropathy: A systematic review and meta-analysis of randomized controlled trials[J]. J Diabetes Complicat, 2024, 38(2): 108691. DOI:10.1016/j.jdiacomp.2024.108691., articleTitle=Disease-modifying therapies for diabetic peripheral neuropathy: A systematic review and meta-analysis of randomized controlled trials, refAbstract=null), Reference(id=1193712785679938088, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, doi=null, pmid=null, pmcid=null, year=2023, volume=35, issue=3, pageStart=691, pageEnd=697, url=null, language=null, rfNumber=[50], rfOrder=49, authorNames=HAN Z F, LI J H, XU Z L, journalName=Chem Res Appl(化学研究与应用), refType=null, unstructuredReference=HAN Z F, LI J H, XU Z L, et al. Novel 3,4-dihydroquinolin-2(1H)-one derivatives as multifunctional aldose reductase inhibitors for treatment of diabetic complications: design,synthesis and biological evaluation[J]. Chem Res Appl(化学研究与应用), 2023, 35(3): 691-697., articleTitle=Novel 3,4-dihydroquinolin-2(1H)-one derivatives as multifunctional aldose reductase inhibitors for treatment of diabetic complications: design,synthesis and biological evaluation, refAbstract=null)], funds=[Fund(id=1193712779707249142, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, awardId=7232258, language=CN, fundingSource=北京市自然科学基金项目资助(7232258), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1193712776968368588, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, xref=null, ext=[AuthorCompanyExt(id=1193712776985145805, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, companyId=1193712776968368588, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Beijing Key Laboratory of Innovative Drug Discovery and Polymorphic Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1193712776993534414, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, companyId=1193712776968368588, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院药物研究所, 脑血管病新药发现及晶型研究北京市重点实验室, 北京 100050)])], figs=[ArticleFig(id=1193712779120046576, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, language=EN, label=null, caption=null, figureFileSmall=hHzMhiyfVX0zCvritZAoaA==, figureFileBig=ZvVg4GnswCkaK66Zq7VIbg==, tableContent=null), ArticleFig(id=1193712779220709873, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, language=CN, label=图1, caption=5种醛糖还原酶抑制剂化学结构式

A-依帕司他;B-托瑞司他;C-唑泊司他;D-泊那司他;E-非达司他。

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项目 要求
入选标准 ①患者年龄 18~65岁之间(截至筛查之日)
② 2型糖尿病病史 依据1999年世卫组织糖尿病诊断标准,病程6个月以上
③糖化血红蛋白 <7%
④神经病变检查(五项中有两项或以上异常) ①体温感知异常;②足部尼龙丝检查感觉减退或消失;③振动感觉异常;④踝关节反射消失;⑤两项或更多的神经传导速度降低
⑤禁用药物及治疗 近3个月未使用甲钴胺、依帕司他、硫辛酸或大剂量糖皮质激素;或在研究前3个月内未参与其他相同疾病的治疗
排除标准 ①其他原因引起的神经病变 如颈椎病变、腰椎病变、脑梗死等
②伴有糖尿病急性代谢并发症 如酮症酸中毒、乳酸酸中毒、糖尿病高渗状态等
③严重疾病或病史 ①严重心脑血管疾病;②肺源性心脏病或肺功能不全;③肾功能衰竭;④严重血脂异常;⑤高血压控制不良;⑥严重肝炎;⑦有恶性肿瘤病史;⑧结核病等消耗性疾病病史
④核磁共振扫描禁忌证 如内部(尤其是口腔)金属植入物、幽闭恐惧症等
⑤其他 ①依从性差或副作用严重者;②孕妇
), ArticleFig(id=1193712779396870643, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, language=CN, label=表1, caption=

“依帕司他对糖尿病患者周围神经病变和中枢神经系统的作用”项目入选与排除标准

, figureFileSmall=null, figureFileBig=null, tableContent=
项目 要求
入选标准 ①患者年龄 18~65岁之间(截至筛查之日)
② 2型糖尿病病史 依据1999年世卫组织糖尿病诊断标准,病程6个月以上
③糖化血红蛋白 <7%
④神经病变检查(五项中有两项或以上异常) ①体温感知异常;②足部尼龙丝检查感觉减退或消失;③振动感觉异常;④踝关节反射消失;⑤两项或更多的神经传导速度降低
⑤禁用药物及治疗 近3个月未使用甲钴胺、依帕司他、硫辛酸或大剂量糖皮质激素;或在研究前3个月内未参与其他相同疾病的治疗
排除标准 ①其他原因引起的神经病变 如颈椎病变、腰椎病变、脑梗死等
②伴有糖尿病急性代谢并发症 如酮症酸中毒、乳酸酸中毒、糖尿病高渗状态等
③严重疾病或病史 ①严重心脑血管疾病;②肺源性心脏病或肺功能不全;③肾功能衰竭;④严重血脂异常;⑤高血压控制不良;⑥严重肝炎;⑦有恶性肿瘤病史;⑧结核病等消耗性疾病病史
④核磁共振扫描禁忌证 如内部(尤其是口腔)金属植入物、幽闭恐惧症等
⑤其他 ①依从性差或副作用严重者;②孕妇
), ArticleFig(id=1193712779468173812, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
联合给药
品种		 时间
/年		 研究者 分组及病例数
/例		 给药时间
及剂量		 结果 参考
文献
加巴喷丁 2022 孙菲 依帕司他组:49
依帕司他+加巴喷丁组:49		 4周
依帕司他:150 mg·d-1
加巴喷丁:首次300 mg,每日增加300 mg,一直到最高剂量1 800 mg		 观察组的疼痛、感觉异常、灼烧感和麻木感评分分别为0.92、1.23、1.02、1.03分,均低于对照组的1.67、1.98、2.05、2.16分 [24]
加巴喷丁+
甲钴胺		 2024 孙仰婷等 加巴喷丁+甲钴胺组:54
依帕司他+加巴喷丁+甲钴胺组:42		 6周
加巴喷丁:2.7 g·d-1
甲钴胺:4.5 mg·d-1
依帕司他:150 mg·d-1		 ①神经传导速度:2组神经传导速度均有显著提升;且观察组的神经传导速均显著快于对照组(P<0.05)
②视觉模拟(VAS)/分:观察组的VAS显著低于对照组(P<0.05)		 [25]
甲钴胺 2022 徐子奇等 甲钴胺组:20
甲钴胺+依帕司他组:20		 4周
500 μg·d-1;150 mg·d-1
500 μg·d-1		 观察组患者正中神经和腓总神经的感觉神经传导速度(SNCV)分别为50.1、52.0 m·s-1,运动神经传导速度(MNCV)分别为53.6、54.2 m·s-1;对照组患者正中神经和腓总神经的SNCV分别为43.2、40.0 m·s-1, MNCV分别为45.0、45.1 m·s-1 [26]
甲钴胺 2024 万晓娟等 甲钴胺组:39
甲钴胺+依帕司他组:39		 12周
1.5 mg·d-1;150 mg·d-1;
1.5 mg·d-1		 观察组显效23例,有效15例,无效例1例,总有效38例;对照组显效15例,有效17例,无效7例,总有效32例(P<0.05) [27]
甲钴胺 2024 唐琪 甲钴胺组:47
甲钴胺+依帕司他组:47		 4周
1.5 mg·d-1;150 mg·d-1;
1.5 mg·d-1		 对照组和观察组的临床治疗总有效率分别为80.85%和95.74%(P<0.05) [28]
甲钴胺+马来酸桂哌齐特 2016 韦丽等 维生素B12组:60
甲钴胺+依帕司他+马来酸桂哌齐特组:60		 12周
维生素B12:0.5 mg·d-1
马来酸桂哌齐特:320 mg·d-1
甲钴胺:1 500 μg·d-1
依帕司他:150 mg·d-1		 对照组和研究组治疗后足底神经、腓总神经、胫神经传导速度均快于治疗前,研究组治疗后均快于对照组;
对照组和研究组治疗后临床症状、体征评分均低于治疗前,研究组治疗后评分均低于对照组,差异均有统计学意义(P<0.05)		 [29]
胰激肽原酶 2022 倪孝兵等 胰激肽原酶组:49
胰激肽原酶+依帕司他组:53		 4周
胰激肽原酶:720 u·d-1
依帕司他:150 mg·d-1		 治疗后,2组正中神经、腓总神经MNCV和SNCV均较治疗前增加,且研究组大于对照组(P<0.05,P<0.01) [30]
α-硫辛酸 2022 张绍华等 α-硫辛酸组:50
α-硫辛酸+依帕司他组:50		 10 d
α-硫辛酸:1 500 mg·d-1
依帕司他:150 mg·d-1		 治疗后,研究组较对照组神经传导速度更快,密歇根糖尿病周围神经病变评分(MDNS)评分与丙二醛(MDA)水平更低,超氧化物歧化酶(SOD)、谷胱甘肽(GSH)水平更高,差异有统计学意义(P<0.05) [31]
硫辛酸 2024 张磊 依帕司他组:36
硫辛酸+依帕司他组:36		 4周
硫辛酸注射液(生产厂家:Siegfried Hameln GmbH;注册证号:国药准字HJ20150670) 10~20 mL溶于100~250 mL生理盐水,静脉滴注30 min,每天1次
依帕司他:150 mg·d-1		 两组SOD、MDA、谷胱甘肽过氧化物(GSH-Px)水平低于治疗前,且观察组低于对照组,差异有统计学意义(P<0.05)。两组正中神经、腓总神经的MNCV、SNCV快于治疗前,且观察组快于对照组,差异有统计学意义(P<0.05)
两组临床症状评分低于治疗前,且观察组低于对照组,差异有统计学意义(P<0.05)		 [32]
α-硫辛酸 2016 宋佳佳等 α-硫辛酸组:98
依帕司他组:98
α-硫辛酸组+依帕司他组:98		 4周
α-硫辛酸:600 mg·d-1
依帕司他:150 mg·d-1		 治疗后,α-硫辛酸组联合依帕司他组在足部压力觉异常点数、密歇根糖尿病周围神经病变筛查表(MNSI)症状问卷、足部检查量表、神经传导速度、生理功能评分、躯体疼痛评分及治疗总有效率改善相比单药治疗效果更为显著 [35]
), ArticleFig(id=1193712779547865589, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674744143773986, language=CN, label=表2, caption=

依帕司他联合其他品种糖尿病周围神经病变药物临床试验结果汇总

, figureFileSmall=null, figureFileBig=null, tableContent=
联合给药
品种		 时间
/年		 研究者 分组及病例数
/例		 给药时间
及剂量		 结果 参考
文献
加巴喷丁 2022 孙菲 依帕司他组:49
依帕司他+加巴喷丁组:49		 4周
依帕司他:150 mg·d-1
加巴喷丁:首次300 mg,每日增加300 mg,一直到最高剂量1 800 mg		 观察组的疼痛、感觉异常、灼烧感和麻木感评分分别为0.92、1.23、1.02、1.03分,均低于对照组的1.67、1.98、2.05、2.16分 [24]
加巴喷丁+
甲钴胺		 2024 孙仰婷等 加巴喷丁+甲钴胺组:54
依帕司他+加巴喷丁+甲钴胺组:42		 6周
加巴喷丁:2.7 g·d-1
甲钴胺:4.5 mg·d-1
依帕司他:150 mg·d-1		 ①神经传导速度:2组神经传导速度均有显著提升;且观察组的神经传导速均显著快于对照组(P<0.05)
②视觉模拟(VAS)/分:观察组的VAS显著低于对照组(P<0.05)		 [25]
甲钴胺 2022 徐子奇等 甲钴胺组:20
甲钴胺+依帕司他组:20		 4周
500 μg·d-1;150 mg·d-1
500 μg·d-1		 观察组患者正中神经和腓总神经的感觉神经传导速度(SNCV)分别为50.1、52.0 m·s-1,运动神经传导速度(MNCV)分别为53.6、54.2 m·s-1;对照组患者正中神经和腓总神经的SNCV分别为43.2、40.0 m·s-1, MNCV分别为45.0、45.1 m·s-1 [26]
甲钴胺 2024 万晓娟等 甲钴胺组:39
甲钴胺+依帕司他组:39		 12周
1.5 mg·d-1;150 mg·d-1;
1.5 mg·d-1		 观察组显效23例,有效15例,无效例1例,总有效38例;对照组显效15例,有效17例,无效7例,总有效32例(P<0.05) [27]
甲钴胺 2024 唐琪 甲钴胺组:47
甲钴胺+依帕司他组:47		 4周
1.5 mg·d-1;150 mg·d-1;
1.5 mg·d-1		 对照组和观察组的临床治疗总有效率分别为80.85%和95.74%(P<0.05) [28]
甲钴胺+马来酸桂哌齐特 2016 韦丽等 维生素B12组:60
甲钴胺+依帕司他+马来酸桂哌齐特组:60		 12周
维生素B12:0.5 mg·d-1
马来酸桂哌齐特:320 mg·d-1
甲钴胺:1 500 μg·d-1
依帕司他:150 mg·d-1		 对照组和研究组治疗后足底神经、腓总神经、胫神经传导速度均快于治疗前,研究组治疗后均快于对照组;
对照组和研究组治疗后临床症状、体征评分均低于治疗前,研究组治疗后评分均低于对照组,差异均有统计学意义(P<0.05)		 [29]
胰激肽原酶 2022 倪孝兵等 胰激肽原酶组:49
胰激肽原酶+依帕司他组:53		 4周
胰激肽原酶:720 u·d-1
依帕司他:150 mg·d-1		 治疗后,2组正中神经、腓总神经MNCV和SNCV均较治疗前增加,且研究组大于对照组(P<0.05,P<0.01) [30]
α-硫辛酸 2022 张绍华等 α-硫辛酸组:50
α-硫辛酸+依帕司他组:50		 10 d
α-硫辛酸:1 500 mg·d-1
依帕司他:150 mg·d-1		 治疗后,研究组较对照组神经传导速度更快,密歇根糖尿病周围神经病变评分(MDNS)评分与丙二醛(MDA)水平更低,超氧化物歧化酶(SOD)、谷胱甘肽(GSH)水平更高,差异有统计学意义(P<0.05) [31]
硫辛酸 2024 张磊 依帕司他组:36
硫辛酸+依帕司他组:36		 4周
硫辛酸注射液(生产厂家:Siegfried Hameln GmbH;注册证号:国药准字HJ20150670) 10~20 mL溶于100~250 mL生理盐水,静脉滴注30 min,每天1次
依帕司他:150 mg·d-1		 两组SOD、MDA、谷胱甘肽过氧化物(GSH-Px)水平低于治疗前,且观察组低于对照组,差异有统计学意义(P<0.05)。两组正中神经、腓总神经的MNCV、SNCV快于治疗前,且观察组快于对照组,差异有统计学意义(P<0.05)
两组临床症状评分低于治疗前,且观察组低于对照组,差异有统计学意义(P<0.05)		 [32]
α-硫辛酸 2016 宋佳佳等 α-硫辛酸组:98
依帕司他组:98
α-硫辛酸组+依帕司他组:98		 4周
α-硫辛酸:600 mg·d-1
依帕司他:150 mg·d-1		 治疗后,α-硫辛酸组联合依帕司他组在足部压力觉异常点数、密歇根糖尿病周围神经病变筛查表(MNSI)症状问卷、足部检查量表、神经传导速度、生理功能评分、躯体疼痛评分及治疗总有效率改善相比单药治疗效果更为显著 [35]
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醛糖还原酶抑制剂治疗糖尿病周围神经病变的临床试验研究进展
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周健 , 方莲花 * , 吕扬 , 杜冠华
中国药学杂志 | 综述 2025,60(6): 553-558
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中国药学杂志 | 综述 2025, 60(6): 553-558
醛糖还原酶抑制剂治疗糖尿病周围神经病变的临床试验研究进展
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周健, 方莲花*, 吕扬, 杜冠华
作者信息
  • 中国医学科学院北京协和医学院药物研究所, 脑血管病新药发现及晶型研究北京市重点实验室, 北京 100050

    • 周健,男,博士研究生 研究方向:心脑血管药理学与新药发现

通讯作者:

*方莲花,女,博士,研究员,博士生导师 研究方向:心脑血管药理学与新药发现 Tel:(010)63165313
Progress in Clinical Trials of Aldose Reductase Inhibitors in the Treatment of Diabetic Peripheral Neuropathy
Jian ZHOU, Lianhua FANG*, Yang LÜ, Guanhua DU
Affiliations
  • Beijing Key Laboratory of Innovative Drug Discovery and Polymorphic Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
出版时间: 2025-03-22 doi: 10.11669/cpj.2025.06.001
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糖尿病周围神经病变是糖尿病最常见的并发症之一,醛糖还原酶是糖尿病周围神经病变等多种糖尿病并发症发病机制中的关键酶。笔者系统综述了5种醛糖还原酶抑制剂用于治疗糖尿病周围神经病变临床试验的有效性与安全性研究进展。依帕司他是至今唯一在临床应用的醛糖还原酶抑制剂,多项临床试验表明其对于糖尿病周围神经病变具有一定的治疗作用且具有足够的安全性,但是长期研究表明其治疗效果不优于甲钴胺。托瑞司他、唑泊司他、泊那司他及非达司他均由于有效性或安全性问题未能上市或被撤市,可能与药物的结构特征有关。从药物结构出发,研究和开发更为有效和安全的醛糖还原酶抑制剂治疗糖尿病周围神经病变将成为未来的研究重点之一。

醛糖还原酶抑制剂  /  糖尿病周围神经病变  /  临床试验  /  依帕司他

Diabetic peripheral neuropathy is one of the most common complications of diabetes. Aldose reductase is a key enzyme in the pathogenesis of diabetic complications. This review systematically reviews the efficacy and safety of five kinds of aldose reductase inhibitors in the treatment of diabetic peripheral nerves. Epalrestat is the only aldose reductase inhibitor in clinical application so far. A number of clinical trials have shown that epalrestat has a certain therapeutic effect on diabetic peripheral neuropathy and has sufficient safety, but long-term studies have shown that its therapeutic effect is not better than mecobalamine. Torrestat, zoporestat, ponastat, and fedastat were all withheld from the market or withdrawn from the market due to efficacy or safety concerns, which was inferred to be related to the structural characteristics of the drugs. Development of more effective and safer aldose reductase inhibitors from the perspective of drug structure will become one of the future research focuses on diabetic peripheral neuropathy.

aldose reductase inhibitor  /  diabetic peripheral neuropathy  /  clinic trial  /  epalrestat
周健, 方莲花, 吕扬, 杜冠华. 醛糖还原酶抑制剂治疗糖尿病周围神经病变的临床试验研究进展. 中国药学杂志, 2025 , 60 (6) : 553 -558 . DOI: 10.11669/cpj.2025.06.001
Jian ZHOU, Lianhua FANG, Yang LÜ, Guanhua DU. Progress in Clinical Trials of Aldose Reductase Inhibitors in the Treatment of Diabetic Peripheral Neuropathy[J]. Chinese Pharmaceutical Journal, 2025 , 60 (6) : 553 -558 . DOI: 10.11669/cpj.2025.06.001
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糖尿病是一种常见的代谢性疾病。根据国际糖尿病联盟(IDF)发布的《IDF世界糖尿病地图(第10版)》报道,成年糖尿病患者人数达到5.37亿。累及多器官、多系统的急、慢性并发症仍是糖尿病患者致残、致死的主要原因[1]。
糖尿病神经病变是最常见的慢性并发症,其中又以远端、对称、多发性的糖尿病周围神经病变最具代表性,约占糖尿病神经病变的75%。临床上对于糖尿病周围神经病变的治疗以药物治疗为主[2],如营养神经药物甲钴胺、改善微循环药物胰激肽原酶肠溶片、抗氧化应激药物乙酰左卡尼汀。此外,临床上也采用镇痛药物如度洛西汀[3]来缓解疼痛症状。但这些药物的作用途径均不是针对糖尿病周围神经病变的发病机制,多以对症治疗为主且治疗效果具有一定的局限性。
多元醇途径醛糖还原酶活性的异常增强被认为是影响糖尿病周围神经病变的因素之一,因此开发安全有效的醛糖还原酶抑制剂(aldose reductase inhibitor,ARI)一直是糖尿病周围神经病变药物治疗领域的关注热点。为了深入认识醛糖还原酶抑制剂的临床效果,本文对醛糖还原酶抑制剂的作用机制、临床研究的有效性与安全性进行系统综述和分析。
1 醛糖还原酶抑制剂的作用机制
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正常情况下在体内,葡萄糖主要是经三羧酸循环后通过氧化磷酸化途径,最终代谢为二氧化碳和水,产生三磷酸腺苷(ATP)维持机体的生理活动。在高血糖条件下,葡萄糖还有另外一个代谢途径,即山梨醇(多元醇)代谢途径,该代谢途径下醛糖还原酶(aldose reductase,AR)被激活[2,4-5],催化由还原型辅酶Ⅱ(NADPH)参与的葡萄糖转化为山梨醇。山梨醇脱氢酶(sorbitol dehydrogenase,SDH)的活性没有相应的变化,导致山梨醇增加。山梨醇的积聚,导致神经细胞内肌醇、氨基酸、K+丢失。同时山梨醇在SDH的催化下生成果糖,果糖生成增加,导致细胞内游离还原型烟酰胺腺嘌呤二核苷酸(NADH)/烟酰胺腺嘌呤二核苷酸(NAD+)的比值增加,导致细胞内氧化还原电势的改变,降低一氧化氮合酶(NOS)和谷胱甘肽还原酶的活性,造成细胞内活性氧(ROS)的增加及氧化防御失衡,引起糖尿病性假性缺氧,对神经组织造成损害[6-8]。AR在ROS的刺激下,还通过将谷胱甘肽脂源醛(GS-HNE)还原为信号分子谷胱甘肽1,4-二羟基壬醇(GS-DHN)参与炎症反应[6]。
ARI能够抑制葡萄糖多元醇转化途径,降低山梨醇的蓄积,进而实现治疗糖尿病周围神经病变的效果[9]。ARI代表药物依帕司他,可显著减少动物模型中坐骨神经细胞内山梨糖醇积累。但是ARI对于受损的神经,未见有保护或修复作用,这也限制了这些药物治疗神经病变的疗效。
目前在国内外临床应用和开展过临床研究的醛糖还原酶抑制剂共有5种,根据其化学结构可分为2类[10]:羧酸类与环状酰亚胺类。羧酸类衍生物的代表包括依帕司他、托瑞司他、唑泊司他、泊那司他等,环状酰亚胺类代表化合物为非达司他,5种化合物的化学结构式见图1。
2 醛糖还原酶抑制剂临床研究的有效性与安全性
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2.1 依帕司他
依帕司他(epalrestat)的原研厂家为日本的Ono Pharmaceutical Co., Ltd.,其商品名为KINEDAK,规格为50 mg,于1992年1月2日在日本首次批准上市。我国于2004年首次批准依帕司他上市,已有该品种仿制药,截至2023年6月,有21项生物等效性试验在我国完成。依帕司他已成为我国临床上用于治疗糖尿病周围神经病变的常用药物。
2.1.1 依帕司他有效性安全性
现阶段,国际临床试验注册机构(ClinicalTrials.gov)登记的依帕司临床试验有4项,2项仍在招募中,已终止的临床试验1项,尚未招募的临床试验1项。在这些项目中,一项由我国中南大学附属湘雅医院发起的名为“依帕司他对糖尿病患者周围神经病变和中枢神经系统的作用”的临床试验,设计了比较严格的入排标准,主要疗效指标与次要疗效指标也较为全面,涵盖了该研究领域的常见要求。该项目的入选与排除标准见表1。
该项目设计的治疗周期为6个月,主要疗效指标包括:①治疗6个月后静息状态功能磁共振成像变化:②脑灰质体积、脑白质面积、局部脑回指数(local gyrus index,LGI)的变化。次要疗效指标有11项,包括:①肌电图;②定量体感测试;③角膜共聚焦;④糖化血红蛋白(HbA1c);⑤焦虑自评量表;⑥抑郁自评量表;⑦多伦多临床评分系统;⑧神经性疼痛量表;⑨密歇根神经病筛查表;⑩基本精神状态检查;11蒙特利尔认知评估。
根据ClinicalTrials.gov中查询的信息显示,中南大学发起的此项研究依帕司他连续给药6个月的有效性试验,尚处于受试者招募阶段,暂无可供参考的观察数据。但该项目对于入排标准及疗效指标的设定较为全面,对于糖尿病周围神经病变的临床研究项目具有一定参考价值。
回顾依帕司他的临床试验研究,来自不同国家的研究团队对其有效性和安全性开展了较为系统的临床试验研究。
Hotta等[11]于1996年对5 249例糖尿病神经病变患者给予每日150 mg剂量的依帕司他,治疗3~12个月后的疗效及不良反应进行分析。统计结果表明:主观症状(如自发性疼痛、麻木、发冷和感觉减退)的改善率为75%;腓神经的运动神经传导速度(motor nerve conduction velocity,MCV)及感觉神经传导速度(sensory nerve conduction velocity,SCV)的改善率为36%。5 249例患者中出现药物不良反应的有129例(2.5%),均无严重不良反应。但该项研究未纳入对照组, 仅对采用依帕司他进行治疗的患者开展了有效性评价。
在上述研究的基础上,该团队[12]于2006年,继续报道了一项长期的、多中心的、非盲的依帕司他治疗糖尿病周围神经病变的有效性临床研究。该项研究持续了3年,共纳入了594例患者:其中289例患者给予依帕司他治疗,每日150 mg的依帕司他片剂;其余305例患者则被作为对照组,对照组患者不接受依帕司他、其他糖尿病周围神经病变药物及安慰剂治疗,仅继续接受常规治疗(饮食治疗、降糖药、胰岛素和降压药)。结果表明,相较于与对照组,依帕司他预防了中位MCV、最小F波潜伏期(minimum F-wave latency)和振动感觉阈值(vibration perception threshold)的恶化,而在对照组中观察到这些参数明显恶化。
依帕司他治疗糖尿病周围神经病变的多项临床研究结果[13-17],均显示依帕司他对于该疾病具有一定的治疗效果。结果表明,依帕司他可以有效控制糖尿病周围神经病变患者运动神经传导速度的恶化,对于患者的感觉异常也有较好的改善作用,同时长期的临床试验也未观察到依帕司他具有严重的不良反应。
2.1.2 依帕司他与甲钴胺比较研究
甲钴胺具有修复损伤的神经细胞,改善神经传导速度的药理学作用,临床上应用于糖尿病周围神经病变的治疗。以甲钴胺作为阳性对照的比较研究也得到广泛开展。通过观察以甲钴胺作为阳性对照的多项临床试验结果[18-20]可以发现,依帕司他组和甲钴胺组均对患者神经传导速度的改善起到一定作用。但是两组并未显示出显著性的统计学差异。
除了评估患者神经传导速度的改善情况,还有研究者对患者的主观症状的改善,如灼烧感、麻木感、自发性疼痛等进行了系统评估[21-23]。综合评价多项临床试验的研究结果,在患者主观症状的改善方面,依帕司他具有优于甲钴胺的效果。
2.1.3 依帕司他联合给药治疗
随着临床用药的发展,临床医生也探索出通过不同药物与依帕司他联用,实现对糖尿病周围神经病变达到更好的治疗效果,并以此为目标开展了多项的临床研究,研究结果汇总见表2。
依帕司他+加巴喷丁:一项临床研究[24]纳入了98例痛性糖尿病周围神经病变患者,随机分为观察组和对照组,每组各49例。对照组采用依帕司他治疗,观察组在依帕司他的基础上加用加巴喷丁治疗。结果表明,治疗后,观察组患者的疼痛、感觉异常、灼烧感和麻木感评分均低于对照组,差异均具有统计学意义(P<0.05)。
另一项临床研究[25]选取了96例痛性糖尿病周围神经病变患者,用随机分组法分为观察组(n=42)与对照组(n=54),对照组用加巴喷丁联合甲钴胺治疗,观察组在对照组治疗的基础上加用依帕司他。结果表明,治疗6周后,与对照组相比,观察组的视觉模拟评分(visual analogue scale,VAS)、神经传导速度均得到了改善。
依帕司他+甲钴胺:多个研究团队[26-28]开展了依帕司他联合甲钴胺治疗糖尿病周围神经病变的临床试验。患者被随机分为观察组和对照组,对照组采用甲钴胺治疗,观察组在甲钴胺的基础上加用依帕司他治疗。结果显示,治疗后观察组的总有效率均高于对照组,同时患者多项神经传导速度改善程度亦呈现观察组显著优于对照组的结果。
依帕司他+甲钴胺+马来酸桂哌齐特:一项临床研究[29]纳入了120例糖尿病周围神经病变患者,分为对照组(维生素B12治疗)60例和研究组(甲钴胺、依帕司他、马来酸桂哌齐特联合给药治疗)60例。结果显示,研究组治疗后多项神经传导速度均快于对照组。
依帕司他+胰激肽原酶:一项临床研究[30]回顾性分析了102例2型糖尿病周围神经病变的临床资料,研究组53例(胰激肽原酶联合依帕司他治疗)和对照组49例(胰激肽原酶治疗)。治疗后,两组研究对象的多项神经传导速度和感觉神经传导速度均较治疗前增加,且研究组大于对照组。
依帕司他+α-硫辛酸:α-硫辛酸可抗氧化应激反应,还可改善糖尿病周围神经病变诱发的感觉异常与细胞能量代谢,但对运动神经功能减退的改善效果并不理想 [31-34]。多项临床研究表明[31-32,35],采用依帕司他联合α-硫辛酸治疗糖尿病周围神经病变可以获得更好的治疗效果:神经传导速度加快、密歇根糖尿病性周围神经病评分(MDNS)降低,同时氧化应激指标下降显著。
上述的多项临床研究结果显示,将依帕司他与营养神经药物、改善循环药物等联用,相较于单药治疗,在改善糖尿病周围神经病变患者多项症状方面效果显著。
2.2 托瑞司他、唑泊司他、泊那司他临床研究
托瑞司他(tolrestat)、唑泊司他(zoporestat)、泊那司他(ponalrestat)均曾进入到临床试验阶段,但终因副作用或者有效性不足而未能上市或被撤市。
托瑞司他:Giugliano等[36]开展一项为期52周的随机、安慰剂对照的托瑞司他治疗糖尿病周围神经病变的临床试验,在该研究中观察到的托瑞司他治疗效果很小。在这项研究的基础上,该研究团队继续进行了托瑞司他对于早期糖尿病周围神经病变的治疗作用[37]。结果显示,托瑞司他组振动感知阈值提高(6±3)V(P<0.001),而安慰剂组恶化至(3±1.8)V(P<0.001)。
托瑞司他对于早期的、症状轻微的糖尿病周围神经病变患者有一定治疗作用。虽然它被批准在几个国家销售,但由于毒性而在美国未通过Ⅲ期临床试验,并且未通过FDA批准。由于其严重肝毒性和死亡风险,已于1997年被惠氏停产。
唑泊司他:唑泊司他是一种醛糖还原酶抑制剂,可用于糖尿病并发症的治疗。Inskeep等[38],对健康男性志愿者口服50~1 200 mg唑泊司他的药动学进行了研究。结果表明,唑泊司他具有较好的药动学特征,但进一步的研究发现,唑泊司他可以导致红细胞衰亡(eryptosis),即引起磷脂酰丝氨酸向红细胞表面易位及Ca2+内流,进而导致红细胞体积收缩和细胞膜功能紊乱[39],因此也制约了唑泊司他的进一步的临床应用。
泊那司他:泊那司他是一种有效的醛糖还原酶抑制剂,对葡萄糖具有纯粹的非竞争性机制[40]。Ziegler等[41]开展了一项双盲、安慰剂对照的临床试验,60名患者以2∶1的比例随机分配,接受泊那司他或安慰剂治疗,600 mg·d-1持续给药12个月。统计结果显示,研究期间各项观察指标在各组之间没有显著差异(P=0.06)。Sundkvist等[42]开展了一项为期18个月的双盲、安慰剂对照的临床试验,结果同样显示,泊那司他对振动感知阈值、神经传导速度和神经动作电位振幅的改善没有有益影响。综上所述,有效性的不足成为制约泊那司他进一步临床应用的重要因素。
2.3 非达司他
非达司他(fidarestat)是一种有效的新型醛糖还原酶抑制剂,动物实验与人体试验均表明非达司他治疗可以使空腹和餐后红细胞中升高的山梨醇含量正常化 [43-45]。
Hotta等[46]纳入279例糖尿病性神经病变患者,其中接受安慰剂组140例,非达司他组139例,持续给药52周。研究结果显示:基线时,安慰剂组和非达司他组的中位FCV(F-wave conduction velocity)均为56.7 m·s-1,52周后,非达司他组0.9 m·s-1,安慰剂组-0.6 m·s-1(P<0.001)。在安全性方面,没有发生需要停止治疗的严重不良反应。
早期的临床试验结果表明,非达司他是一种新型的、有效的、安全的醛糖还原酶抑制剂。但是根据药物检索结果显示,非达司他的药物全球最高研发状态已于2015年时终止在Ⅲ期临床试验,具体原因未见药物原研方披露。
3 总结与展望
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糖尿病及其并发症发病机制复杂导致其治疗上同样存在复杂性,目前高糖环境下葡萄糖的山梨醇代谢途径被认为是与糖尿病周围神经病变关系密切的发病机制。因此针对山梨醇途径中起到关键作用的醛糖还原酶进行其抑制剂开发,并对现有的醛糖还原酶抑制剂的有效性与安全性开展进一步的评价,应成为该领域药物研发工作的重点。
依帕司他自上市以来,依旧是近三十年里唯一上市并持续在临床一线使用的醛糖还原酶抑制剂。本文综合回顾了7项由多国研究者发起的安慰剂对照或依帕司他单药治疗的临床试验。这些研究均表明,其在糖尿病周围神经病的治疗中可起到积极作用,同时在各项临床试验中均未表现出严重的不良反应。但长期临床研究表明,依帕司他治疗糖尿病周围神经病变可以使患者的神经传导速度水平不再恶化,但并不会有较为显著的修复效果。
在此基础上,笔者系统分析了3项以甲钴胺作为阳性药物对照的临床试验。结果显示,依帕司他改善神经传导速度的能力并不优于甲钴胺,依帕司他联合其他糖尿病周围神经病变治疗药物,在改善患者主观症状和神经传导速度方面均要优于其单药治疗。同时近几年有多项临床及荟萃分析研究均显示,甲钴胺在糖尿病周围神经病变治疗中所体现的疗效仍需进一步考察,尤其是在患者疼痛评分及神经症状改善方面不具备积极结果[47-49],因此对于依帕司他单药治疗并改善糖尿病周围神经病变的能力仍有待进一步确认。
托瑞司他、唑泊司他、泊那司他和非达司他,此4种药物均在临床试验过程中或者上市后表现出较强的副作用或者未体现出明确的治疗作用,故而未通过临床试验或者遭到撤市。这些临床表现上的失败,推测可能与其化学结构特点有关。
综上所述,现有的醛糖还原酶抑制剂对于糖尿病周围神经病变具有一定的治疗作用,但相较于传统的治疗药物未见更为出众的临床表现。同时诸多的醛糖还原酶抑制剂也由于其自身结构产生的相应问题,制约了它们在临床上的应用。但由于在多种糖尿病周围神经病变治疗药物中,醛糖还原酶抑制剂属于直接针对该疾病发病机制发挥作用的一类药物,对醛糖还原酶抑制剂进行深入开发,具有积极意义,目前已有研究报道,通过结构改造获得的新型醛糖还原酶抑制剂在保持对醛糖还原酶强抑制活性的基础上兼具显著的抗氧化活性[50]。因此对醛糖还原酶抑制剂进行结构改造,研究和开发更安全、治疗效果更好的醛糖还原酶抑制剂也是该领域药物研发的战略考量。
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doi: 10.11669/cpj.2025.06.001
  • 接收时间：2024-09-12
  • 首发时间：2025-11-07
  • 出版时间：2025-03-22
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  • 收稿日期：2024-09-12
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北京市自然科学基金项目资助(7232258)
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    中国医学科学院北京协和医学院药物研究所, 脑血管病新药发现及晶型研究北京市重点实验室, 北京 100050

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*方莲花,女,博士,研究员,博士生导师 研究方向:心脑血管药理学与新药发现 Tel:(010)63165313
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
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