糖尿病并发症的药物治疗

糖尿病并发症对人类健康造成极大危害，针对各种糖尿病并发症的病因开发其治疗药物已成为人们关注的热点，并取得可喜进展。本文分类概述糖尿病并发症治疗药物的作用机制、临床应用及疗效研究，其药物包括醛糖还原酶抑制剂、糖基化终产物抑制剂、抗氧剂以及血管紧张素转换酶抑制剂。     

抗心力衰竭药物的研究进展

随着社会进入老龄化 ,老年人心衰的发病率明显增高 ,心力衰竭已成为老年人患病和死亡的主要原因之一。据统计 ,对于较重心衰患者 ,在 2a内死亡的男性和女性分别为37%及 38% ;6a内 ,男女分别 80 %及 6 7%。而对于患有充血性心衰的男性病人平均存活时间为 1.7a,女性为 3.2年 ,其总发病率约 0 .5 %～ 2 % ,在西方发达国家老年人中 ,高达10 %。如在美国 ,据估计 2 0 0多万人患有此症 ,每年新诊断病例约 4 0万 ,每年约有 2 5万人死于心衰 ,每年用于治疗心衰的直接费用超过 70亿美元 ,其住院费用是用于所有恶性肿瘤费用的 2倍[1] 。心力衰竭是由于…     

血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂治疗糖尿病肾病的临床疗效分析

目的探讨血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂在延缓糖尿病肾病患者肾功能衰竭方面的临床疗效。方法选取笔者所在医院糖尿病肾病患者200例,分别给予血管紧张素转换酶抑制剂、血管紧张素受体拮抗剂治疗以及两者联用,观察三组血压、血肌酐及24h尿蛋白定量,并比较三组疗效。结果 3组血压差异无统计学意义(P>0.05),血肌酐方面,培哚普利组与厄贝沙坦组间差异无统计学意义(P>0.05),联合组与贝那普利组和氯沙坦组差异均有统计学意义(P<0.05),24h尿蛋白定量,培哚普利组与厄贝沙坦组间差异无统计学意义(P>0.05),联合组与另外两组间差异均有统计学意义(P<0.05)。结论血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂在糖尿病肾病患者中能够很好的延缓肾衰竭的进程,保护肾功能,两者联用可以取得更好的疗效。     

肾素血管紧张素系统与糖尿病肾病相关性研究进展

肾素血管紧张素系统是生理功能颇为复杂的内分泌系统,对糖尿病肾病的发生、发展有重要影响.     

肾素血管紧张素系统与糖尿病肾病

肾素血管紧张素系统是生理功能颇为复杂的内分泌系统，广泛存在于机体各个组织。该系统的关键基因决定着个体的糖尿病肾病易感性。血管紧张素Ⅱ通过细胞外基质成分合成增多、降解减少而促使肾小球硬化。血管紧张素转化酶抑制剂及血管紧张素受体拮抗刑具有独立于血压的治疗糖尿病肾病的作用。     

血管紧张素转换酶抑制剂联合血管紧张素受体拮抗剂治疗糖尿病肾病的临床观察

糖尿病肾病(diabetic nephropathy,DN)是糖尿病常见的微血管并发症,也是糖尿病死亡的主要原因。如何有效地治疗DN,以逆转肾功能或延缓肾功能减退的进展,是临床亟待解决的问题。本研究通过联合血管紧张素转换酶抑制剂(ACEI)及血管紧张素受体拮抗剂(ARB)治疗糖尿病肾病,取得较好的效果。     

糖尿病肾脏疾病药物治疗研究进展

糖尿病肾脏疾病(diabetic kidney disease,DKD)是由糖尿病所致的慢性肾脏疾病(chronic kidney disease,CKD),是终末期肾脏疾病的重要病因。目前DKD的治疗主要包括生活方式改变,加强血压、血糖控制,减少蛋白尿,预防心脑血管并发症以及终末期的肾脏替代治疗等。糖尿病肾脏疾病仍存在患病率高,缺乏有效延缓肾脏病进展手段等问题。近年来,随着对DKD发病机制研究的深入,新型降糖药物、肾素-血管紧张素-醛固酮系统(reninangiotensin-aldosterone system,RAAS)抑制剂以及针对糖尿病肾脏疾病发病机制的药物,为DKD的药物治疗提供了新的选择。本文从DKD的病理及发病机制出发,重点综述了DKD的药物治疗进展。     

抗血管生成药物致高血压的降压治疗的合理用药

高血压是抗血管生成药物常见不良反应之一,多为轻、中度。一般通过标准降压治疗即可控制,而严重者可影响患者的抗肿瘤疗效果甚至中断靶向药物治疗。因此,合理选择降压药物对于患者的抗肿瘤治疗具有重要意义。笔者主要探讨抗血管生成药物致高血压的降压药物选择,以期为临床用药提供参考。     

不同方法治疗早期糖尿病肾病的临床研究

目的探讨血管紧张素转换酶抑制剂（ACEI）联用血管紧张素Ⅱ型受体（AT-Ⅱ）拮抗剂治疗早期糖尿病肾病的合理性。方法60例2型糖尿病并发的早期糖尿病肾病患者，随机分为贝那普利组（n=20）、厄贝沙坦组（n=20）及两药联用组（n=20）治疗18周，治疗前后对平均动脉压（MAP）、尿白蛋白排泄率（UAER）、内生肌酐清除率（OD）、血清肌酐（Scr）、血清尿素氮（BUN）、空腹血糖（FBG）、餐后2h血糖（2hBG）、糖化血红蛋白（HbA1c）、血脂分析、血清钾进行比较。结果贝那普利组UAER治疗后比治疗前下降了33．9％（t=3．278，P=0．004），厄贝沙坦组下降了36．2％（t=4．234，P〈0．01），两药联用组（贝那普利＋厄贝沙坦）下降了60．9％（t=5．754，P〈0．01），两单药组间下降幅度无明显差异（P〉0．05），联用组较单药组下降幅度总体增加26．1％。结论ACIEI与AT1拮抗剂联合应用治疗早期糖尿病肾病有一定的临床价值。     

醛糖还原酶抑制剂筛选的研究进展*

醛糖还原酶是多元醇通路中的关键限速酶,高血糖浓度下,此通路代谢旺盛,与糖尿病并发症的发生和恶化有密切关系。醛糖还原酶抑制剂因此而成为糖尿病并发症的药物治疗因子,它主要是通过山梨醇通路降低体内血糖浓度,减少山梨醇在体内组织中的堆积达到治疗目的。目前已从植物、微生物中或化学合成获得了许多醛糖还原酶抑制剂,其中2个分别在日本和爱尔兰上市,还有部分正进行临床试验。现主要概述醛糖还原酶抑制剂筛选的研究进展。     

Novel aldose reductase inhibitors: a patent survey (2006 – present)

Introduction: Initially studied for its central role in the pathogenesis of chronic diabetic complications, aldose reductase (ALR2) gains more attention over the years as its implication in inflammatory diseases is being established, along with the therapeutic potential of its inhibitors.

Areas covered: Reviewing the patents that were published since 2006, it is getting clear that the search for new chemical entities has subsided, giving rise to natural products and plant extracts with ALR2 inhibitory activity. Other aspects that were prominent were the search for proper forms of known inhibitors, in a way to improve their impaired physicochemical profile, as well as potential combination therapies with other compounds of pharmaceutical interest. On the spotlight were patents enhancing the therapeutic usage of aldose reductase inhibitors (ARIs) to various pathological conditions including cancer and inflammation-mediated diseases such as sepsis, asthma, and cancer.

Expert opinion: Although new chemical entities are scarcely registered and patented after many years of inconclusive clinical trials, the involvement of ALR2 to inflammatory pathologies might renew the interest in the field of ARIs.     

小檗碱预防性治疗糖尿病肾病的研究进展

糖尿病肾病是糖尿病微血管并发症之一,其发病机制复杂,与糖脂代谢紊乱、炎症、氧化应激、自噬受损、肠道菌群失调等因素交叉关联,也是导致终末期肾病的主要原因。综述了糖尿病肾病的主要发病机制以及小檗碱预防性治疗糖尿病肾病的研究进展,旨在为糖尿病肾病治疗药物的研发提供参考。     

New aldose reductase inhibitors as potential agents for the prevention of long-term diabetic complications

The results of recent clinical trials emphasise the importance of an improved glycaemic control in diabetic patients in order to prevent or at least to delay long-term complications. The difficulty in obtaining normalisation of blood glucose values has underlined the importance of the search for new and effective aldose reductase inhibitors (ARIs) to control the consequences of elevated glucose levels, therefore delaying the onset and retarding the progression of diabetic complications such as neuropathy, nephropathy, retinopathy and cataract. Although the physiological role of aldose reductase (ALR2) has not been clearly elucidated yet, it has been shown that this enzyme, the first of the polyol pathway, is responsible for the production of sorbitol from glucose. There are several pieces of evidence which link this process to the occurrence of diabetic complications. Orally active aldose reductase inhibitors can be grouped into two chemical classes: cyclic imide and carboxylic acid derivatives. This review describes the recent insights into these two classes of inhibitors, and the further development of ARIs provided with antidiabetic and antihyperlipidaemic properties. The most recent developments in understanding of the structure, catalytic mechanism and biochemical behaviour of ALR2 are also reported.     

内皮素受体阻滞剂在糖尿病并发症中的应用*

内皮素是目前已知的缩血管活性最强的生物活性肽之一,通过与内皮素受体结合发挥广泛的生物学活性。内皮素的异常表达与肺动脉高压、前列腺癌、慢性心力衰竭等多种疾病的发生和发展有密切关系。近年来又有大量研究证实内皮素与糖尿病并发症的发生、发展有着重要的关系,内皮素受体阻滞剂可能成为糖尿病并发症治疗的新型药物。现综述内皮素受体阻滞剂在糖尿病并发症中的应用。     

维生素C对糖尿病大鼠肾脏醛糖还原酶活性的影响

目的 :探讨不同剂量维生素C对糖尿病大鼠肾脏醛糖还原酶(AR)活性的影响。方法 :体重195g 左右的雄性Wistar大鼠50只 ,随机分为5组 :C组 :正常对照组 ;D组 :糖尿病组 ;DT1 组 :糖尿病鼠 +维生素C30mg/(kg·d)组 ;DT2 组 :糖尿病鼠 +维生素C90mg/(kg·d)组 ;DT3 组 :糖尿病鼠 +维生素C270mg/(kg·d)组。实验第9wk检测血浆、肾脏维生素C水平和AR活性。结果 :与正常对照组比较 ,糖尿病组血浆、肾脏维生素C水平显著下降 (P<0 05) ,肾皮质AR活性明显升高 (P<0 01) ;3种剂量维生素C治疗组血浆、肾脏维生素C水平与正常对照组比较差异无显著性 ,AR活性较糖尿病组明显降低 (P<0 05)。结论 :补充维生素C可显著增加糖尿病大鼠血浆肾脏维生素C水平 ,明显降低糖尿病大鼠肾皮质AR活性。     

Ranirestat as a therapeutic aldose reductase inhibitor for diabetic complications

Background: There are currently very few drugs available to directly treat diabetic complications. Those that are indicated clinically provide symptomatic relief and do not address the underlying biochemical problems. The involvement of the sorbitol pathway in complications has provided mechanistic insights into the biochemistry of complications and the key enzyme, aldose reductase, has become an attractive pharmacologic target. Objective: Among the aldose reductase inhibitors, the most promising is ranirestat. This review outlines the studies with ranirestat and compares its efficacy with other similar inhibitors. Methods: A survey of in vitro and in vivo studies was conducted, and with publicly available data from clinical trials, ranirestat efficacy was compared with other similar agents. Results/conclusion: Ranirestat is safe, exhibits some efficacy and is perhaps the only agent advanced enough in clinical trials to warrant further consideration for diabetic complications.     

野菊花提取物对糖尿病肾病大鼠的影响及作用机制

目的 观察野菊花提取物对糖尿病肾病大鼠的影响及作用机制。方法 将48只SD大鼠,♀,随机分为正常对照组、模型对照组和野菊花低、中、高剂量组和阳性药依帕司他组(n=8)。除正常对照组外,其余各组大鼠腹腔注射链脲佐菌素35 mg·kg^-1,成功造模后野菊花组分别给予1,2,4 g·kg^-1野菊花提取物,依帕司他组给予10 mg·kg^-1依帕司他,连续灌胃8周后,检测大鼠血糖、体质量、肾脏脏体比、24 h尿白蛋白量、肾组织超氧化歧化酶(SOD)、过氧化氢酶(CAT)的活性及丙二醛(MDA)的含量;HE染色检测肾脏病理改变,ELISA法检测醛糖还原酶(AR)活性并测定其基因表达。结果 与正常对照组相比,模型对照组上述指标除CAT外均有显著改变;与模型对照组相比,野菊花能明显降低大鼠血糖水平、AR活性及其基因表达,明显减少24 h尿白蛋白,升高肾组织SOD、CAT活性,显著降低MDA含量。结论 野菊花提取物对大鼠糖尿病肾病有一定治疗作用,在调节血糖的同时,可能通过提高机体抗氧化能力、减少肾脏AR活性与基因表达以抑制多元醇通路的激活发挥其肾功能的保护作用。     

Recent advances in aldose reductase inhibitors: potential agents for the treatment of diabetic complications

The development of long-term diabetic complications in diabetes patients is considered to be closely related to hyperglycaemia. Aldose reductase was first found to be implicated in the aetiology of secondary complications of diabetes. A variety of structurally diverse compounds have been observed to inhibit aldose reductase and effective, orally-active inhibitors of the enzyme have been investigated for almost 30 years. Although several of these compounds have progressed to the clinical level, only a few are currently on the market. Furthermore, the number of patents related to aldose reductase inhibitors has declined during recent years, whereas the number for other compounds, such as the inhibitors of the formation of advanced glycated end products and antioxidants, has increased. In this review, recent patents relevant to aldose reductase inhibitors are presented, following a short summary of early works. Lastly, rational approaches to the discovery of aldose reductase inhibitors are briefly reviewed.