α-葡萄糖苷酶抑制剂的研究及应用

概述α-葡萄糖苷酶抑制剂的化学结构特点、作用机制、制备途径与临床应用情况。临床上常用的降糖药阿卡波糖、伏格列波糖、米格列醇为一类微生物来源的α-葡萄糖苷酶抑制剂,其与寡糖结构类似,因此可竞争性地与α-葡萄糖苷酶结合,阻滞寡糖水解成单糖,从而降低餐后血糖峰值。并且某些α-葡萄糖苷酶抑制剂还具有抗HIV活性。     

糖尿病的治疗药物进展

随着人们对糖尿病基础研究的深入，已开发出αk葡萄糖苷抑制剂、胰岛素增敏剂、胰岛素分泌促进剂、醛糖还原酶抑制剂及抗肿瘤坏死因子—α药物等。本文介绍了伏格列波糖、阿卡波糖、吡格列酮、罗格列酮、瑞格列奈等，临床使用或临床研究的新型抗糖尿病药物。     

阿卡波糖和米格列醇治疗2型糖尿病的效果比较

目的对临床现用的两种α-葡萄糖苷酶抑制剂的疗效及安全性进行评价比较。方法对根据WHO的诊断标准确诊为2型糖尿病的90例患者进行为期8周的治疗观察,自身对照比较治疗前、治疗2、4、8周的血糖、糖化血红蛋白(HbA1c)、肾功能、体重、血压等指标的变化。结果 2种药物在治疗8周后均能降低餐后血糖、HbA1c及血清胰岛素的水平(P<0.05或<0.01)。2组药物在治疗前后无肝、肾、胰腺等损害,治疗初期患者有胃肠道不适,但随着进一步的治疗,该不良反应可以消失。结论阿卡波糖和米格列醇均为一种安全有效的口服降糖药物。     

阿卡波糖片治疗2型糖尿病的应用研究进展

阿卡波糖片是一种α-糖苷酶抑制剂,该药物对2型糖尿病的治疗效果理想。为总结阿卡波糖片的临床疗效,本研究通过查阅国内外文献,分析药物治疗的优点,旨在对2型糖尿病的防治提供有利参考。     

用固定化酶筛选模型从天然产物中筛选α-葡萄糖苷酶抑制剂

目的:用固定化酶筛选模型从天然产物中筛选α-葡萄糖苷酶抑制剂.方法:把α-葡萄糖苷酶固定化,模拟其在体内小肠壁上的情况,建立固定化酶筛选模型,先用α-葡萄糖苷酶抑制剂阿卡波糖对该模型进行验证,然后用该筛选模型对2种天然产物-虎杖水溶性部位和广西血竭甲醇溶液进行筛选.结果:阿卡波糖对固定化α-葡萄糖苷酶和游离α-葡萄糖苷酶的IC50分别为0.413 mg·mL-1和0.126 mg·mL,虽然固定化酶被阿卡波糖抑制的IC50值是游离酶的3.3倍,但固定化酶筛选模型更准确地反映阿卡波糖的体内作用.虎杖水溶性部位和广西血竭的甲醇溶液对固定化α-葡萄糖苷酶的IC50分别为0.224 mg·mL-1和5.5 μg·mL-1.结论:该筛选模型能很好的进行体外α-葡萄糖苷酶抑制剂的筛选,其筛选结果和文献报道相符.     

阿卡波糖致肝损害1例报告

阿卡波糖是α葡萄糖苷酶抑制剂,是一类以延缓肠道碳水化合物吸收而达到治疗糖尿病目的的药物.目前阿卡波糖是临床上一种成熟的治疗糖尿病的药物,临床应用广泛而安全.我院发现1例阿卡波糖(拜糖苹)治病人肝功能损害病例,现报道如下. 1 病例介绍 患者,男,49岁.因反复口干、多饮、多尿,体重下降4年,乏力2个月入院.4年前在我院诊断为2型糖尿病,曾服用瑞格列奈,现在一直口服阿卡波糖片(50mg tid)降糖治疗.既往体健,无不良嗜好.入院查体:神清,体型中等,皮肤巩膜无黄染,心肺正常,肝脾不大,肝区无叩痛,余未见异常.辅助检查:入院时门诊查ALT:853U/L,AST:406U/L.     

采用Meta分析法评价α-葡萄糖苷酶抑制剂的降糖差异

目的：系统评估阿卡波糖与伏格列波糖控制2型糖尿病患者血糖效果的差异。方法：在PubMed、OVID、Springer、Medline、CNKI、维普和万方等数据库检索相关文献。因为没有直接比较的研究,故采用间接比较法,纳入包括阿卡波糖或伏格列波糖与安慰荆或二甲双胍比较治疗的对照研究,分析阿卡波糖与伏格列波糖的降糖差异。结果：Meta分析结果显示：与安慰剂相比,阿卡波糖降低HbAIc的水平（-0．70％）优于伏格列波糖（-0．18％）,敏感性分析结果稳定。与二甲双胍相比,伏格列波糖降低餐后两小时血糖的水平（-2．09mmol／L）高于阿卡波糖（-1．30mmol／L）,但敏感性分析结果不稳定。结论：阿卡波糖降低HbAlc的效果优于伏格列波糖。在降低餐后两小时血糖水平上,两药的降糖差异还值得进一步探讨。     

米格列醇对比阿卡波糖治疗2型糖尿病患者有效性和安全性的Meta分析

目的:采用Meta分析,系统评价米格列醇对比阿卡波糖治疗2型糖尿病患者的有效性和安全性,为临床治疗提供循证参考。方法:通过计算机检索The Cochrane Library、EMBASE、PubMed、中国期刊全文数据库、万方数据库和维普数据库,以米格列醇、阿卡波糖和2型糖尿病为关键词,检索米格列醇对比阿卡波糖治疗患者2型糖尿病的随机对照研究(RCT)文献,筛选文献、提取资料,并评价纳入研究的偏倚风险后,采用RevMan 5.3版软件进行Meta分析。结果:纳入12个RCT文献,合计973例患者;经Meta分析结果显示(,1)米格列醇组糖化血红蛋白改善值〔MD=-0.59,95%Cl(-0.94,-0.24),P<0.01〕显著高于阿卡波糖组;(2)米格列醇组不良反应发生率〔RR=0.40,95%Cl (0.27,0 60),P<0.01〕显著低于阿卡波糖组(;3)米格列醇组与阿卡波糖组在空腹血糖、餐后2 h血糖和体质量指数的改善值经组间比较其差异均无统计学意义(P>0.05)。结论:米格列醇在治疗患者2型糖尿病的有效性和安全性方面优于阿卡波糖;但受纳入研究的样本数量和质量所限,尚需开展更多高质量研究予以验证。     

米格列奈治疗2型糖尿病的疗效观察

目的比较国产米格列奈钙和阿卡波糖治疗初发2型糖尿病的疗效、安全性。方法 40例初诊2型糖尿病随机分为2组,米格列奈组患者20例首先给予米格列奈治疗3个月后改予阿卡波糖治疗;阿卡波糖组患者20例首先给予阿卡波糖治疗3个月后改予米格列奈治疗;换药中间有1周药物洗脱期。比较二组用药前后、交叉换药前后的糖化血红蛋白、空腹血糖、餐后血糖、空腹胰岛素。结果治疗后,组空腹血糖、餐后2h血糖、糖化血红蛋白及空腹胰岛素水平均能有效降低。2种药物间作用比较比较未见统计学差异（P〉0.05）。不良反应主要为轻度胃肠道反应。结论国产米格列奈能显著降低餐后血糖且无明显药物不良反应。     

45份Ⅱ型糖尿病病历用药分析及疗效评价

目的：对45份Ⅱ型糖尿病（NIDDM）住院病历的用药及疗效进行分析。方法：疗效指标参照WHO推荐的判断标准。结果：（1）血糖控制理想、较好、一般、欠佳的分别有10例，15例，12例，4例，可疑或确证为低血糖反应的有4例。（2）治疗主要以口服降糖药为主，应用最多的降糖药有甲福明，其次是格列吡嗪、阿卡波糖等。结论：（1）促进组织对糖的摄取和利用的双胍类药物甲福明能安全有效降低血糖，费用适宜，可作为一般Ⅱ型糖尿病的首选用药。（2）α-葡萄糖苷酶抑制剂阿卡波糖对降低餐后血糖有独到的疗效，特别适用于以淀粉类为主食的糖尿病人及老年糖尿病患者。（3）碘酰脲类药物相对较易导致低血糖。应用于老年患者应特别谨慎。（4）某些药物能影响到磺酰脲类药物的疗效。联用时应注意监测血糖。     

多羟基苯甲醛席夫碱的合成及其 α-葡萄糖苷酶抑制活性

目的 设计合成系列多羟基苯甲醛席夫碱,初步测定其对 α-葡萄糖苷酶的抑制活性。方法 以羟基取代苯甲醛及芳香胺为原料,采用微波辅助合成法合成多羟基苯甲醛席夫碱,并对目标化合物进行α-葡萄糖苷酶抑制活性实验。结果 合成了18个目标化合物,其结构均经红外光谱及核磁共振氢谱确证,化合物2、3、4、8、13、14、15、16为已知化合物,其余 10 个化合物为新化合物。结论 所合成的目标化合物具有较强的α-葡萄糖苷酶抑制活性,其中3-羟基苯胺-3,4-二羟基苯甲醛席夫碱(10)、3-羟基苯胺-2,4,6-三羟基苯甲醛席夫碱(12)、苯胺-2,4-二羟基苯甲醛席夫碱(15)的α-葡萄糖苷酶抑制活性均强于参照物白藜芦醇（IC₅₀=23.9 μmol·L^-1）,它们的IC₅₀值分别为 8.93、4.69、8.59 μmol·L^-1。酶抑制动力学实验表明该系列化合物为α-葡萄糖苷酶的非竞争性抑制剂。     

珠光香青对α-葡萄糖苷酶的抑制活性研究

目的对珠光香青石油醚部分、乙酸乙酯部分、甲醇部分提取物的α-葡萄糖苷酶抑制作用进行研究。方法以96微孔板法测定α-葡萄糖苷酶抑制作用。结果珠光香青石油醚部分提取物的活性最好（IC50=173.3μg/ml）。结论珠光香青具有良好的潜在开发价值。     

Effect of Ficus racemosa stem bark on the activities of carbohydrate hydrolyzing enzymes: An in vitro study

Herbal medicines have been used since prehistoric times by different cultures worldwide for the treatment of diabetes. The present investigation evaluated the effect of Ficus racemosa Linn. (Moraceae) stem bark on carbohydrate hydrolyzing enzymes, viz., porcine pancreatic α-amylase, rat intestinal α-glucosidase, sucrase, and almond β-glucosidase, using in vitro model systems. In addition, the effect of heat treatment was also studied. Untreated F. racemosa bark (FRB) significantly inhibited (p?≤?0.05) α-amylase, α-glucosidase, β-glucosidase, and sucrase in a dose-dependent manner. Heat treatment of the sample comparably increased α-amylase, α-glucosidase, and sucrase inhibitory activities, while a marginal decrease in β-glucosidase inhibitory activity was observed; however, no statistical differences were noted. Untreated FRB showed IC₅₀ values of 0.94% and 280, 212, and 367 μg/mL for α-amylase, α-glucosidase, β-glucosidase, and sucrase, respectively, while the IC₅₀ values for heat treated FRB were 0.58% and 259, 223, and 239 μg/mL, respectively. Further, a significant correlation (p?≤?0.01; r?=?0.791) was observed between α-amylase, α-glucosidase, β-glucosidase, and sucrase inhibitory activities of both untreated and heat treated FRB. The results clearly demonstrate that inhibition of carbohydrate hydrolyzing enzymes is one mechanism through which F. racemosa stem bark exerts its hypoglycemic effect in vivo. Therefore, the potential exists to explore the utilization of F. racemosa stem bark in the development of nutraceuticals and functional foods for the management of diabetes and related symptoms/disorders.     

5-对甲苯磺酰氨基酞酰亚胺衍生物的设计合成及α-糖苷酶抑制活性

目的寻找具有新型结构的OL-糖苷酶抑制剂类降血糖药物。方法N-取代-5-对甲苯磺酰氨基酞酰亚胺类目标化合物（I1～I8）以邻苯二甲酰亚胺为起始物,经硝化后,通过烃化反应在亚胺氮上引入含芳基的不同取代结构,再经还原及磺酰化反应合成;N-取代结构的苯环上含有酚羟基的目标化合物（Ⅱ1～Ⅱ3）采用乙酰化保护后再进行还原及磺酰化、去保护基等步骤制得;目标化合物Ⅱ。和Ⅱ。的合成是以5一硝基酞酰亚胺为原料,先与甲醛反应,在亚胺氮上引入羟甲基,再与酚性结构进行偶联反应引入相应取代基,最后经还原及磺酰化制得。采用4-硝基苯-“-D-吡喃葡萄糖苷反应体系对目标化合物的a一糖苷酶抑制活性进行评价;采用计算机辅助药物设计软件进行分子Docking分析。结果合成了13个未见报道的新化合物,其结构经MS及1H—NMR谱确证。所有目标化合物对酵母a-糖苷酶均表现出明显的抑制活性,其IC50值小于阳性药物阿卡波糖（Acar）;Docking分析显示,5-对甲苯磺酰氨基酞酰亚胺与酶活性催化位点的氨基酸残基能形成多个氢键,N-取代结构以疏水作用或氢键与酶分子产生相互作用而影响酶活性。结论5-对甲苯磺酰氨基酞酰亚胺结构是产生α-糖苷酶抑制活性的有利结构,亚胺氮原子上取代结构对抑酶活性有重要影响,此结果得到分子对接分析的支持。     

Inhibitory activity of α-amylase and α-glucosidase by plant extracts from the Brazilian cerrado

Diabetes mellitus is the most common disease in the world. One therapeutic approach for treating diabetes is inhibition of α-amylase and α-glucosidase activities to reduce postprandial blood glucose levels. In vitro tests showed that several plant extracts from Brazilian cerrado species can inhibit the activity of α-amylase and α-glucosidase. The extracts of Eugenia dysenterica, Stryphnodendron adstringens, Pouteria caimito, Pouteria ramiflora, and Pouteria torta showed strong α-amylase and α-glucosidase inhibitory activity. Eugenia dysenterica, P. caimito, P. ramiflora, and P. torta aqueous extracts exerted the highest activity against α-amylase (IC??) values of 14.93, 13.6, 7.08, and 5.67 μg/mL, respectively) and α-glucosidase (IC?? values of 0.46, 2.58, 0.35, and 0.22 μg/mL, respectively). Stryphnodendron adstringens ethanol extract also exhibited inhibitory activity against both enzymes (IC??) 1.86 μg/mL against α-amylase and 0.61 μg/mL against α-glucosidase). The results suggest that the activity of these cerrado plants on α-amylase and α-glucosidase represents a potential tool for development of new strategies for treatment of diabetes.     

不同产地槐米炮制前后主成分的含量变化对α－葡萄糖苷酶活性抑制的影响

目的：比较研究10批不同产地槐米炒制前后对槐米中芦丁,槲皮素的含量变化及其对α－糖苷酶活性抑制作用的影响。方法对10批不同产地的槐米药材分别进行炒制,采用高效液相色谱法分别测定各槐米药材提取液中芦丁和槲皮素含量;以对硝基苯酚－β－1,4－葡萄糖苷（ pNPG）为底物,阿卡波糖为阳性对照,测定各槐米药材提取液对α－葡萄糖苷酶活性抑制率,比较了芦丁和槲皮素含量变化对α－葡萄糖苷酶的抑制活性的影响。结果经过炒制后,10批槐米炒制品中的芦丁含量均有所降低,而槲皮素含量则明显升高;槐米炒制品对α－糖苷酶活性抑制作用均优于生品。结论不同产地槐米炮制后,由于槲皮素含量的普遍升高,导致了槐米炒制品对α－葡萄糖苷酶活性抑制作用升高,表明槲皮素在对α－糖苷酶抑制活性起着重要作用。在治疗糖尿病疾病时选用炒制槐米更为合理。     

知母提取物的降血糖作用

目的对知母进行系统提取分离,筛选提取物的降血糖作用活性组分。方法用四氧嘧啶及链脲佐菌素诱导的糖尿病小鼠和大鼠模型,以空腹血糖值为指标研究知母各提取物的降糖作用;从其活性部位知母总酚中继续分离得3个化合物(拔契皂苷元、芒果苷、新芒果苷),并探讨知母总酚及其成分对α-葡萄糖苷酶活性的影响。结果知母总酚能显著降低四氧嘧啶和链脲佐菌素引起的糖尿病动物的空腹血糖,从中分离得到的芒果苷体外有较好的抑制α-葡萄糖苷酶活性的作用。结论知母总酚对糖尿病动物有较好的降糖作用,其中芒果苷对α-葡萄糖苷酶活性的抑制可能是其降糖作用机制之一。     

Dieckol isolated from Ecklonia cava inhibits α-glucosidase and α-amylase in vitro and alleviates postprandial hyperglycemia in streptozotocin-induced diabetic mice

This study was designed to investigate whether dieckol may inhibit α-glucosidase and α-amylase activities, and alleviate postprandial hyperglycemia in streptozotocin-induced diabetic mice. Dieckol isolated from Ecklonia cava, brown algae, evidenced prominent inhibitory effect against α-glucosidase and α-amylase. The IC₅₀ values of dieckol against α-glucosidase and α-amylase were 0.24 and 0.66 mM, respectively, which evidenced the higher activities than that of acarbose. Dieckol did not exert any cytotoxic effect in human umbilical vein endothelial cells (HUVECs) at various concentrations (from 0.33 to 2.69 mM). The increase of postprandial blood glucose levels were significantly suppressed in the dieckol administered group than those in the streptozotocin-induced diabetic or normal mice. Moreover, the area under curve (AUC) was significantly reduced via dieckol administration (259 versus 483 mmol min/l) in the diabetic mice as well as it delays absorption of dietary carbohydrates. Therefore, these result indicated that dieckol might be a potent inhibitor for α-glucosidase and α-amylase.     

Contribution of momilactones A and B to diabetes inhibitory potential of rice bran: Evidence from in vitro assays

This study was the first to detect the presence of the two compounds momilactone A (MA) and momilactone B (MB) in rice bran using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). By in vitro assays, both MA and MB exhibited potent inhibitory activities on pancreatic α-amylase and α-glucosidase which were significantly higher than γ-oryzanol, a well-known diabetes inhibitor. Remarkably, MA and MB indicated an effective inhibition on trypsin with the IC₅₀ values of 921.55 and 884.03 µg/mL, respectively. By high-performance liquid chromatography (HPLC), quantities of MA (6.65 µg/g dry weight) and MB (6.24 µg/g dry weight) in rice bran were determined. Findings of this study revealed the α-amylase, α-glucosidase and trypsin inhibitors MA and MB contributed an active role to the diabetes inhibitory potential of rice bran.     

Promising anti-diabetic potential of capillin and capillinol isolated from <Emphasis Type="Italic">Artemisia capillaris</Emphasis>

Caffeoylquinic acids, flavonoids, and coumarins isolated from Artemisia capillaris have recently emerged as therapeutic candidates for diabetes and diabetic complications; however, there have been very few studies of the anti-diabetic potential of polyacetylenes. In the present study, we investigated the anti-diabetic potential of two polyacetylenes isolated from A. capillaris, namely capillin and capillinol by investigating their ability to inhibit α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), and rat lens aldose reductase (RLAR). Capillin displayed potent inhibitory activity against α-glucosidase, PTP1B, and RLAR, while capillinol showed moderate inhibitory activity against α-glucosidase and PTP1B at the concentrations tested. In addition, a kinetic study revealed that capillin inhibited α-glucosidase and RLAR in a noncompetitive manner, while inhibited PTP1B in a mixed-type manner. Capillinol inhibited α-glucosidase and PTP1B in a mixed-type manner. Docking simulations of these compounds demonstrated negative binding energies and close proximity to residues in the binding pocket of PTP1B, indicating that these polyacetylenes have a high affinity and tight binding capacity for the active site of the enzyme. Furthermore, capillin dose-dependently inhibited peroxynitrite (ONOO^?)-mediated tyrosine nitration. The results clearly demonstrate the promising potential of capillin and capillinol as therapeutic interventions for the management of diabetes as well as diabetes-associated complications.