Effects of acipimox and cholestyramine on serum lipoproteins,non-cholesterol sterols and cholesterol absorption and elimination

Summary The hypolipidaemic and metabolic effects of cholestyramine combined with acipimox or placebo have been evaluated in a double-blind ninety-day study in 18 patients with xanthomatous familial hypercholesterolaemia.Serum LDL-cholesterol was reduced by 35% in the cholestyramine group and 39% in the acipimoxcholestyramine group. The latter treatment increased the HDL-cholesterol level. Serum VLDL-cholesterol and triglyceride concentrations were unchanged.Cholesterol absorption efficiency was significantly reduced, and bile acid synthesis and faecal cholesterol elimination in both groups were increased. The metabolic changes were similar in the two treatment groups, but the increase in faecal neutral sterol excretion was significant only when acipimox was added.The serum cholesterol precursor sterol contents were similarly increased during the two treatments, indicating enhancement of endogenous cholesterol synthesis.The decrease in cholesterol absorption and the increase in neutral sterol excretion were more pronounced in subjects with >30% than in those with <30% reduction in LDL-cholesterol.The changes in serum total and LDL-cholesterol levels and cholesterol metabolism were not related to apoE phenotype, but the increase in HDL-cholesterol was higher in E4 then in E3 subjects.     

Bioactives for cholesterol lowering: targeting of cholesterol absorption pathways

The relationship between serum cholesterol and coronary heart disease is well established. Inhibitors of endogenous cholesterol synthesis (statins) have been shown to reduce cardiovascular events. Similarly, strategies directed towards the gastrointestinal tract may also be effective, as cholesterol absorption via the intestinal lumen is known to contribute to the total amount of cholesterol in the body. Although the exact mechanism(s) remain elusive, several naturally occurring compounds (bioactives), such as plant sterols, have been shown to influence the cholesterol absorption process. Accordingly, new targets, such as cholesterol esterase and cholesterol transport protein (Niemann-Pick C1-like 1 protein), may serve as worthy candidates for biologically active targets. This article discusses some of the potential benefits of targeting key proteins involved in cholesterol absorption and biosynthesis.     

New azetidinone cholesterol absorption inhibitors

Since their initial discovery, azetidinones have been extensively studied as potent cholesterol absorption inhibitors. Ezetimibe is the first-in-class and only member in the clinics either as a monotherapy or in combination with statins for treatment of hypercholesterolemia. The recent identification of Niemann–Pick C1-like 1 protein in the brush border membrane of the small intestine as a possible molecular target has opened the door for the design and synthesis of new anticholesterol drugs. This article reviews the important literature and patents on cholesterol absorption inhibitors.     

Inhibition of cholesterol absorption by HMG-CoA reductase inhibitor

Summary In subjects with familial hypercholesterolemia cholesterol absorption efficiency was insignificantly reduced during a short-term more consistently during longterm pravastatin treatment. A cholesterol feeding had no effect on LDL cholesterol level but reduced absorption efficiency during a long-term lovastatin treatment.     

新型胆固醇吸收抑制剂依泽替米贝

依泽替米贝是新型选择性胆固醇吸收抑制剂,现对其作用机制、药动学及临床单独使用或与他汀类药物联用治疗高胆固醇血症的研究进展进行综述.     

Update on patented cholesterol absorption inhibitors

Background: Atherosclerosis is one of the most life-threatening diseases primarily associated with hypercholesterolemia and is characterized by increased serum cholesterol level. Cholesterol originates from both its de novo synthesis within the hepatic cells and its absorption into the intestine in the form of dietary or bile cholesterol. Interventions influencing both of these processes are promising therapeutic options to lower the cholesterol level. Hydroxymethyl glutaryl-CoA reductase inhibitors, commonly known as statins, effectively block the rate determining step in the biosynthesis of cholesterol. Ezetimibe is the first new class of drugs used to treat hypercholesterolemia by inhibition of cholesterol absorption through Niemann Pick C1 Like 1 membrane of enterocytes. Therefore, combination therapy of ezetimibe and statins offers an efficacious new approach for the prevention and treatment of hypercholesterolemia. Objectives: The present review focuses on updates on ezetimibe and patented profile of novel cholesterol absorption inhibitors followed by critical analysis of different targets such as cholesterol esterase inhibitors, bile acid transport inhibitors or phospholipase-A₂ inhibitors, etc.which play an important role in the lipid absorption. Conclusion: The discovery of ezetimibe has opened a new door for the management of hyper-cholesterolemia in combination with statins. There are newer analogues that are under clinical trials, among which darapladib, FM-VP4 and A-002 are promising compounds.     

Discovery, synthesis and evaluation of novel cholesterol absorption inhibitors

Chemical-based common feature pharmacophore modelling of Niemann Pick C1 Like 1 inhibitors was performed to provide some insights on the important pharmacophore features essential for Niemann Pick C1 Like 1 inhibition using Discovery Studio V2.5. After in-house database screening, a new series of substituted oxazolidinones, selected from the top ranked hits, have been synthesized and evaluated as novel cholesterol absorption inhibitors. All compounds demonstrated effect of different degrees in lowering the total cholesterol in serum, especially compounds 1a, 2a and 2d, the potency of which was comparable to that of ezetimibe. It was also found that 1a, 1d and 2d could raise high-density lipoprotein cholesterol levels markedly. Interestingly, compounds 2a-2f appeared to have the moderate potential to lower triglyceride levels, which were superior to that of normal cholesterol absorption inhibitors including ezetimibe.     

Bile acid sequestrants: Mechanisms of action on bile acid and cholesterol metabolism

Summary Interruption of the enterohepatic circulation of bile acids by cholestyramine or colestipol influences the hepatic metabolism of cholesterol in many ways. The synthesis of bile acids is increased, as reflected by a several-fold increase in the activity of the cholesterol 7 hydroxylase, the rate-determining enzyme in bile acid synthesis. The increased metabolism of cholesterol to bile acids causes an enhanced demand of cholesterol in the hepatocytes, which respond with both new synthesis of cholesterol, as reflected in a several-fold increase of the HMG-CoA reductase activity, and increased expression of LDL receptors. As a consequence, the plasma level of LDL-cholesterol is lowered. The hepatic secretion rate of VLDL particles is increased. Cholestyramine therapy does not affect the output of biliary lipids or the cholesterol saturation of bile, indicating that treatment with bile acid sequestrants should not be associated with any increased risk of gallstone formation.     

植物甾醇肠道吸收研究进展

植物甾醇是一类具有降胆固醇作用的天然活性物质,作为食品添加剂在世界各国广泛使用,在我国也被批准为新资源食品。鉴于植物甾醇的降胆固醇作用与其肠道吸收过程密切相关,本文针对该过程关键蛋白(NPC1L1、ABCG5/G8、ACAT、ApoB-48、MTP)进行综述,探讨植物甾醇在肠道对胆固醇吸收的影响。     

Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin

AIMS: The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective. METHODS: Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C) >or=130 mg dl-1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only. RESULTS: In both studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL-C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean -17%, 95% CI -27.7, -6.2, and -18%, -28.4, -7.4, respectively) in LDL-C than simvastatin alone. CONCLUSIONS: The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.     

Inhibition of cholesterol absorption by neomycin,benzodiazepine derivatives and ketoconazole

Summary Neomycin and a benzodiazepine derivative (RO16-0521) inhibit similarly cholesterol absorption in man but the serum cholesterol level is reduced only by neomycin. Reason(s) for the difference are unknown. Ketoconazole inhibits 14-demethylation of lanosterol so that cholesterol synthesis is reduced. The agent inhibits also cholesterol absorption. The serum cholesterol level is reduced by about 20%, the lowering being potentiated by a simultaneous cholestyramine treatment.     

小檗碱对葡萄糖吸收的抑制作用

目的研究小檗碱的吸收特性和对肠道葡萄糖吸收的影响,探索小檗碱抗糖尿病作用机制。方法采用在体肠灌流模型观察小檗碱的吸收特性;用Caco-2细胞模型研究小檗碱对肠上皮细胞二糖酶(麦芽糖酶)活力的影响和对葡萄糖转运蛋白的作用。结果小檗碱在肠道内几乎不吸收(2.5 h吸收量小于5%),但能有效抑制小肠上皮细胞上二糖酶活力,其抑制蔗糖酶的ID50为1.830 mg·L^-1;对麦芽糖酶也有抑制作用,但无明显的剂量关系。小檗碱对于葡萄糖在Caco-2细胞上的摄取也有一定抑制作用。结论小檗碱抗糖尿病作用可能主要通过抑制蔗糖酶、麦芽糖酶等二糖酶活力,作为一种α-葡糖苷酶抑制剂发挥其抗糖尿病作用。     

新型选择性胆固醇吸收抑制剂依泽麦布

依泽麦布为一种新型口服调血脂药物，它能选择性抑制肠道对胆固醇和相关植物甾醇的吸收。单独应用或与他汀类药物合用，均能降低具有冠心病风险患者的血清胆固醇水平。本文主要对其作用机制、药代动力学、临床疗效和安全性进行综述。     

胆固醇吸收抑制剂依折麦布的临床应用

胆固醇吸收抑制剂是一类新型调脂药物．一系列临床研究表明,胆固醇吸收抑制剂无论是单用还是与他汀类联用都能取得良好的降脂效果．尤其在降低低密度脂蛋白胆固醇（LDL—C）水平上效果显著且不良反应少。依折麦布作为第一个也是目前唯一一个批准上市的胆固醇吸收抑制剂．它能很好地代表这一类药物的临床使用情况。本文从依折麦布的药理学作用、临床应用、有争议的相关研究和安全性四个方面对其进行详细综述。     

月桂氮芯卓酮促阿司匹林透皮吸收作用

目的：研究不同浓度的月桂氮Zhuo酮对阿司欧林小鼠离体皮肤渗透性的影响。方法：用改良的Franze扩散池，选不同浓度的月桂氮Zhuo酮（0％，2％，5％）作促渗剂，紫外法测定药物累积释放量（Q）、稳态流量（J）、渗透系数（KP）。结果：含2％和5％月桂氮Zhuo酮的乳膏的稳态流量（J）分别比空白乳膏增加14．9％和6．6％。结论：含不同浓度的月桂氮Zhuo酮均可促进阿司匹林的透过，药物从乳剂型基质向皮肤的渗透符合Higuchi方程。     

川芎嗪的鼻腔吸收及冰片的促进作用

目的 :探讨川芎嗪的鼻腔吸收及冰片的促进作用。方法 :采用大鼠在体鼻腔重循环法 ,研究川芎嗪鼻腔吸收的量效关系及冰片对其鼻腔吸收的影响。结果 :循环液中川芎嗪的浓度在 0 .2 5 ,0 .75 ,1.2 5g·L- 1时 ,鼻腔的吸收速率常数分别为 0 .0 195、0 .0 2 2 7、0 .0 2 4 1min- 1;但当药液浓度为 2 .5 ,5 .0g·L- 1时 ,鼻粘膜吸收速率常数随川芎嗪浓度的增加反而减少。结论 :川芎嗪可通过鼻腔吸收 ,冰片对其鼻腔吸收具有促进作用。     

亲水性胆汁酸防治胆固醇结石作用机制的研究进展

胆汁酸主要在肝脏中合成,是胆汁的主要成分之一,其含量和成分的改变与胆固醇结石形成具有密切关系。亲水性胆汁酸在胆固醇结石的形成、治疗中起重要作用,其具有溶解胆汁中胆固醇并调节胆固醇饱和度的重要作用,减少成核异常及保护并改善胆囊收缩功能的作用。对亲水性胆汁酸对防治胆固醇结石形成的作用机制进行综述。     

月桂氮酮促甲巯咪唑透皮吸收作用

本文观察了不同浓度的月桂氮酮对甲巯咪唑小鼠离体皮肤渗透性的影响。通过对药物累积释放量（Ｑ）、稳态流量（Ｊ）、渗透系数（Ｋｐ）的测定和计算，表明含不同浓度月桂氮酮的甲巯咪唑乳剂均能增加药物的皮肤渗透性。药物从乳剂基质向皮肤的渗透符合Ｈｉｇｕｃｈｉ方程。     

吸收促进剂对蚓激酶肠道吸收的影响

目的研究蚓激酶(YJM-I)和吸收促进剂合用时在大鼠肠道各段的吸收特点，寻找YJM-I经肠道吸收的最佳位置和考察吸收促进剂对YJM-I在肠道吸收过程中的影响。方法采用体外扩散池法、十二指肠部位直接给药、在体循环灌流及肠段原位结扎等方法对荧光标记的FITC-YJM-I在大鼠肠道的吸收情况进行了研究。结果十二指肠部位给药后的药代动力学和药效学评价结果显示YJM-I药物分子可被大鼠肠道吸收进入血液循环并保持生物学活性，但其绝对生物利用度较低。体外肠黏膜通透性试验及体内肠段吸收试验结果显示部分吸收促进剂表现出良好的促进YJM-I肠道吸收的作用。十二指肠、空肠和回肠段体外肠黏膜通透性均显示了相似的吸收促进剂作用强弱趋势： 1%壳聚糖>1%去氧胆酸钠>1% Na₂EDTA>1%十二烷基硫酸钠>1%辛酸钠>1%泊洛沙姆>1%羟丙基-β-环糊精。而在体内十二指肠部位给药则显示的强弱顺序为： 2.5%去氧胆酸钠>2.5% Na₂EDTA>2.0%壳聚糖>2.5%十二烷基硫酸钠>2.5%辛酸钠>2.5%泊洛沙姆>2.5%羟丙基-β-环糊精。结论吸收促进剂能有效地增加YJM-I肠道吸收程度，其中具有生物黏附作用的壳聚糖有望成为YJM-I肠道吸收的良好促进剂。