新型降酯药--罗伐他汀

罗伐他汀是一种全合成的具有高度肝选择性的新甲基羟戌二酰辅酶(HMG-CoA)还原酶抑制药。该药通过抑制内源性胆固醇的合成,明显降低血清胆固醇的含量,同时还能降低低密度脂蛋白-胆固醇(LDL—C)、总胆固醇和载脂蛋白(apo)B的水平,升高高密度脂蛋白-胆固醇(HDL-C)的水平,具有抗动脉粥样硬化的作用,对原发性高胆固醇血症及混合性高胆固醇血症等各种类型的血脂异常均有效,其耐受性良好,不良反应轻微。本文通过文献检索综述了罗伐他汀的药理作用、药代动力学及临床评价。     

新型高效降脂药物罗伐他汀

目的:介绍一种新型的3羟基-3甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂罗伐他汀.方法:通过查阅文献,从结构特征与优势、抑酶活性及肝细胞选择性、药效学、药动学、临床研究、安全性6个方面的内容对该药进行综合性评述.结果:该药不仅具有强力的HMG-CoA还原酶抑制活性,而且这种作用还呈肝细胞选择性.其药效学、药动学性质优异,安全性高.结论:罗伐他汀是一个颇具发展潜力的新一代他汀类降脂药物.     

HMG-CoA还原酶抑制剂阿伐他汀

介绍国外对阿伐他汀药理临床研究的成果及世界开发动态。     

罗伐他汀

罗伐他汀(rosuvastatin,ROS)是一种用于治疗脂血症的HMG-CoA还原酶抑制剂。ROS不易发生代谢作用，具有较低的药物相互作用。ROS在改善高胆固醇血症患者的脂类水平方面优于阿托伐他汀、辛伐他汀和普伐他汀。ROS比阿托伐他汀可使更多的患者达到“美国国家胆固醇教育计划(HCEP，成年治疗组Ⅱ)”所制定的低密度脂蛋白—胆固醇(LDL-C)水平指标(98％：87％)，对高危患者效果更加明显(97％：61％)。另一项试验表明，ROS可使88％的患者达到NCEP所制定的血清LDL-C水平指标，而普伐他汀和辛伐他汀分别使60％和73％的患者达标。对于高危患者这种对比效果更加明显。另外，ROS还可改善杂合型或纯合型家族性高胆固醇血症、高甘油三酯血症或混合型脂血症患者的脂类水平。ORS具有很好的耐受性。     

阿托伐他汀—— 一种新的HMG-CoA还原酶抑制剂

大量研究结果证实,动脉粥样硬化和冠心病(CHD)与高胆固醇血症有着密切的关系。据估计,欧美有15％成年人因血脂水平升高而处于罹患心血管疾病的风险中。因此,高水平的总胆固醇(TC)和低密度脂蛋白胆固醇(LD-L-C)已成为预防CHD的主攻目标。 人体胆固醇有两个来源,每日从食物中吸收约300～500mg和内源性生物合成700～900mg,可见抑制生物合成是降低血胆固醇水平的重要途径。而胆固醇生物合成的第一个限速酶是羟甲戊二酰辅酶A(HMG-CoA)还原酶。因此,自20a前发现第1种HMG-CoA还原酶抑制剂以来,对高胆固醇血症的药物治疗已取得了长足的进展;事实上,HMG-CoA还原酶抑制剂已经成为降低TC和LDL-C最有效的药物。美国国家胆固醇教育方案(NCEP)已把这类药物定为抗高脂血症的主要药物。此前,已有洛伐他汀(lovastatin),氟伐他汀(fluvastatin),普伐他汀(pravas-     

阿伐他汀钙

流行病学研究已确定：心血管的发病率及死亡诣与总胆固醇和低密度脂肪蛋白胆固醇水平成正比,而与高密度脂肪蛋白胆固醇水平成反比,作为新型ＨＭＧ－ＣｏＡ还原酶抑制剂阿伐他汀钙具有独特药代动力学特性及确切疗效;使升高的ＬＤＬ－Ｃ明显降低４０％￣８０％,使ＨＤＬ－Ｃ升高１０％,其治疗费用－疗效比优于其它他汀类药物。预计在２００５年将成为世界最畅销药物。     

降血脂药罗舒伐他汀

罗舒伐他汀 (Rosuvastatin)是由AstraZaneca公司研制的一种竞争性HMG CoA还原酶抑制剂 ,可用于高胆固醇血症、血脂代谢紊乱症及单纯高甘油三酯血症的治疗 ,商品名为Crestor,曾用代号 :ZD 4 5 2 2临床研究表明 ,本品在药效和安全性方面均具有令人满意的结果 ,被称之为“超级他汀”。AstraZaneca公司于 2 0 0 2年在美国和欧盟同时递交该药的上市申请。 2 0 0 3年 2月首次在加拿大面市 ,并且陆续在新西兰与英国上市 ,目前临床的使用剂量为 10～ 80mg。CAS :14 70 98 2 0 2化学结构式 :罗舒伐他汀对HMG CoA还原酶有着较高的亲合力 (Ki…     

降血脂新药--罗伐他汀

综合相关文献,评价降血脂新药——罗伐他汀的药动学、药效学、临床应用及不良反应等。研究表明,罗伐他汀对酶具有高亲和力,亲水性较高,被肝细胞选择性吸收,通过细胞色素P450代谢。该药可有效降低三酰甘油、富含三酰甘油脂蛋白、非高密度脂蛋白胆固醇,增加高密度脂蛋白胆固醇。罗伐他汀是一种高效的β羟基β甲基戊酰辅酶A(HMGCoA)还原酶抑制药,其降血脂性能高于所有其他的他汀类药物,抗动脉粥样硬化作用强,耐受性良好。     

No effect of age or gender on the pharmacokinetics of rosuvastatin: a new HMG-CoA reductase inhibitor

The effects of age and gender on the pharmacokinetics of rosuvastatin (Crestor) were assessed in healthy young (18-35 years) and elderly (> 65 years) males and females in this open, nonrandomized, noncontrolled, parallel-group trial. Sixteen males and 16 females (8 young and elderly volunteers per gender group) were enrolled. Mean (range) ages were 24 (18-33) and 68 (65-73) years for young and elderly volunteers, respectively. Volunteers were given a single oral 40 mg dose of rosuvastatin. Blood samples for measurement of rosuvastatin plasma concentration were collected up to 96 hours following dosing. Age and gender effects were assessed by constructing 90% confidence intervals (CIs) around the ratios of young/elderly and male/female geometric least square means (glsmeans) for AUC(0-t) and Cmax (derived from ANOVA of log-transformed parameters). Small differences in rosuvastatin pharmacokinetics were noted between age and gender groups. Glsmean AUC(0-t) was 6% higher (90% CI = 0.86-1.30) and glsmean Cmax, 12% higher (90% CI = 0.83-1.51) in the young compared with the elderly group. Glsmean AUC(0-t) was 9% lower (90% CI = 0.74-1.12) and glsmean Cmax 18% lower (90% CI = 0.61-1.11) in the male compared with the female group. These small differences are not considered clinically relevant, and dose adjustments based on age or gender are not anticipated. Rosuvastatin was well tolerated in all volunteers.     

Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor

Rosuvastatin, a new statin, has been shown to possess a number of advantageous pharmacological properties, including enhanced HMG-CoA reductase binding characteristics, relative hydrophilicity, and selective uptake into/activity in hepatic cells. Cytochrome p450 (CYP) metabolism of rosuvastatin appears to be minimal and is principally mediated by the 2C9 enzyme, with little involvement of 3A4; this finding is consistent with the absence of clinically significant pharmacokinetic drug-drug interactions between rosuvastatin and other drugs known to inhibit CYP enzymes. Dose-ranging studies in hypercholesterolemic patients demonstrated dose-dependent effects in reducing low-density lipoprotein cholesterol (LDL-C) (up to 63%), total cholesterol, and apolipoprotein (apo) B across a 1- to 40-mg dose range and a significant 8.4% additional reduction in LDL-C, compared with atorvastatin, across the dose ranges of the two agents. Rosuvastatin has also been shown to be highly effective in reducing LDL-C, increasing high-density lipoprotein cholesterol (HDL-C), and producing favorable modifications of other elements of the atherogenic lipid profile in a wide range of dyslipidemic patients. In patients with mild to moderate hypercholesterolemia, rosuvastatin has been shown to produce large decreases in LDL-C at starting doses, thus reducing the need for subsequent dose titration, and to allow greater percentages of patients to attain lipid goals, compared with available statins. The substantial LDL-C reductions and improvements in other lipid measures with rosuvastatin treatment should facilitate achievement of lipid goals and reduce the requirement for combination therapy in patients with severe hypercholesterolemia. In addition, rosuvastatin's effects in reducing triglycerides, triglyceride-containing lipoproteins, non-HDL-C, and LDL-C and increasing HDL-C in patients with mixed dyslipidemia or elevated triglycerides should be of considerable value in enabling achievement of LDL-C and non-HDL-C goals in the numerous patients with combined dyslipidemias or metabolic syndrome who require lipid-lowering therapy. Rosuvastatin is well tolerated alone, and in combination with fenofibrate, extended-release niacin, and cholestyramine, and has a safety profile similar to that of currently marketed statins. A large, long-term clinical trials program is under way to investigate the effects of rosuvastatin on atherosclerosis and cardiovascular morbidity and mortality.     

A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid

Recent studies have reported that hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have vasculoprotective effects independent of their lipid-lowering properties, including anti-inflammatory actions. We used intravital microscopy of the rat mesenteric microvasculature to examine the effects of rosuvastatin, a new HMG-CoA reductase inhibitor, on leukocyte-endothelium interactions induced by thrombin. Intraperitoneal administration of 0.5 and 1.25 mg kg(-1) rosuvastatin 18 h prior to the study, significantly and dose-dependently attenuated leukocyte rolling, adherence, and transmigration in the rat mesenteric microvasculature superfused with 0.5 u ml(-1) thrombin. This protective effect of rosuvastatin was reversed by intraperitoneal injection of 25 mg kg(-1) mevalonic acid 18 h before the study. Immunohistochemical detection of the endothelial cell adhesion molecule P-selectin showed a 70% decrease in endothelial cell surface expression of P-selectin in thrombin-stimulated rats given 1.25 mg kg(-1) rosuvastatin. In addition, rosuvastatin enhanced release of nitric oxide (NO) from the vascular endothelium as measured directly in rat aortic segments. Moreover, rosuvastatin failed to attenuate leukocyte-endothelium interactions in peri-intestinal venules of eNOS(-/-) mice. These data indicate that rosuvastatin exerts important anti-inflammatory effects via inhibition of endothelial cell adhesion molecule expression, and that this protective action of rosuvastatin requires release of nitric oxide by the vascular endothelium. These data also demonstrate that the mechanism of the non-lipid lowering actions of HMG-CoA reductase inhibitors in vivo may be due to reduced formation or availability of mevalonic acid within endothelial cells.     

Pitavastatin (NK-104), a new HMG-CoA reductase inhibitor

Pitavastatin calcium (NK-104) is a new synthetic hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin). Animal studies suggest that, in addition to reducing low-density lipoprotein (LDL) cholesterol, the drug may produce marked reductions in triglyceride-rich particles (very-low-density [VLDL] and intermediate-density lipoproteins [IDL]). It is not metabolized by the common cytochrome P-450 3A4 enzyme, possibly reducing the risk for drug interactions. Early studies suggest that it may be quite useful for treating common dyslipidemias (isolated elevations of LDL cholesterol and combined disorders with elevations of LDL cholesterol and triglycerides). Such improvements in lipid profiles are proven to have positive effects on cardiovascular risk. Human studies are under way to further elucidate the effects of the drug and procure approval by various regulatory bodies. (c) 2001 Prous Science. All rights reserved.     

Rosuvastatin: a high-potency HMG-CoA reductase inhibitor.

OBJECTIVE: To summarize the relevant pharmacologic, clinical, and safety data regarding rosuvastatin (Crestor--AstraZeneca), the most recently marketed 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor approved for the treatment of dyslipidemia. DATA SOURCES: Medline search from years 1990 thru 2005 using the keywords HMG-CoA reductase inhibitor, hypercholesterolemia, lipid-lowering agents, rosuvastatin, and statins. Study Selection: Review articles, clinical trials, case reports, abstracts, and data on file from the manufacturer concerning rosuvastatin and other statins were considered for inclusion. DATA EXTRACTION: English-language studies were selected for inclusion. DATA SYNTHESIS: Multiple clinical trials have revealed that use of rosuvastatin is associated with greater reductions in low-density lipoprotein cholesterol (LDL-C) across the dose range of 5-40 mg/day than any other currently available statins. Rosuvastatin also significantly increases high-density lipoprotein cholesterol and reduces triglycerides significantly as well. In clinical trials, rosuvastatin was well tolerated, with a low incidence of adverse events and a safety profile similar to that of the other marketed statins. At present, no large-scale primary or secondary prevention clinical trials document either long-term safety of rosuvastatin or its effectiveness in preventing coronary events. CONCLUSION: Compared with other statins, rosuvastatin offers the greatest lipid-lowering efficacy at the lowest dose in treating patients with dyslipidemia and with a similar safety profile over the short-term. Rosuvastatin may allow more patients to achieve their LDL-C goals than any other statin and at a lower dose than other agents.     

Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor,rosuvastatin, after morning or evening administration in healthy volunteers

AIMS: To compare the lipid-regulating effects and steady-state pharmacokinetics of rosuvastatin, a new synthetic hydroxy methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, following repeated morning and evening administration in volunteers with fasting serum low-density lipoprotein cholesterol (LDL-C) concentrations < 4.14 mmol l-1. METHODS: In this open-label two-way crossover trial 24 healthy adult volunteers were randomized to receive rosuvastatin 10 mg orally each morning (07.00 h) or evening (18.00 h) for 14 days. After a 4 week washout period, volunteers received the alternative regimen for 14 days. Rosuvastatin was administered in the absence of food. RESULTS: Reductions from baseline in serum concentrations of LDL-C (-41.3%[morning]vs-44.2%[evening]), total cholesterol (-30.9%vs-31.8%), triglycerides (-17.1%vs-22.7%), and apolipoprotein B (-32.4%vs-35.3%) were similar following morning and evening administration. AUC(0,24 h) for plasma mevalonic acid (MVA), an in vivo marker of HMG-CoA reductase activity, decreased by -29.9% (morning) vs-32.6% (evening). Urinary excretion of MVA declined by -33.6% (morning) vs-29.2% (evening). The steady-state pharmacokinetics of rosuvastatin were very similar following the morning and evening dosing regimens. The Cmax values were 4.58 vs 4.54 ng ml-1, and AUC(0,24 h) values were 40.1 vs 42.7 ng ml-1 h, following morning and evening administration, respectively. There were no serious adverse events during the trial, and rosuvastatin was well tolerated after morning and evening administration. CONCLUSIONS: The pharmacodynamic effects and pharmacokinetics of rosuvastatin are not dependent on time of dosing. Morning or evening administration is equally effective in lowering LDL-C.     

NK-104: a novel synthetic HMG-CoA reductase inhibitor

An elevated level of low-density lipoprotein (LDL)-cholesterol has been recognised as the most important risk factor for coronary artery disease (CAD). Development of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) (‘statins’), a rate-limiting key enzyme of cholesterol synthesis pathway, has revolutionised the cholesterol-lowering therapy. In the last decade, effective primary and secondary preventive measures have been established in several statin trials to prevent future events of CAD by lowering LDL-cholesterol levels. These results supported the ‘lower is better’ hypothesis in the relationship between LDL-cholesterol levels and CAD. NK-104 (pitavastatin, previously named as itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) has recently been developed as a new chemically synthesised and powerful statin. On the basis of reported data, the potency of NK-104 is dose-dependent and appears to be equivalent to that of atorvastatin. This new statin is safe and well-tolerated in the treatment of patients with hypercholesterolaemia. The cytochrome P450 system only slightly modifies NK-104, which suggests the clinical advantage of this agent, because the prevalence of clinically significant interactions with a number of other commonly used drugs can be considered to be extremely low. NK-104 can provide a new and potentially superior therapeutic agent when compared with currently available other statins. Randomised controlled clinical trials to assess the long-term effects of this new statin on CAD would be required.     

NK-104: a novel synthetic HMG-CoA reductase inhibitor

An elevated level of low-density lipoprotein (LDL)-cholesterol has been recognised as the most important risk factor for coronary artery disease (CAD). Development of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) ('statins'), a rate-limiting key enzyme of cholesterol synthesis pathway, has revolutionised the cholesterol-lowering therapy. In the last decade, effective primary and secondary preventive measures have been established in several statin trials to prevent future events of CAD by lowering LDL-cholesterol levels. These results supported the 'lower is better' hypothesis in the relationship between LDL-cholesterol levels and CAD. NK-104 (pitavastatin, previously named as itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) has recently been developed as a new chemically synthesised and powerful statin. On the basis of reported data, the potency of NK-104 is dose-dependent and appears to be equivalent to that of atorvastatin. This new statin is safe and well-tolerated in the treatment of patients with hypercholesterolaemia. The cytochrome P450 system only slightly modifies NK-104, which suggests the clinical advantage of this agent, because the prevalence of clinically significant interactions with a number of other commonly used drugs can be considered to be extremely low. NK-104 can provide a new and potentially superior therapeutic agent when compared with currently available other statins. Randomised controlled clinical trials to assess the long-term effects of this new statin on CAD would be required.     

Photostability of pitavastatin—A novel HMG-CoA reductase inhibitor

The photostability of pitavastatin, an HMG-CoA reductase inhibitor used in the treatment of hypercholesterolemia, was investigated. The sample solution was exposed to UV-A radiation and the photodegradation process was monitored by means of spectrophotometric method and HPLC–DAD. Pitavastatin was shown to be photolabile and its photodegradation reaction followed the first-order kinetics with the rate constant k = 3.54 × 10⁻⁴ ± 9.43 × 10⁻⁶ s⁻¹.The chromatograms revealed the presence of four major photoproducts (PP-1–PP-4). The separated and isolated photolytic products were identified using a mass spectrometer coupled with a time of flight (TOF) analyzer. The main reaction observed during exposure to radiation of pitavastatin was photocyclisation leading to formation of four-ring photoproducts.