HMG-CoA还原酶抑制剂的合成(下)

2芳杂环与侧链的缩合反应 2.1卤代甲基芳香化合物与含醛基6碳侧链的缩合Wittig反应或Wittig-Hornor反应是合成HMG-CoA还原酶抑制剂类药物的常用方法.     

HMG-CoA还原酶抑制剂与放射性肺损伤

放射性肺损伤(RILI)是胸部肿瘤放射治疗常见的并发症之一,是胸部放疗主要的剂量限制性因素,目前仍缺乏理想的治疗手段。既往研究表明,氧化应激及炎性因子在肺损伤和肺纤维化中发挥重要作用。作为羟甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂,他汀类药物的多效性也体现在抗氧化应激、抗炎、抗纤维化等方面。本文将主要从机制上探讨他汀类药物对RILI潜在的治疗作用,为他汀类药物用于RILI的治疗提供线索和依据。     

HMG-CoA还原酶抑制剂-他汀类药物的作用及机制

心血管疾病是人类生命与健康的首要威胁之一。他汀类药物作为HMG-CoA还原酶天然底物的类似物,能竞争性抑制HMG-CoA还原酶还原HMG-CoA,进而减少内源性胆固醇的生成,从而大大减少了致命性和非致命性心血管疾病的事件的发生。本文针对心血管疾病的发病机制及以他汀类药物为中心的治疗方式进行了概述。     

HMG-CoA还原酶抑制剂在调脂方面的临床应用

3羟-基3-甲基戊二酰辅酶A还原酶抑制制(HM G-CoA)是一类新型调节血脂药物。目前销售和使用的主要有5种:洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀。本文就从其构数关系,几年来的临床应用情况作对照比较,最后它得出显著降低TC、LDL-C,中度降低TG,不同程度升高HDL-C,不良反应少,安全性好,且是一类临床疗效不错的调脂药。     

HMG-CoA还原酶抑制剂临床应用现状

3一羟基一3一甲基戊二酸辅酶A（3一切企。Xy－3－methylglutaryl－coenzymeA,HMG－CoA）还原酶抑制剂是一类新型降血脂药物,为临床防治动脉粥样硬化首选药。目前已用于临床有5种：洛伐他汀（lovastatin,默克公司创制）;辛伐他汀（simvastatin,默克公司创制）;普伐他汀（pravastatin,日本三井公司创制）;氟伐他汀（flulatatin,瑞士sandoz公司创制）;atorvastatin（美国Parke－Davis／PFizerLtd创制）。三构效关系洛伐他汀和辛伐他汀都是一种非活性的内酯化前体药物,通过肝脏水解成活性代谢产物或其衍生物而起作用。在洛伐他…     

穿心莲内酯的选择性还原

目的 寻找和设计新的HMG-CoA还原酶抑制剂。方法 采用硼氢化钠-氯化镍法对穿心莲内酯的α，β′-不饱和内酯的双键在甲醇溶液中，-5～5℃下进行选择性还原，并研究了反应条件。结果与讨论 通过该选择性还原反应。得到一种占主要成分的12，13．双氢穿心莲内酯和14-脱氯-12，13-双氢穿心莲内酯的副产物，对其反应条件的初步探索表明：低温有助于主要产物的生成。     

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。     

二氢叶酸还原酶抑制剂溴莫普林的合成

以３,５－二羟基苯甲酸为起始原料,合成了二氢叶酸还原酶抑制剂溴莫普林。     

血脂调节剂的研究——Ⅱ.HMG-CoA还原酶抑制剂M-8614A及MH-2688B的分离和鉴别

从青霉M-8614的发酵液中分离到血脂调节剂M-8614A。诱变M-8614得到的MH-2638菌株的发酵液中分离到化合物MH-2688B。它们的理化性质和波谱分析表明M-8614A和Mevastatin相同,MH-2688和Lovastatin同质。     

HMG-CoA还原酶抑制剂代谢及相关的药物相互作用

细胞色素Ｐ4 5 0 (ＣＹＰ)混合功能氧化酶参与大部分异物及内源性生化物质的氧化生物转化。已有30多种不同的人类ＣＹＰ得到鉴定。与药物代谢有关的包括ＣＹＰ1Ａ ,2Ｂ ,2Ｃ ,2Ｄ ,2Ｅ及 3Ａ等亚科[1 2 ] 。其中ＣＹＰ3Ａ亚科中的 3Ａ4 ,ＣＹＰ2Ｃ亚科中的 2Ｃ8,2Ｃ9和 2Ｃ19尤为重要。ＨＭＧ ＣｏＡ还原酶抑制剂 (他汀类药物 )为临床常用的降脂药物 ,一般口服给药 ,大部分经过ＣＹＰ进行生物转化 ,有不同程度的首关效应 ,所以当该类药物与ＣＹＰ底物 /抑制剂 /诱导剂合用时将可能产生药动学方面的药物相互作用。1　主要通过ＣＹＰ3Ａ4转化…     

HMG-CoA Reductase Inhibitors in Chronic Kidney Disease

The incidence of chronic kidney disease (CKD) is on the rise in the USA. Cardiovascular events are the leading cause of death in this patient population, therefore reducing the risk of these events has become a major focus. The aim of this review is to assess current literature on the use of statins in CKD and end-stage renal disease. Cholesterol reduction is important in preventing the development and progression of coronary heart disease and its negative effects. Statins have been widely studied and proven to reduce cardiovascular risk in the general population. The information gained from trials has been extrapolated to special populations, including CKD, despite these patients often being excluded. However, recent studies have begun to focus on CKD, hemodialysis, and transplant patients and the use of cholesterol-lowering agents and the potential association with decreased cardiovascular events. In addition, due to the unique pharmacokinetic and pharmacodynamic changes that occur in these patients, choosing the appropriate cholesterol-lowering agent becomes important for both safety and efficacy. The complexity of CKD patients is an important consideration when choosing cholesterol-lowering medication. Patients with CKD are often on medications that may interact with many of the cholesterol-lowering agents. Ensuring drug interactions are minimized is essential to the prevention of adverse events from the medications.     

Improvement of Endothelial Function by HMG-CoA Reductase Inhibitors

Endothelial dysfunction is the early and crucial state of atherosclerosis that is associated with a poor prognosis. Mechanistically, endothelial dysfunction is caused by reduced nitric oxide bioactivity. HMG-CoA reductase inhibitors (statins) effectively lower cholesterol plasma levels and profoundly decrease the cardiovascular risk of hypercholesterolemic patients. It is well established that statins improve endothelial dysfunction in those patients. The underlying mechanisms are less clear. It is thought that pleiotrophic, cholesterol-independent effects of statins such as increase of nitric oxide bioactivity and reduction of oxidative stress may contribute to the vasoprotective effects of statins. Therefore, it is speculated that statins, at least in part, improve endothelial function independent of plasma cholesterol concentrations and may thereby exert beneficial clinical effects. This notion of statins as general atheroprotective drugs has been underlined by in vitro experiments, animal studies and small clinical trials. However, large-scale clinical intervention studies are needed to confirm a positive influence of statins on endothelial dysfunction and cardiac event rates in normochlesterolemic patients. (c) 2002 Prous Science. All rights reserved.     

How Do HMG-CoA Reductase Inhibitors Prevent Stroke?

Stroke is a heterogeneous disorder with significantly high morbidity and mortality. The relationship between serum cholesterol level and the incidence of stroke remains controversial. Recent evidence from primary and secondary prevention trials suggests that treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors may reduce the incidence of stroke in patients with coronary artery disease (CAD). In this review, we attempt to outline and describe the potential mechanisms of HMG-CoA reductase inhibitors in the prevention of stroke. In addition to their lipid-lowering action HMG-CoA reductase inhibitors appear to exert their beneficial effects by various nonlipid-lowering mechanisms including anti-inflammatory effects, effect on endothelial function and coagulation cascade. Treatment with HMG-CoA reductase inhibitors is associated with decreased progression, plaque stablilization and even regression of atheromatous plaque in the carotid arteries. HMG-CoA reductase inhibitors also inhibit the coagulation cascade at various levels such as activation of prothrombin, factor V, factor X and liberation of tissue factor in response to vascular injury. Inhibition of fibrinolysis occurs secondary to inhibition of plasmin generation. Pravastatin therapy is associated with a reduction in the size of aortic atheroma which is an independent risk factor for stroke. Lastly, left ventricular dysfunction after acute myocardial infarction is associated with an increased risk of stroke and HMG-CoA reductase inhibitors may indirectly decrease the incidence of stroke by reducing coronary events. Most of these effects are independent of the cholesterol-lowering effects of HMG-CoA reductase inhibitors. In conclusion, HMG-CoA reductase inhibitors may have a role in primary prevention of stroke in patients with CAD.     

The Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

Vascular endothelial dysfunction is a complex phenomenon that is caused by an imbalance of vasodilator and vasoconstrictor factors that regulate the equilibrium-maintaining vascular tone. In the early phase of hypercholesterolemia, endothelial dysfunction precedes vascular wall lesions. One of the earliest recognizable benefits of treatment with HMG-CoA reductase inhibitors (statins) is the normalization of endothelium-dependent relaxation in hypercholesterolemia; this effect occurs before significant lowering of serum cholesterol levels. Recent insights into cellular mechanisms indicate that statins promote vasorelaxation by upregulating the expression of endothelial nitric oxide (NO) synthase, activating the phosphatidylinositide 3-kinase/Akt pathway, inhibiting superoxide anion generation and endothelin synthesis, and by anti-inflammatory effects. These effects appear to be linked to the inhibition of geranylgeranylation of small G proteins such as Rho and Rac GTPases. In this regard, statins preserve endothelial function through the improvement of NO bioavailability and the reduction of oxidative stress, thereby shifting the balance from vasoconstriction to vasodilation. This review highlights the various mechanisms underlying the vasculoprotective effects of statins, independent of their effects on cholesterol lowering.     

HMG-CoA Reductase Inhibitors (Statins) Characterized as Direct Inhibitors of P-Glycoprotein

Purpose. HMG-CoA reductase inhibitors (statins) are commonly prescribed for lipid lowering to treat hypercholesterolemia. Although they are well tolerated, their pharmacokinetic interactions with other drugs can lead to some adverse clinical consequences. The avenue of interaction has been asserted to be CYP3A4 because most (or all) known interactions are with CYP3A4 inhibitors, and statin oxidative metabolism is mediated by CYP3A4 as well as other CYP enzymes. However, these same drugs that exert a clinical pharmacokinetic effect on statin disposition are generally also P-gp substrates/inhibitors; hence, this transporter may be, or may contribute to, the mechanism of interaction. Methods. This study shows directly, as well as quantifies, the inhibition of P-gp-mediated transport of a fluorescent marker substrate. Results. Lovastatin and simvastatin are very potent and effective inhibitors of P-gp transport with IC₅₀'s of 26 and 9 M, respectively, for the human enzyme. Atorvastatin is also an effective P-gp inhibitor, but at higher concentrations. Uniquely, pravastatin, whose functional groups render it an inferior inhibitor of P-gp in the whole cell, had no effect in this assay. This result is consistent with known clinical interactions. The effect of these statins on ATP consumption by P-gp was also assessed, and the K_m results were congruent with the IC₅₀ observations. Conclusions. Therefore, the clinical interactions of statins with other drugs may be due, in part or all, to inhibition of P-gp transport.     

Atorvastatin Calcium: An Addition to HMG-CoA Reductase Inhibitors

Atorvastatin calcium is an HMG-coenzyme A (CoA) reductase inhibitor that was approved by the Food and Drug Administration on December 17, 1996. Like other such agents, it inhibits the action of HMG-CoA reductase and thereby decreases endogenous cholesterol synthesis, leading to a decrease in circulating low-density lipoprotein cholesterol. In addition to its effect on lipoprotein profile, atorvastatin reduces triglycerides to a greater extent than other HMG-CoA reductase inhibitors. These actions occur in a dose-dependent fashion. The adverse effect profile is similar to that of other agents in this class. Indications for atorvastatin include primary hypercholesterolemia as well as other lipid disorders.     

Impact of Genetic Polymorphisms on the Efficacy of HMG-CoA Reductase Inhibitors

Although pharmacologic treatment for cholesterol reduction represents an advance in cardiovascular and atherosclerosis treatment, the benefits of such therapy are still limited because of interindividual variability in the response to these drugs. Disease severity, treatment adherence, physiologic conditions, biologic conditions, and the patient's genetic profile could be cited as important factors in the evaluation of interindividual variability. In regard to the latter consideration, three large groups of genes could be investigated: (i) genes that code for proteins involved in metabolism and/or drug transport, thereby influencing the pharmacokinetics of these compounds; (ii) genes that code for proteins involved in the mechanism of action and/or in the metabolic pathway of drug action, and which therefore influence pharmacodynamics; and (iii) genes that code for proteins involved in direct development of the disease or in intermediate phenotypes. In this review we discuss pharmacogenetic studies of the HMG-CoA reductase inhibitors (statins) and the implications of pharmacogenetic considerations for predicting treatment efficacy and reducing the adverse effects of these drugs. Once new studies have been performed and most of the genetic variability associated with drug action has been revealed, the great challenge will be to apply this knowledge in clinical medicine.     

Cost Effectiveness of HMG-CoA Reductase Inhibitors in the Management of Coronary Artery Disease

HMG-CoA reductase inhibitors significantly reduce the risk of coronary artery disease (CAD) events and CAD-related mortality in patients with and without established CAD. Consequently, HMG-CoA reductase inhibitors have a central role within recommendations for lipid-modifying therapy. However, despite these guidelines, only one-third to one-half of eligible patients receive lipid-lowering therapy and as few as one-third of these patients achieve recommended target serum levels of low density lipoprotein-cholesterol. The underuse of HMG-CoA reductase inhibitors in eligible patients has important implications for mortality, morbidity and cost, given the enormous economic burden associated with CAD; direct healthcare costs, estimated at $US16–53 billion (2000 values) in the US and £1.6 billion (1996 values) in the UK alone, are largely driven by inpatient care. Hospitalization costs are reduced by treatment with HMG-CoA reductase inhibitors, particularly in high-risk groups such as patients with CAD and diabetes mellitus in whom net cost savings may be achieved. HMG-CoA reductase inhibitors are underused because of institutional factors and clinician and patient factors. Also, the vast number of patients eligible for treatment means that the use of HMG-CoA reductase inhibitors is undoubtedly limited by budgetary considerations. Secondary prevention in CAD using HMG-CoA reductase inhibitors is certainly cost effective. Primary prevention with HMG-CoA reductase inhibitors is also cost effective in many patients, depending upon CAD risk and drug dosage. As new, more powerful, HMG-CoA reductase inhibitors come to market, and the established HMG-CoA reductase inhibitors come off patent, the identification of the most cost-effective therapy becomes increasingly complex. Research in to the relative cost effectiveness of alternative HMG-CoA reductase inhibitors, taking full account of the institutional, clinician and patient barriers to uptake should be undertaken to identify the most appropriate role for the new therapies.     

Effects of Acid and Lactone Forms of Eight HMG-CoA Reductase Inhibitors on CYP-Mediated Metabolism and MDR1-Mediated Transport

Purpose With the growing clinical usage of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), the number of reports concerning serious drug–drug interaction has been increasing. Because recent studies have shown that conversion between acid and lactone forms occurs in the body, drug–drug interaction should be considered on both acid and lactone forms. Thus, we investigated the inhibitory effects of acid and lactone forms of eight statins, including one recently withdrawn, cerivastatin, and two recently developed, pitavastatin and rosuvastatin, on cytochrome P450 (CYP) 2C8, CYP2C9, and CYP3A4/5 metabolic activities and multidrug resistance protein 1 (MDR1) transporting activity. Methods The inhibitory effects of statins on CYP metabolic activities and MDR1 transporting activity were investigated using human liver microsomes and MDR1-overexpressing LLC-GA5-COL150 cells, respectively. Results The acid forms had minimal inhibitory effects on all CYP activities tested, except for fluvastatin on CYP2C9-mediated tolbutamide 4-hydroxylation (IC₅₀ = 1.7 μM) and simvastatin on CYP3A4/5-mediated paclitaxel 3-hydroxylation (12.0 μM). Lactone forms showed no or minimal inhibitory effects on CYP2C8, CYP2C9, and CYP2C19 activities, except for rosuvastatin on the CYP2C9 activity (20.5 μM), whereas they showed stronger inhibitory effects on the CYP3A4/5 activity with the rank order of atorvastatin (5.6 μM), cerivastatin (8.1 μM), fluvastatin (14.9 μM), simvastatin (15.2 μM), rosuvastatin (20.7 μM), and lovastatin (24.1 μM). Pitavastatin and pravastatin had little inhibitory effect, and a similar order was found also for testosterone 6β-hydroxylation. MDR1-mediated transport of [³H]digoxin was inhibited only by lactone forms, and the rank order correlated with that of inhibitory effects on both CYP3A4/5 activities. Inhibitory effects on MDR1 activity, and on both CYP3A4/5 activities, could be explained by the lipophilicity; however, a significant correlation was found between the lipophilicity and inhibitory effects on CYP2C8-mediated paclitaxel 6α-hydroxylation. Conclusions We showed the difference between the acid and lactone forms in terms of drug interaction. The lipophilicity could be one of the important factors for inhibitory effects. In the case of statins, it is important to examine the effects of both forms to understand the events found in clinical settings, including the pleiotropic effects.