有机阴离子转运多肽1B1（OATP1B1）基因多态性对他汀类药物影响的研究进展

有机阴离子转运多肽1B1(OATP1B1)是一种负责转运多种内外源性物质进入肝细胞发挥作用的摄入型转运蛋白。他汀类药物又称3-羟基-3-甲基戊二酸单酰辅酶A(HMG-CoA)还原酶抑制剂,临床上广泛应用于调脂及心脑血管疾病的预防,其疗效及不良反应有显著的个体化差异。研究表明OATP1B1基因多态性是导致他汀类药物个体化差异的重要因素。对OATP1B1基因多态性对他汀类药物影响的研究进展进行综述,为他汀类药物的个体化、安全化应用提供可能的理论指导。     

不同基因多态性对他汀类药物影响的研究进展

他汀类药物是目前临床应用最广泛的降脂药物,为心血管疾病的一级、二级预防的基石。他汀类药物为羟基-甲基戊二酰辅酶A还原酶抑制剂,可以显著降低血清总胆固醇、低密度脂蛋白胆固醇、三酰甘油水平,同时可轻度升高高密度脂蛋白胆固醇水平。目前研究的参与他汀类药物代谢的酶、转运蛋白、受体等基因多态性对他汀类药物安全性、不良反应有重要影响。阐述遗传因素载脂蛋白E、SLCO1B1、ATP结合盒转运蛋白B1、ABCG2、CYP、3-羟基-3-甲基戊二酰辅酶A还原酶基因等相关基因多态性对他汀类药物疗效和安全性的影响,为他汀类药物的个体化用药提供参考依据。     

药物转运体有机阴离子转运多肽1B1基因多态性的研究进展

有机阴离子转运多肽1B1(OATP1B1)是肝脏中重要的药物转运通路之一,其遗传多态性可改变药动学参数,影响多种药物在体内的分布,继而影响药效及药物不良反应. 该文对OATP1B1结构与功能,OATP1B1编码基因的结构及多态性对功能的影响,SLCO1B1多态性对他汀类药物的影响,SLCO1B1多态性对口服降糖药的影响,SLCO1B1多态性对抗肿瘤药的影响等进行综述.     

基因组学相关基因遗传多态性对他汀类药物代谢、转运及药效的影响

他汀类药物为羟甲戊二酰铺酶A(HMG-CoA)还原酶抑制剂,可降低心血管疾病患者的发病率及死亡率,然而此类药物有发生肌病等不良反应的风险,因此,研究导致该类药物个体差异大的原因具有重大意义。通过研究CYP450酶、药物转运体(OATP1B1、ABCG2)、药效基因(APOE、HMG-CoA还原酶)的基因多态性对他汀类药物代谢、转运及药效的影响,以期为指导他汀类的临床用药打下坚实的理论基础,确保临床用药的安全性和有效性,真正实现临床上的个体化给药。     

强化他汀降脂治疗的发展方向

血浆胆固醇尤其是低密度脂蛋白胆固醇(LDL-C)是动脉粥样硬化斑块的主要组成部分。虽然临床研究表明强化他汀治疗在降低LDL-C水平以及对临床终点事件的影响方面均优于常规他汀治疗,但目前他汀类药物在临床实际应用中使用率较低,降脂幅度有限,药物的肝脏和肌肉毒性等问题,使得强化他汀降脂难以完成其使命。因此,强化降脂治疗的发展方向是联合应用具有不同降胆固醇机制的药物。依折麦布是一种肠道胆固醇吸收抑制剂,与他汀类药物合用不仅具有强大的降低LDL-C作用,还可以减少他汀药物的剂量,从而降低不良反应的发生率。     

他汀类药物化学结构和理化性质对其药效及药动学特性的影响

他汀类药物能安全有效地降低血浆低密度脂蛋白胆固醇(LDL-C),是治疗高胆固醇血症的首选药物.已上市的他汀类药物作用机制大致相同,但化学结构有差异,导致其水溶性、亲脂亲水性不同,进而影响在人体内的吸收、分布、代谢及排泄特征.本文综述了此类药物化学结构和理化性质对其药效及药动学特性的影响.所有他汀类药物均有首过效应,因而药物可在肝脏富集.已上市药物中,瑞舒伐他汀降低LDL-C的效果较好,阿托伐他汀、辛伐他汀及普伐他汀次之.     

PCSK9抑制剂在动脉粥样硬化性心血管疾病中的临床研究进展

动脉粥样硬化性心血管疾病(ASCVD)现已成为危害人类健康的主要疾病之一。降低胆固醇治疗尤其是低密度脂蛋白-胆固醇(LDL-C),是ASCVD防治的基石,目前指南推荐控制LDL-C水平首选他汀类药物。但在临床实践中,经过他汀治疗的ASCVD患者仍存在较高剩留风险,另仍有部分患者不能耐受他汀类药物或在他汀类药物最大耐受剂量的情况下血脂仍不能达标。人前蛋白转化酶枯草溶菌素9(PCSK9)与LDL-C代谢密切相关,近年来大量基础和临床研究均证实PCSK9抑制剂能够显著降低血LDL-C水平,且耐受性和安全性良好。目前国外已批准PCSK9抑制剂用于临床。本文将系统综述有关PCSK9基因与血脂代谢的关系、PCSK9抑制剂的研发过程,总结其在基础和临床研究的最新进展。     

阿托伐他汀诱导肝脏Cyp7a1和时钟基因的表达

<正>他汀类药物是羟甲戊二酰辅酶A(HMGCR)选择性抑制剂,是临床防治冠心病的重要药物~([1-2])。研究表明,阿托伐他汀能升高肝脏中胆固醇7羟化酶(Cyp7a1)的表达,改变体内胆汁酸代谢~([3]),并可能与其长期使用所致肝脏不良反应有关~([4])。Cyp7a1表达受时钟基因的调控,具有昼夜节律性~([5])。本研究采用长期给予临床剂量阿托伐他汀,观察其对小鼠肝Cyp7a1基因和时钟基因表达的影响。     

有机阴离子转运多肽1B3的研究进展

有机阴离子转运多肽1B3(organic anion transporting polypeptide 1B3,OATP1B3)属于溶质转运体(solute carrier,SLC)超家族,主要负责将内、外源物质转运至肝细胞代谢。OATP1B3是肝脏特异性转运体,通常局限性地分布于肝细胞窦状隙侧肝细胞膜上,近期研究发现在前列腺癌、结肠癌、肺癌等肿瘤组织和细胞中也存在着高表达。溶质转运体1B3(SLCO1B3)具有明显的基因多态性,334T>G和699G>A单体型可明显影响OATP1B3的转运活性,从而介导药物-药物相互作用的发生,导致临床用药的个体差异。此外,OATP1B3可通过作用于孕烷X受体(pregnane X receptor,PXR)和组成性雄甾烷受体(constitutive androstane receptor,CAR)等核受体配体的转运,影响体内PXR和CAR的转录活性,从而调控药物代谢酶如细胞色素P450 3A4(CYP3A4)的表达。本文将对OATP1B3近年来的研究进展进行综述。     

SLCO1B1基因多态性的辛伐他汀个体化用药临床研究分析

辛伐他汀(Simvastatin)是一种临床常用的降血脂药物,其常见的药物不良反应是横纹肌溶解、肌病等肌肉相关症状。SLCO1B1基因多态性是导致辛伐他汀肌肉不良反应个体化差异的主要原因之一。SLCO1B1编码的产物参与辛伐他汀的肝摄取,其功能丧失性变异可引起辛伐他汀的血药水平升高,导致更多的药物暴露。对于服用辛伐他汀的患者,检测SLCO1B1基因型可指导患者的精准用药,但目前尚无研究讨论常规开展SLCO1B1基因检测的临床意义。对于携带功能降低的等位基因患者,推荐服用小剂量的辛伐他汀或者换用其他他汀类(阿托伐他汀、瑞舒伐他汀等)药物,以降低可能的肌肉不良反应风险。本研究综述了SLCO1B1基因与辛伐他汀个体化用药的相关研究,为辛伐他汀的合理应用提供参考。     

长期他汀类药物的使用与冠心病患者心理障碍的关系

目的观察长期服用他汀药物对冠心病患者心理状态的影响。方法研究对象来自潍坊市人民医院心血管科及老年医学科,在入组时及随访中评价心理状况,干预因素为长期服用他汀药物,观察指标为抑郁、焦虑、敌对状态。计算优势比及95%置信区间代表他汀使用与异常心理评分的关联性。结果研究对象平均随访4年,最多随访7年,比较140例长期连续服用他汀药物患者的异常心理评分,在对基础状态进行校正后,优势比分别为抑郁（OR0.63,95%CI0.43～0.93）、焦虑（OR0.69,95%CI0.47～0.99）及敌对（OR0.77,95%CI0.58～0.93）。他汀药物的心理获益与胆固醇水平关系不大。结论冠心病患者长期他汀药物服用与抑郁、焦虑、敌对等心理状态好转有关。     

Impact of SLCO1B1 (OATP1B1) and ABCG2 (BCRP) genetic polymorphisms and inhibition on LDL-C lowering and myopathy of statins

Statins are the preferred class of drugs for treating patients with atherosclerosis and related coronary heart disease. Treatment with statins leads to significant low-density lipoprotein cholesterol (LDL-C) lowering, resulting in reductions in major coronary and vascular events. Statins are generally well tolerated and safe; however, their use is complicated by infrequent, but often serious, muscular adverse events. For many statins, both efficacy and risk of adverse muscle events can be influenced by membrane transporters, which are important determinants of statin disposition. Genetic polymorphisms and drug-drug interactions (DDIs) involving organic anion-transporting polypeptide 1B1 and breast cancer resistance protein have shown the capacity to reduce the activity of these transporters, resulting in changes in LDL-C lowering by statins, as well as changes in the frequency of adverse muscle events associated with their use. This review presents evidence for how reduced transporter activity impacts the safety and pharmacology of statins. It expands on the scope of other recent statin reviews by providing recommendations on in vitro evaluation of statin interaction potential, discussing how reduced transporter activity impacts statin management during drug development, and proposing ideas on how to evaluate the impact of DDI on statin efficacy during clinical trials. Furthermore, the potential clinical consequences of perturbing statin efficacy via DDI are discussed.     

Effect of high-dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors

Asymmetric dimethylarginine (ADMA) and monomethylarginine (LMMA) are endogenous inhibitors of nitric oxide synthase. A high level of ADMA in plasma has shown to be a significant risk factor for acute coronary syndromes and elevated plasma ADMA levels are prevalent in patients with hypercholesterolemia. It was therefore hypothesized that lowering plasma cholesterol levels with statin treatment would also lower ADMA concentrations. This double-blind study addressed the effect of high-dose statin treatment on plasma levels of ADMA and LMMA. Forty-eight subjects with mild hypercholesterolemia were randomly assigned to receive simvastatin 80 mg/d, atorvastatin 40 mg/d, or placebo for 8 weeks. Both statins decreased low-density lipoprotein cholesterol effectively (simvastatin 54% and atorvastatin 49%). However, concentrations of arginine derivatives remained unchanged during statin treatment and did not correlate with cholesterol levels. This study indicates that statin treatment has no clear influence on plasma ADMA or LMMA concentrations.     

Impact of SLCO1B1 (OATP1B1) and ABCG2 (BCRP) genetic polymorphisms and inhibition on LDL-C lowering and myopathy of statins

1. Statins are the preferred class of drugs for treating patients with atherosclerosis and related coronary heart disease. Treatment with statins leads to significant low-density lipoprotein cholesterol (LDL-C) lowering, resulting in reductions in major coronary and vascular events. Statins are generally well tolerated and safe; however, their use is complicated by infrequent, but often serious, muscular adverse events.

2. For many statins, both efficacy and risk of adverse muscle events can be influenced by membrane transporters, which are important determinants of statin disposition. Genetic polymorphisms and drug–drug interactions (DDIs) involving organic anion-transporting polypeptide 1B1 and breast cancer resistance protein have shown the capacity to reduce the activity of these transporters, resulting in changes in LDL-C lowering by statins, as well as changes in the frequency of adverse muscle events associated with their use.

3. This review presents evidence for how reduced transporter activity impacts the safety and pharmacology of statins. It expands on the scope of other recent statin reviews by providing recommendations on in vitro evaluation of statin interaction potential, discussing how reduced transporter activity impacts statin management during drug development, and proposing ideas on how to evaluate the impact of DDI on statin efficacy during clinical trials. Furthermore, the potential clinical consequences of perturbing statin efficacy via DDI are discussed.

     

Effect of apolipoprotein E polymorphism on statin-induced decreases in plasma lipids and cardiovascular events

Hypercholesterolemia or dyslipidemia is an independent risk factor for cardiovascular disease and statins (inhibitors of a key enzyme of cholesterol synthesis, 3-hydroxymethyl glutaryl coenzyme A reductase) are the drugs of choice for decreasing plasma cholesterol. It has been estimated that genetic factors can explain 40%-60% of final cholesterol concentrations and approximately 70% of the efficacy of statin treatment. The gene most often analyzed in the context of statin efficacy is the gene for apolipoprotein E (APOE). This review summarizes evidence of the association between variations in the APOE gene locus and the response of plasma lipids to statin therapy. Although the results are not consistent, carriers of the APOE4 allele seems to be less responsive to statins than carriers of APOE2 and APOE3 alleles. This effect is partially context-dependent (gene-gender interactions; gene-nutrition and gene-smoking interactions have not yet been studied) and the absolute differences vary between different population groups.     

Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same?

The 3-hydroxy-3-methyl coenzyme A (HMG-CoA) reductase inhibitors or statins, specifically inhibit the enzyme HMG-CoA in the liver, thereby inhibiting the rate limiting step in cholesterol biosynthesis and so reducing plasma cholesterol levels. Numerous studies have consistently demonstrated that cholesterol lowering with statin therapy reduces morbidity and mortality from coronary heart disease, whilst recent evidence has demonstrated that benefits of statin therapy may also extend into stroke prevention. Since hypercholesterolaemia is a chronic condition, the long-term safety and tolerability of these agents is an important issue. Numerous large-scale clinical trials have consistently demonstrated a positive safety and tolerability profile for statins. Hepatic, renal and muscular systems are rarely affected during statin therapy, with adverse reactions involving skeletal muscle being the most common, ranging from mild myopathy to myositis and occasionally to rhabdomyolysis and death. Postmarketing data supports the positive safety and tolerability profile of statins, with an overall adverse event frequency of less than 0.5% and a myotoxicity event rate of less than 0.1%. The recent withdrawal of cerivastatin from the world market due to deaths from rhabdomyolysis has, however, focused attention on the risk of adverse events and in particular myotoxicity associated with statins. Indeed, initial clinical trial data supports postmarketing data, demonstrating a higher incidence of myotoxicity associated with cerivastatin, particularly when used in combination with fibrates. The potential mechanisms underlying statin-induced myotoxicity are complex with no clear consensus of opinion. Candidate mechanisms include intracellular depletion of essential metabolites and destabilisation of cell membranes, resulting in increased cytotoxicity. Cytochrome P450 3A4 is the main isoenzyme involved in statin metabolism. Reduced activity of this enzyme due to either reduced expression or inhibition by other drugs prescribed concomitantly such as cyclosporin or itraconazole may increase drug bioavailability and the risk of myotoxicity. Such factors may partly account for the interindividual variability in susceptibility to statin-induced myotoxicity, although other as of yet unclarified, genetic factors may also be involved. The risk of rhabdomyolysis is increased with combination fibrate-statin therapy, with initial evidence suggesting that gemfibrozil-statin combination may particularly increase the risk of myotoxicity, with pharmacodynamic as well as pharmacokinetic mechanisms being involved.     

Statins in acute coronary syndromes

The development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) has been a very significant development in the management of coronary artery disease. Large prospective clinical trials have provided unequivocal evidence that cholesterol lowering therapy with statins reduces all-cause mortality in patients with coronary artery disease. There is now accumulating data indicating that statin treatment should be initiated early after an acute coronary syndrome. This body of evidence is based on large databases in which investigators compared outcomes among patients taking statins with those patients who were not prescribed cholesterol lowering therapy. Prospective, randomized, clinical trials also indicate that early statin therapy reduces recurrent ischemia. Finally, studies examining long-term compliance with statin therapy suggest increased adherence to therapy when statins are prescribed during the initial hospitalization for an acute coronary syndrome. In tandem with these clinical observations, there is a large body of scientific data that highlights many important cellular and molecular mechanisms through which statins may confer early benefit. These effects involve relatively rapid improvement in endothelial function, antiischemic, antithrombotic and antiinflammatory actions of statins.     

Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials

Ample evidence exists in support of the potent anti-inflammatory properties of statins. In cell studies and animal models statins exert beneficial cardiovascular effects. By inhibiting intracellular isoprenoids formation, statins suppress vascular and myocardial inflammation, favorably modulate vascular and myocardial redox state and improve nitric oxide bioavailability. Randomized clinical trials have demonstrated that further to their lipid lowering effects, statins are useful in the primary and secondary prevention of coronary heart disease (CHD) due to their anti-inflammatory potential. The landmark JUPITER trial suggested that in subjects without CHD, suppression of low-grade inflammation by statins improves clinical outcome. However, recent trials have failed to document any clinical benefit with statins in high risk groups, such in heart failure or chronic kidney disease patients. In this review, we aim to summarize the existing evidence on statins as an anti-inflammatory agent in atherogenesis. We describe the molecular mechanisms responsible for the antiinflammatory effects of statins, as well as clinical data on the non lipid-lowering, anti-inflammatory effects of statins on cardiovascular outcomes. Lastly, the controversy of the recent large randomized clinical trials and the issue of statin withdrawal are also discussed.     

不同他汀类药物治疗早发冠心病急性心肌梗死患者的近期临床随访研究

目的本文主要分析不同他汀类药物在治疗早发冠心病急性心肌梗死患者中近期的临床疗效,为今后临床能合理的使用他汀类药物提供一个有效的依据。方法随机选取2010年7月至2011年7月这一时期来我院就诊的80例早发冠心病急性心肌梗死患者作为本次研究的对象,并将其随机分为数目相等的A、B两组,A组患者采取瑞舒伐他汀10mg/d进行治疗,而B组采用阿托伐他汀20mg/d进行治疗。最后比较两组治疗后空腹血糖、血脂及超敏C-反应蛋白,检测内皮功能(FMD)及心脏功能(LVEF)等结果。结果 A、B两组患者在治疗6个月后,两组患者的总胆固醇(TC)低密度脂蛋白胆固醇(LDL-C)及hs-CRP水平间的差异具有显著性有统计学意义(P<0.05),两组患者治疗6个月期间预后都很好,不存在患者死亡的现象。结论本次研究结果显示,瑞舒伐他汀和阿托伐他汀在治疗早发冠心病急性心肌梗死患者中近期的疗效相似,二者都可以通过降低患者体内的血脂、减轻炎性反应以及改善内皮功能等方面来协助改善早发冠心病急性心肌梗死患者的预后从而取得良好的近期疗效。     

Non-lipid effects of statins: emerging new indications

Statins are beneficial both in the primary and secondary prevention of atherosclerotic vascular disease and acute events in a broad spectrum of patient subgroups. However, the observed clinical benefit with statin therapy is much greater than expected through the reduction of cholesterol levels alone. Clinical and experimental studies suggested that several antiatherosclerotic effects other than lipid lowering also contribute to the observed benefit of statin therapy. These 'pleiotropic effects' include improvement of endothelial function, antitrombotic actions, plaque stabilization, reduction of the vascular inflammatory process and anti-oxidation. Statins may also exhibit a wide variety of actions other than antiatherosclerotic effects. Recent observational data documented a potential association between statin use and improvement of fracture risk in osteoporosis. Despite the lack of randomized trials, epidemiological and limited clinical data suggested that statins might retard the pathogenesis of Alzheimer's disease. Observational data indicated that the progression of aortic stenosis and valvular calcification might be delayed in statin users. In addition, the deterioration of congestive heart failure may be delayed with statins via anti-inflammatory, vascular endothelial and antiatherosclerotic actions. Furthermore, preliminary clinical studies suggested that, by their immunosuppressive actions statins might reduce the incidence of rejection following organ transplantation. Currently, there is not enough evidence to prescribe therapy for such patients. However, ongoing studies are exploring the role of statin therapy for these new indications. This review will discuss several non-lipid effects of statin therapy currently under investigation.