Pitavastatin: efficacy and safety in intensive lipid lowering

Pitavastatin, (+)-monocalcium bis(3R,5S,6E)-7-(2-cyclopropyl-4-[4-fluorophenyl]-3-quinolyl-3,5-dihydroxy-6-heptenoate), is a totally synthetic statin developed in Japan with a molecular weight of 880.98. Pitavastatin achieves its potent pharmacologic action by strongly binding and inhibiting the active site of 3-hydroxy-3-methyl-glutaryl-CoA reductase, and has potent low-density lipoprotein-cholesterol-lowering effects similar to atorvastatin and rosuvastatin. One other characteristic of the agent is that pitavastatin is minimally metabolized by the cytochrome P450 isozymes; it undergoes glucuronidation and is converted to the inactive lactone form, and, therefore, the incidence of any drug interactions is reduced. Due to the promising results observed in clinical trials, it has the potential to be an excellent addition to the worldwide lipid management market.     

匹伐他汀对急性冠状动脉综合征疗效及安全性研究

目的观察急性冠状动脉综合征（acute coronary syndrome,ACS）患者接受匹伐他汀应治疗的安全性及疗效。方法 60例ACS患者,含20例非ST段抬高心肌梗死（NSTEMI）服用1周匹伐他汀（力清之,4 mg/次,1次/d）,观察其调脂疗效。同时比较NSTEMI患者服用匹伐他汀与阿托代他汀后PCI手术即刻疗效。结果 60例患者服用1周匹伐他汀,胆固醇（total cholesterol,TC）及低密度脂蛋白（low density lipoprotein,LDL）明显降低,且无肝肾功能及肌肉的损害;NSTEMI患者服用匹伐他汀与阿托代他汀PCI术后近期效果无显著差异,且匹伐他汀临床副作用明显小于阿托代他汀。结论对于ACS患者,无论是否行PCI手术治疗,服用1周匹伐他汀（4 mg/次,1次/d）强化治疗是安全有效的。     

Safety and Efficacy of Pitavastatin in Patients With Impaired Fasting Glucose and Hyperlipidemia: A Randomized,Open-labeled,Multicentered, Phase IV Study

PurposeAlthough the role of high-intensity lipid-lowering therapy in cardiovascular protection has broadened, concerns still exist about new-onset diabetes mellitus (NODM), especially in vulnerable patients. This study aimed to compare the effect of high-dose (4 mg/d) and usual dose (2 mg/d) pitavastatin on glucose metabolism in patients with hyperlipidemia and impaired fasting glucose (IFG).MethodsIn this 12-month study, glucose tolerance and lipid-lowering efficacy of high-dose pitavastatin (4 mg [study group]) was compared with that of usual dose pitavastatin (2 mg [control group]) in patients with hyperlipidemia and IFG. The primary end point was the change of glycosylated hemoglobin (HbA_1c) after 24 weeks of treatment. The secondary end points were as follows: (1) NODM within 1 year after treatment, (2) change of lipid parameters, (3) changes of adiponectin, and (4) change of blood glucose and insulin levels.FindingsOf the total 417 patients screened, 313 patients with hypercholesterolemia and IFG were randomly assigned into groups. The mean (SD) change in HbA_1c was 0.06% (0.20%) in the study group and 0.03% (0.22%) in the control group (P = 0.27). Within 1 year, 27 patients (12.3%) developed NODM, including 12 (10.6%) of 113 patients in the study group and 15 (14.2%) of 106 in the control group (P = 0.43). The study group had a significantly higher reduction of total cholesterol and LDL-C levels and a higher increase in apolipoprotein A1/apolipoprotein B ratio (0.68 [0.40] vs 0.51 [0.35], P < 0.01).ImplicationsThe high-dose pitavastatin therapy did not aggravate glucose metabolism compared with the usual dose therapy. Moreover, it had a better effect on cholesterol-lowering and apolipoprotein distribution in the patients with hyperlipidemia and IFG.     

The role of OATP1B1 and BCRP in pharmacokinetics and DDI of novel statins

The aim of this review is to provide useful information not only for studying the effect of OATP1B1 and/or BCRP gene mutation on pharmacokinetics of novle statins of pitavastatin and rosuvastatin but also for studying drug-drug interactions (DDI) between the novle statins and other substrates of OATP1B1 and/or BCRP. Intra- and inter-ethnic differences in pharmacokinetic profiles of clinically relevant drugs are important issues reported in many papers not only for scenes of appropriate drug used in clinical settings but also for those of the drug development. Pharmacogenomics is extremely useful for understanding these racial differences. Recent pharmacogenetics study have disclosed important roles of drug transporters in the pharmacokinetic (PK) profiles of some clinically relevant drugs. In this presentation, we introduce single nucleotide polymorphisms (SNPs) of OATP1B1 and BCRP and review the contribution of genetic polymorphisms of the transporters to the pharmacokinetics of dual substrates as pitavastatin and rosuvastatin from recent study. At the same time, the DDIs between pitavastatin or rosuvastatin and other drug have been extensively concerned because of inhibiting OATP1B1-mediated hepatic uptake or BCRP-mediated hepatic efflux of pitavastatin and rosuvastatin. This review summarized the current studies about the role of OATP1B1 and BCRP in DDIs between pitavastatin or rosuvastatin and other clinically relevant drugs. The role of OATP1B1 and BCRP gene mutation can affect the PK profiles of pitavastatin and rosuvastatin. The DDIs between the novle statins and other substrates of OATP1B1 or BCRP may occur and cause change in the pharmacokinetic of the novle statins.     

刺葡萄籽油对匹伐他汀健康人体药动学的影响

 目的研究健康志愿者服用刺葡萄籽油后对匹伐他汀药动学的影响。方法用自身前后对照随机交叉的试验方法,筛选8名健康受试者,男女各半,一组连续7d口服匹伐他汀钙片,另一组连续7d同时口服刺葡萄籽油软胶囊和匹伐他汀钙片,洗脱2周后,两组交叉服用药物。用HPLC-MS/MS测定血浆匹伐他汀的浓度,用DAS2.0软件计算药动学参数。结果联用刺葡萄籽油软胶囊和匹伐他汀钙片与单用匹伐他汀钙片的主要药动学参数:AUC分别为(152.9±66.26)和(135.556±76.133)μg·h·L^-1,ρ_max分别为(33.51±15.121)和(33.109±21.324)μg·L^-1,t_max分别为(0.688±0.259)和(0.875±0.443)h,t_1/2分别为(15.76±12.118)和(11.753±6.892)h,CL分别为(15.4±1.764)和(17.106±5.027)L·h^-1。结论在健康受试者体内连续服药时,除半衰期延长外,刺葡萄籽油对匹伐他汀的其他主要药动学参数未产生显著性影响。     

Lipid peroxidation-induced VEGF expression in the skin of KKAy obese mice

Obesity is known to be associated with a number of effects on skin physiology. KKA(y) obese mouse is a model of type 2 diabetes characterized by systemic oxidative stress because of severe obesity, hypertriglyceridaemia, hyperglycaemia and hyperinsulinaemia. We investigated lipid peroxidation and vascular endothelial growth factor (VEGF) expression in the skin of KKA(y) obese mice. We also investigated the effect of lipid peroxidation derivatives on VEGF production and proliferation in human epidermal keratinocyte cell line (HaCaT). The lipid peroxidation level in the mouse skin tissue was determined by measuring the levels of thiobarbituric acid-reactive substances. The levels of VEGF expression, p44/p42 mitogen-activated protein kinase (MAPK) activation and CD36 expression were analysed by Western blot. Their localization was examined by immunofluorescence. For the in vitro experiments, an enzyme-linked immunosorbent assay was utilized to measure VEGF secretion in the medium. In vitro experiments demonstrated that lipid peroxidation derivatives increased VEGF production in HaCaT cells, which was blocked by a p44/p42 MAPK inhibitor and anti-CD36 antibody. We observed increased levels of lipid peroxidation derivatives, p44/p42 MAPK activation and VEGF expression in the skin of KKA(y) obese mice. Notably, pitavastatin, an inhibitor of competitive 3-hydroxy-3-methylglutaryl coenzyme A reductase, suppressed all of these processes. Our results suggest that lipid peroxidation induces VEGF expression via CD36 and p44/p42 MAPK pathway in the skin of obese mice.     

匹伐他汀钙有关物质的合成

目的：为控制匹伐他汀钙的质量,合成原药中3种有关物质。方法：以（8）为原料经不对称羟醛缩合、反立体选择性还原得到了有关物质（3）和有关物质（4）。匹伐他汀钙经DDQ氧化得到了有关物质（7）。结果与结论：合成了匹伐他汀钙原药中3种有关物质,并经1H-NMR和MS等确证结构,纯度经HPLC 检测均在96%以上,可以作为匹伐他汀钙原药质量控制的对照品。     

Lack of effect of genetic polymorphisms of SLCO1B1 on the lipid-lowering response to pitavastatin in Chinese patients

Aim:

To investigate the SLCO1B1 388A>G and 521T>C polymorphisms in hyperlipidemia patients and evaluate the effect of the two polymorphisms on the lipid-lowering efficacy of pitavastatin.

Methods:

The functional polymorphisms of SLCO1B1 (388A>G and 521T>C) were genotyped in 140 Chinese patients with essential hyperlipidemia using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and one-step tetra-primers ARMS-PCR. Eighty-five patients were enrolled in the clinical trial and given 2 mg of pitavastatin daily for 8 weeks. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) serum levels were measured at baseline, after 4 weeks and after 8 weeks of treatment.

Results:

The allele frequencies of SLCO1B1 388A>G and 521T>C in essential hyperlipidemia patients were 71.1% and 11.1%, respectively. The 4- and 8-week treatment with pitavastatin significantly reduced TC, TG, and LDL levels, but there was no statistical difference among patients with wild type, SLCO1B1 388A>G or SLCO1B1 521T>C in the lipid-lowering efficacy of pitavastatin.

Conclusion:

The present study found that the allele frequencies of SLCO1B1 388A>G and 521T>C in Chinese patients with essential hyperlipidemia are comparable to those in healthy Chinese population. SLCO1B1 388A>G and 521T>C do not affect the lipid-lowering efficacy of pitavastatin.     

匹伐他汀钙片治疗高胆固醇血症的有效性和安全性研究

目的 评价匹伐他汀钙片治疗高胆固醇血症的有效性和安全性.方法 360例高胆固醇血症患者接1∶1∶1比例随机分为匹伐他汀钙片l mg组、2 rng组和阿托伐他汀钙片10 mg组,经4周筛选期后,符合入选标准的患者接受l mg/2 mg匹伐他汀钙片或10 mg阿托伐他汀钙片治疗(一日1次,口服),治疗8周,观察各组治疗前后血清低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、总胆固醇(TC)和甘油三酯(TG)变化情况.结果 治疗8周后各组LDL-C下降显著,分别为-30.06％、-35.04％和-34.34％,组间差异无统计学意义.匹伐他汀钙片2 mg组降低LDL-C的疗效非劣于阿托伐他汀钙片组,匹伐他汀钙片1 mg组降低LDL-C的疗效劣于阿托伐他汀钙片组.治疗4、8周后匹伐他汀钙降低TC、HDL-C和TG作用与阿托伐他汀钙比较差异无统计学意义.结论 匹伐他汀钙片治疗高胆固醇血症安全有效.     

匹伐他汀对高血压患者高敏C反应蛋白水平的影响

目的观察口服匹伐他汀对高血压患者血清高敏C反应蛋白(hs-CRP)水平的影响。方法 60例高血压患者,随机分为对照组和匹伐他汀组,每组30例,分别单服用硝苯地平30 mg.d-1和服用匹伐他汀2 mg.d-1及硝苯地平30 mg.d-1,疗程为3 mo。观察治疗前和治疗3 mo后血压、血脂、血清hs-CRP和补体的变化。结果 2组患者用药3 mo后血压均明显下降(P<0.01),匹伐他汀组与对照组相比血压下降幅度有增大趋势,但无显著差异(P>0.05)。对照组患者治疗前后血脂各项指标无显著变化(P>0.05),匹伐他汀组治疗3 mo后总胆固醇、低密度脂蛋白胆固醇和三酰甘油水平较治疗前均明显降低(P<0.01),与对照组比较有显著差异(P<0.01)。2组治疗前后补体C3、C4水平无显著差异。治疗3 mo后对照组hs-CRP水平与治疗前相比无显著变化(P>0.05),匹伐他汀组hs-CRP水平较治疗前显著降低(P<0.05),与对照组相比差异显著(P<0.05)。结论匹伐他汀可以在调脂的同时降低高血压患者血清高敏C反应蛋白的水平。