国产匹伐他汀钙片调脂疗效及安全性的试验研究
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摘要
目的:许多临床研究表明,用他汀类药物降低患者的血浆胆固醇水平可以预防并降低冠心病的风险及其总死亡率。这种抗动脉粥样硬化作用与他汀类药物降低低密度脂蛋白胆固醇(LDL-C)的水平有关。因此,各种临床指南都明确将降低LDL-C水平作为降脂治疗的主要目标。尽管给予他汀类药物治疗,仍有许多患者在一级和二级预防中未能达到降低LDL-C的目标。这表明现有的调脂药物仍不能满足临床的需求,因此,需要更强效更安全的他汀类药物使血脂达标。近期开发的新型他汀类药物匹伐他汀钙(Pitavastatin Calcium),因其良好的降胆固醇作用而被称为“超级他汀类药物”。国外临床研究表明,匹伐他汀钙具有良好的调脂作用和耐受性,与同类调脂药物相比,其在降低总胆固醇(TC)、LDL-C和甘油三酯(TG),升高高密度脂蛋白胆固醇(HDL-C)的作用优于已上市的其它他汀类药物,而国内尚未见相关报道。本课题旨在评价国产匹伐他汀钙片治疗原发性高胆固醇血症的临床疗效和安全性,并与辛伐他汀片进行比较,为今后调脂治疗提供一个更佳选择。
方法:
研究对象选择我院2007年1月至2007年8月来自门诊的原发性高胆固醇血症患者36例。其中男性19例,女性17例。均符合:(1)年龄18-75岁,(2)空腹血清TC>5.72mmol/ L(220mg/dl)和空腹血清LDL–C > 3.64mmol / L(140mg/dl),空腹血清TG<4.52mmol/L(400mg/dl),(3)停用非试验所用的其它调脂药物及其它对试验结果有影响的药物,(4)均签署知情同意书。须排除:(1)体重指数(BMI)<19kg/m2;(2) 6个月内新发生的急性冠脉综合征或脑卒中;(3)血压控制不良(SBP≥180mmHg和/或DBP≥110mmHg);(4)严重心律失常患者(频发室早、室速、Ⅱ度或Ⅲ度房室传导阻滞等);(5)心功能NYHAⅢ级以上;(6)肝功能AST和/或ALT≥正常上限值2倍;(7)血清Cr>正常上限值;(8)患有肌肉疾病或血清肌酸激酶(CK)≥正常上限值2倍;(9) 1型糖尿病或病情不稳定的2型糖尿病患者(有低血糖发作或空腹血糖≥9.99mmol/L)。
研究方法采用随机、双盲、双模拟、阳性药平行组间对照研究的方法,所有入选患者首先给予口服安慰剂(匹伐他汀钙模拟分散片或辛伐他汀模拟片),每日1次,每次2片,连续服用4w。筛选期结束后,将筛选合格的受试者随机分为三组:匹伐他汀钙片2mg组(A组,n=12)、辛伐他汀20mg组(B组,n=12)、匹伐他汀钙片1mg组(C组,n=12),三组患者均每晚服药一次,连续服药8w。分别于服药前-4w、0w和服药后4w、8w测定血清TC、LDL–C、HDL–C、TG、血糖(GLU)、CK和肝肾功能,并记录患者服药期间的不良反应。
统计学处理所有数据经统计软件SPSS13.0处理,计量资料以均数士标准差表示,采用重复测量资料方差分析,组间两两比较采用LSD法。计数资料采用X2检验,Fisher精确概率法。P<0.05为差异有显著性。
结果:
1 36例患者按照试验方案要求完成试验。
2服药后4w和8w时,与治疗前(0w)比较,三组患者血清TC和LDL-C水平均较0w明显下降(均P<0.05),TG和HDL-C较0w无统计学差异(均P>0.05)。服药后8w与4w比较,血清TC、LDL-C、TG和HDL-C水平均无显著差异(均P>0.05)。
3服药前(0w)三组患者血清TC、LDL-C、HDL-C、TG水平均无显著差异(均P>0.05)。服药后4w、8w,A组、B组血清LDL-C水平较C组显著降低(均P<0.05),A组与B比较,血清LDL-C水平无显著性差异(P>0.05)。三组间同期比较,血清TC、TG和HDL-C水平无显著性差异(均P>0.05)。
4按照2007年《中国成人血脂异常防治指南》LDL-C达标标准,A组、B组及C组在服药4w后血清LDL–C水平达标率分别为83.3%、83.3%和75.0%;服药8w后血清LDL–C水平达标率分别为91.7%、83.3%和75.0%,同期组间比较无显著性差异(均P>0.05)。
5三组患者不良反应发生率无统计学差异(P>0.05)。
结论:匹伐他汀2mg组及匹伐他汀1mg组均能明显降低血清TC、LDL-C水平。在降低LDL-C方面,匹伐他汀2mg组优于匹伐他汀1mg组。与辛伐他汀组相比,匹伐他汀组LDL-C达标率较高。匹伐他汀组与辛伐他汀组的不良反应发生率无明显差异。国产匹伐他汀的疗效确切,不良反应少见,是值得临床推广的调脂药。
Objective: Many clinical trials have demonstrated that statins, 3-Hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, can prevent and reduce coronary heart disease and total mortality risk by lowering serum cholesterol level. The anti-atherosclerotic effect of statins on serum lipoproteins can be explained largely by the reduction of serum low-density lipoprotein cholesterol ( LDL-C ) levels. Therefore, various clinical practice guidelines have made lowering serum LDL-C level as the primary target of cholesterol lowering therapy. In spite of statin treatment, there are many patients in primary and secondary prevention who fail to reach the target LDL-C levels. It indicates that lipid–modulating medicine can not meet clinical demands at present. Therefore, more powerful drugs without severe adverse are thought to be needed. More recently,the newly developed pitavastatin calcium is called superstatin for well cholesterol-lowering. Abroad clinical trials have showed that pitavastatin calcium is well-tolerated and effective in lipid–modulating and more efficacious than other currently available statins in reducing TC, TG , LDL-C and increasing HDL-C. However,there is no relative report at home. This study was designed to assess the lipids-regulating effect and the safety of domestic pitavastatin calcium and compare it with simvastatin in order to provide a potentially better therapertic choice for lipid-modulating therapy.
Methods:
Patient’s selection: The study group comprised of 36 patients who were suffering from primary hypercholesterolemia in outpatient service of the General Hospital of HeBei Province from January 2007 to August 2007, including 19 male patients and 17 female patients. Eligible patients were between the ages of eighteen and seventy-five years with serum TC level>5.72mmol/L(220mg/dl), serum LDL cholesterol level LDL–C>3.64mmol/L(140mg/dl) and serum TG level<4.52mmol/L(400mg/dl).Study participants could not concurrently take drugs known to affect lipid levels or interact with the study results. Written informed consent to participate in the study was obtained from each patient ahead of time. The following exclusion criteria were required for patients enrollment:①BMI<19kg/m2,②a history of acute conoary syndrome or cerebral apoplexy in recent 6 months,③uncontrolled hypertension(systolic blood pressure≥180mmHg or diastolic blood pressure≥110mmHg),④serious arythmia such as frequent ventricular premature beats, frequent ventricular tachycardia, second degree A-V block or third degree A-V block,⑤Patients had heart failure of New York Heart Association (NYHA) class III or IV,⑥AST and/or ALT≥2 times upper limit of normal,⑦ serum Cr>upper limit of normal,⑧myopathy or serum CK≥2 times upper limit of normal,⑨type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (glycopenia or fasting blood sugar≥9.99mmol/L ).
We adopted randomized double-blind double-imitated parallel controlled design. All patients should firstly take 2 tablets placebo (pitavastatin calcium–matched placebo or simvastatin-matched placebo) once a day for 4 weeks. After run-in period, 36 patients qualified for the test were randomly divided into 3 groups. There were 12 patients in group A, B and C(A= pitavastatin 2mg, B= simvastatin 20mg, C=pitavastatin 1mg).They took medicine orally each night for 8 weeks continuously. TC, LDL-C, HDL-C, TG, Glucose, creatine kinase,hepatic function and renal function were measured regularly at week -4, 0, before study entry and at week 4, 8, during the study period. Chief complaints were recorded during the follow-up.
Statistics analysis: All data were managed by SPSS 13.0. Measurement data were expressed as mean士standard deviation. Statistical methods include repeated measurements ANOVA. LSD was used to compare the two groups. Chi-square test and Fisher exact test were used for analysis of categorical data.P value <0.05 was considered statistically significant.
Results: 1 36 patients finished the trial altogether.
2 After 4, 8 weeks’treatment, serum TC, LDL-C were significantly reduced striking (P<0.05) and serum TG was decreased (P>0.05), serum HDL-C was increased (P>0.05) compared with baseline (0week) among three groups. There was no more significant at the 8 week than at the 4 week to three groups in serum TC, LDL-C, TG and HDL-C level (P>0.05).
3 TC, LDL-C, HDL-C, TG did not differ significantly among three groups at 0 week (P>0.05). After 4, 8 weeks’treatment, group A and B yielded significantly reduction from 0 week in serum LDL-C compared with group C respectively (P<0.05). There was no significant difference between group A and B in serum LDL-C level after 4, 8 weeks’treatment. The data also showed there was no significant difference in serum TC, TG and HDL-C level among the three groups after 4, 8 weeks’treatment (P>0.05).
4 According to the LDL-C goals of therapy recommended by《China guideline for prevention and treatment of adult dyslipidemia》(2007),cases attaining the goals in group A, B and C were 83.3%, 83.3%, 75.0% at the 4 week respectively and 91.7%, 83.3%, 75.0% at the 8 week respectively. There were no significant difference in reaching LDL-C target among the there groups at 4 and 8 week(P>0.05).
5 The incidence of side effects in the three groups was similar(P>0.05).
Conclusions: Pitavastatin 2mg and 1mg can significantly decrease LDL-C, TC level. In decreasing LDL-C, pitavastatin 2mg was more effective than pitavastatin 1mg. The LDL-C goal achievement rate of pitavastatin was higher than that of simvastatin. The adverse event profile was similar for pitavastatin and simvastatin groups. The clinical effects of pitavastatin was exact and safe, and it was worthy of applying for the clinical treatment.
方法:
研究对象选择我院2007年1月至2007年8月来自门诊的原发性高胆固醇血症患者36例。其中男性19例,女性17例。均符合:(1)年龄18-75岁,(2)空腹血清TC>5.72mmol/ L(220mg/dl)和空腹血清LDL–C > 3.64mmol / L(140mg/dl),空腹血清TG<4.52mmol/L(400mg/dl),(3)停用非试验所用的其它调脂药物及其它对试验结果有影响的药物,(4)均签署知情同意书。须排除:(1)体重指数(BMI)<19kg/m2;(2) 6个月内新发生的急性冠脉综合征或脑卒中;(3)血压控制不良(SBP≥180mmHg和/或DBP≥110mmHg);(4)严重心律失常患者(频发室早、室速、Ⅱ度或Ⅲ度房室传导阻滞等);(5)心功能NYHAⅢ级以上;(6)肝功能AST和/或ALT≥正常上限值2倍;(7)血清Cr>正常上限值;(8)患有肌肉疾病或血清肌酸激酶(CK)≥正常上限值2倍;(9) 1型糖尿病或病情不稳定的2型糖尿病患者(有低血糖发作或空腹血糖≥9.99mmol/L)。
研究方法采用随机、双盲、双模拟、阳性药平行组间对照研究的方法,所有入选患者首先给予口服安慰剂(匹伐他汀钙模拟分散片或辛伐他汀模拟片),每日1次,每次2片,连续服用4w。筛选期结束后,将筛选合格的受试者随机分为三组:匹伐他汀钙片2mg组(A组,n=12)、辛伐他汀20mg组(B组,n=12)、匹伐他汀钙片1mg组(C组,n=12),三组患者均每晚服药一次,连续服药8w。分别于服药前-4w、0w和服药后4w、8w测定血清TC、LDL–C、HDL–C、TG、血糖(GLU)、CK和肝肾功能,并记录患者服药期间的不良反应。
统计学处理所有数据经统计软件SPSS13.0处理,计量资料以均数士标准差表示,采用重复测量资料方差分析,组间两两比较采用LSD法。计数资料采用X2检验,Fisher精确概率法。P<0.05为差异有显著性。
结果:
1 36例患者按照试验方案要求完成试验。
2服药后4w和8w时,与治疗前(0w)比较,三组患者血清TC和LDL-C水平均较0w明显下降(均P<0.05),TG和HDL-C较0w无统计学差异(均P>0.05)。服药后8w与4w比较,血清TC、LDL-C、TG和HDL-C水平均无显著差异(均P>0.05)。
3服药前(0w)三组患者血清TC、LDL-C、HDL-C、TG水平均无显著差异(均P>0.05)。服药后4w、8w,A组、B组血清LDL-C水平较C组显著降低(均P<0.05),A组与B比较,血清LDL-C水平无显著性差异(P>0.05)。三组间同期比较,血清TC、TG和HDL-C水平无显著性差异(均P>0.05)。
4按照2007年《中国成人血脂异常防治指南》LDL-C达标标准,A组、B组及C组在服药4w后血清LDL–C水平达标率分别为83.3%、83.3%和75.0%;服药8w后血清LDL–C水平达标率分别为91.7%、83.3%和75.0%,同期组间比较无显著性差异(均P>0.05)。
5三组患者不良反应发生率无统计学差异(P>0.05)。
结论:匹伐他汀2mg组及匹伐他汀1mg组均能明显降低血清TC、LDL-C水平。在降低LDL-C方面,匹伐他汀2mg组优于匹伐他汀1mg组。与辛伐他汀组相比,匹伐他汀组LDL-C达标率较高。匹伐他汀组与辛伐他汀组的不良反应发生率无明显差异。国产匹伐他汀的疗效确切,不良反应少见,是值得临床推广的调脂药。
Objective: Many clinical trials have demonstrated that statins, 3-Hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, can prevent and reduce coronary heart disease and total mortality risk by lowering serum cholesterol level. The anti-atherosclerotic effect of statins on serum lipoproteins can be explained largely by the reduction of serum low-density lipoprotein cholesterol ( LDL-C ) levels. Therefore, various clinical practice guidelines have made lowering serum LDL-C level as the primary target of cholesterol lowering therapy. In spite of statin treatment, there are many patients in primary and secondary prevention who fail to reach the target LDL-C levels. It indicates that lipid–modulating medicine can not meet clinical demands at present. Therefore, more powerful drugs without severe adverse are thought to be needed. More recently,the newly developed pitavastatin calcium is called superstatin for well cholesterol-lowering. Abroad clinical trials have showed that pitavastatin calcium is well-tolerated and effective in lipid–modulating and more efficacious than other currently available statins in reducing TC, TG , LDL-C and increasing HDL-C. However,there is no relative report at home. This study was designed to assess the lipids-regulating effect and the safety of domestic pitavastatin calcium and compare it with simvastatin in order to provide a potentially better therapertic choice for lipid-modulating therapy.
Methods:
Patient’s selection: The study group comprised of 36 patients who were suffering from primary hypercholesterolemia in outpatient service of the General Hospital of HeBei Province from January 2007 to August 2007, including 19 male patients and 17 female patients. Eligible patients were between the ages of eighteen and seventy-five years with serum TC level>5.72mmol/L(220mg/dl), serum LDL cholesterol level LDL–C>3.64mmol/L(140mg/dl) and serum TG level<4.52mmol/L(400mg/dl).Study participants could not concurrently take drugs known to affect lipid levels or interact with the study results. Written informed consent to participate in the study was obtained from each patient ahead of time. The following exclusion criteria were required for patients enrollment:①BMI<19kg/m2,②a history of acute conoary syndrome or cerebral apoplexy in recent 6 months,③uncontrolled hypertension(systolic blood pressure≥180mmHg or diastolic blood pressure≥110mmHg),④serious arythmia such as frequent ventricular premature beats, frequent ventricular tachycardia, second degree A-V block or third degree A-V block,⑤Patients had heart failure of New York Heart Association (NYHA) class III or IV,⑥AST and/or ALT≥2 times upper limit of normal,⑦ serum Cr>upper limit of normal,⑧myopathy or serum CK≥2 times upper limit of normal,⑨type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (glycopenia or fasting blood sugar≥9.99mmol/L ).
We adopted randomized double-blind double-imitated parallel controlled design. All patients should firstly take 2 tablets placebo (pitavastatin calcium–matched placebo or simvastatin-matched placebo) once a day for 4 weeks. After run-in period, 36 patients qualified for the test were randomly divided into 3 groups. There were 12 patients in group A, B and C(A= pitavastatin 2mg, B= simvastatin 20mg, C=pitavastatin 1mg).They took medicine orally each night for 8 weeks continuously. TC, LDL-C, HDL-C, TG, Glucose, creatine kinase,hepatic function and renal function were measured regularly at week -4, 0, before study entry and at week 4, 8, during the study period. Chief complaints were recorded during the follow-up.
Statistics analysis: All data were managed by SPSS 13.0. Measurement data were expressed as mean士standard deviation. Statistical methods include repeated measurements ANOVA. LSD was used to compare the two groups. Chi-square test and Fisher exact test were used for analysis of categorical data.P value <0.05 was considered statistically significant.
Results: 1 36 patients finished the trial altogether.
2 After 4, 8 weeks’treatment, serum TC, LDL-C were significantly reduced striking (P<0.05) and serum TG was decreased (P>0.05), serum HDL-C was increased (P>0.05) compared with baseline (0week) among three groups. There was no more significant at the 8 week than at the 4 week to three groups in serum TC, LDL-C, TG and HDL-C level (P>0.05).
3 TC, LDL-C, HDL-C, TG did not differ significantly among three groups at 0 week (P>0.05). After 4, 8 weeks’treatment, group A and B yielded significantly reduction from 0 week in serum LDL-C compared with group C respectively (P<0.05). There was no significant difference between group A and B in serum LDL-C level after 4, 8 weeks’treatment. The data also showed there was no significant difference in serum TC, TG and HDL-C level among the three groups after 4, 8 weeks’treatment (P>0.05).
4 According to the LDL-C goals of therapy recommended by《China guideline for prevention and treatment of adult dyslipidemia》(2007),cases attaining the goals in group A, B and C were 83.3%, 83.3%, 75.0% at the 4 week respectively and 91.7%, 83.3%, 75.0% at the 8 week respectively. There were no significant difference in reaching LDL-C target among the there groups at 4 and 8 week(P>0.05).
5 The incidence of side effects in the three groups was similar(P>0.05).
Conclusions: Pitavastatin 2mg and 1mg can significantly decrease LDL-C, TC level. In decreasing LDL-C, pitavastatin 2mg was more effective than pitavastatin 1mg. The LDL-C goal achievement rate of pitavastatin was higher than that of simvastatin. The adverse event profile was similar for pitavastatin and simvastatin groups. The clinical effects of pitavastatin was exact and safe, and it was worthy of applying for the clinical treatment.
引文
1 Stein, Evan A, Managing dyslipidemia in the high-risk patient. Am J Cardiol, 2002, 89:50～57
2 王钟林.血脂与心血管病的流行病学研究.实用老年医学,1998, 12:201～202
3 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet, 1994, 344:1383～1389
4 Sacks FM, Pteffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med, 1996, 335:1001～1009
5 Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet, 2002, 360:1623～1630
6 Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS (Air Force/Texas Coronary Atheroscl -erosis Pre-vention Study)JAMA, 1998, 279: 1615～1662
7 Heart Protection Study Collaborative Group. MRC/BHFHeart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals:a randomized placebo-controlled trial. Lancet, 2002, 360:7～22
8 Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. N Engl J Med, 1998, 339:1349～1357
9 Schwartz G, Ezekowitz M, Olsson A, et al. Effect of atrovastatin on early recurrent ischemic events in acute coronary syndromes.The MIRACL study a randomized controlled trial. JAMA, 2001, 285:1711～1718
10 Spencer FA , Allegrone J, Goldberg RJ, et al. Association of statin therapy with outcomes of acute coronary syndrome: The GRACE study.Ann Intern Med, 2004, 140:857～866
11 Saito Y, Yamada N, Teramoto T, et al. Clinical efficacy of pitavastatin,a new 3- hydroxyl -3- methylglutaryl coenzyme a reductase inhibitor,in patients with hyperlipidemia. Dose-finding study using the double-blind, three-group parallel comparison. Arzneimittelforschung, 2002, 52:251～255
12 Kajinami K, Koizumi J, Ueda K, et al. Effects of NK-104,a new hydroxymethylglutarylcoenzyme reductase inhibitor, on low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia.Hokuriku NK-104 Study Group. Am J Cardiol, 2000, 85:178～183
13 Sone H, Takahashi A, Shimano H, et al. HMG-CoA reductase inhibitor decreases small dense low-density lipoprotein and remnant-like particle cholesterol in patients with type-2 diabetes. Life Sci, 2002, 71:2403～2412
14 Nissen SE,Tuzcu EM,Schoenhagen P,et al. Effect of intensive compared with moderate lipid-lowering therapy on progressionof coronary atherosclerosis: a randomized controlled trial. JAMA,2004,291:1071～1080
15 Cannon CP,Braunwald E,Mccabe CH,et al. Pravastatin or atorvastatin Evaluation and Infection Therapy 一Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med, 2004, 350:1495～1504
16 LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med, 2005, 352:1425～1435
17 Grundy SM, Cleeman JI, Merz CN, et al. Implications of recen tclinica ltrials for the National Cholesterol Education Program Adult Treat men Panel Ⅲ Guidelines. Circulation, 2004, 110:227～239
18 Olsson AG, Istad H, Luurila O, on behalf of the Rosuvastatin Investigators Group. Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia. Am Heart J 2002, 144: 1044～1051
19 Brown WV, Bays HE, Hassman DR, for the Rosuvastatin Study Group. Efficacy and safety of rosuvastatin comparedwith pravastatin and simvastatin in patients with hypercholesterolemia: a randomized, double-blind, 52-week trial. Am Heart J 2002, 44:1036～1043
20 Knopp RH. Drug treatment of lipid disorders. N Engl J Med, 1999, 341:498～511
21 Aoki T, Nishimura H, Nakagawa S, et al. Pharmacological profile of a novel synthetic inhibitor of 3– hydroxyl –3- methylglutaryl – coenzyme A reductase. Arzneimittelf -orschung. 1997, 47:904～909
22 Isley WL. Pitavastatin (NK-104), a new HMG-CoA reductase inhibitor.Drugs Today(Barc). 2001, 37:587～589
23 Saito Y, Yamada N, Teramoto T, et al. A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia. Atherosclerosis, 2002, 162:373～379
24 血脂治疗现状调查协作组,我国血脂异常治疗现状的调查.中华心血管病杂志,2001,29:15～17
25 徐成斌.血脂异常的药物治疗新进展.中华心血管病杂志,2001, 29:189～192
26 中国成人血脂异常防治指南制订联合委员会.中国成人血脂异常防治指南.中华心血管病杂志. 2007, 35: 390～413
27 Park S, Kang HJ, Rim SJ, et al. A Randomized, Open-Label Study to Evaluate the Efficacy and Safety of PitavastatinCompared with Simvastatin in Korean Patients with Hypercholesterolemia. Clin Ther, 2005, 27:1074～1082
28 Flores NA. Pitavastatin: Nissan/Kowa Yakuhin/ Novartis/ Sankyo. Curr Opin Invest Drugs, 2002, 3:1334～1341
29 Takayuki Yokoyama, Katsumi Miyauchi, Takeshi Kurata, et al. Inhibitory efficacy of pitavastatin on the early inflammatory response and neointimal thickening in a porcine coronary after stenting. Atherosclerosis, 2004, 174:253～259
30 Saka M, Obata K, Ichihara S, et al. Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. J Cardiovasc Pharmacol, 2006, 47: 770～779
1 Maejima T, Yamazaki H, Aoki T, et al. Effect of pitavastatin on apolipoprotein A-I production in HepG2 cell.Biochem Biophys Res Commun. 2004, 324:835～839
2 Nakagawa S, Tanabe S, Tamaki T, et al. Effect of NK-104,an HMG-CoA reductase inhibitor on lipid metabolism in HepG2 cells. Jpn pharmacol Ther, 2001, 29:1～56
3 Ooyen C, Zecca A, Bersino AM, et al. NK-104, a potent 3- hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor, decreases apolipoprotein B-100 ecretion from HepG2 cells. Atherosclerosis, 1999, 145:87～95
4 Kojima J, Ohshima T, Yoneda M, et al. Effect of biliary excretion on the pharmacokinetics of pitavastatin (NK-104) in dogs. Xenobiol Metab Dispos, 2001, 16:497～502
5 Suzuki H, Yamazaki H, Aoki T, et al. Lipid-lowering and antiatherosclerotic effect of NK-104, a potent 3-hydroxy -3- methylglutaryl coenzyme A reductase inhibitor, in Watanabe heritable hyperlipidemic rabbits. Arzneimittelforschung, 2000, 50:995～1003
6 Suzuki H, Yamazaki H, Aoki T, et al. Hypolipidemic effect of NK-104 and other 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors in guinea pigs. Arzneimittelfo -rschung, 2001, 51:38～45
7 Kajinami K, Takekoshi N, Saito Y. Pitavastatin: efficacyand safety profiles of a novel synthetic HMG-CoAreductase inhibitor.Cardiovasc Drug Rev, 2003, 21:199～215
8 Shibuta T, Kato Y, Akiba T, et al. Single dose toxicity studies of ( + )-monocalcium bis[(3R, 5S, 6E) -7- [2- cyclopropyl -4-(4-fluorophenyl)-3-quinolyl]-3, 5- dihydroxy
6-heptenoate](NK-104) in rats and dogs. Pharmacometrics, 1998, 56:67～72
9 Nishigaki K, Moriwaki T, Akiba T, et al. Reproductive and developmental toxicity studies of (1)- monocalcium bis [(3R,5S, 6E, 7- [2 –cyclopropyl – 4- (4-fluorophenyl)–3 -quinolyl]-3, 5- dihydroxy -6- heptenoate)(NK-104): 4. Perinatal and postnatal study in rats by oral administration. Pharmacometrics, 1998, 56:161～177
10 Nishigaki K, Moriwaki T, Akiba T, et al. Reproductive and developmental toxicity study of (1)-monocalcium bis[(3R, 5S,6E, 7- [2- cyclopropyl -4- (4-fluorophenyl) -3- quinolyl] -3, 5- dihydroxy -6- heptenoate)(NK-104): 3.Teratogenicity study in rabbits by oral administration. Pharmacometrics, 1998, 56:153～159
11 Saito Y, Yamada N, Teramoto T, et al. Clinical efficacy of pitavastatin, a new 3-hydroxy -3- methylglutaryl coenzyme a reductase inhibitor, in patients with hyperlipidemia. Dose- finding study using the double-blind, three-group parallel comparison. Arzneimittelforschung, 2002, 52:251～255
12 Teramoto T, Salto Y, Nakaya N, et al. Clinical evaluation of NK-104(pitavastatin) in long-term treatment of patientswith hyperlipidemia. Atheroselerosis, 2000, 151:53
13 Kajinami K, Koizumi J, Ueda K, et al. Effects of NK-104, a new hydroxymethylglutarylcoenzyme reductase inhibitor, on low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia.Hokuriku NK-104 Study Group. Am J Cardiol, 2000, 85:178～183
14 Noji Y, Higashikata T, Inazu A, et al. Long-term treatment with pitavastatin (NK-104), a new HMG-CoA reductase inhibitor, of patients with heterozygous familial hypercholes -terolemia. Atherosclerosis, 2002, 163:157～164
15 Sone H, Takahashi A, Shimano H, et al. HMG-CoA reductase inhibitor decreases small dense low-density lipoprotein and remnant-like particle cholesterol in patients with type-2 diabetes. Life Sci, 2002, 71:2403～2412
16 Saito Y,Yamada N,Teramoto T, et al. A randomized, double - blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholester -olemia. Atherosclerosis, 2002, 162:373～379
17 Park S, Kang HJ, Rim SJ, et al. A Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Pitavastatin Compared with Simvastatin in Korean Patients with Hypercholesterolemia.Clin Ther, 2005, 27:1074～1082
18 Yoshitomi Y, Ishii T, Kaneki M, et al. Efficacy of a low dose of pitavastatin compared with atorvastatin in primary hyperlipidemia: results of a 12-week, open label study. J Atheroscler Thromb, 2006, 13:108～113
19 Flores NA. Pitavastatin: Nissan/Kowa Yakuhin / Novartis /Sankyo. Curr Opin Invest Drugs, 2002, 3:1334～1341
20 Shinozaki K, Nishio Y, Ayajiki K, et al. Pitavastatin Restores Vascular Dysfunction in Insulin-Resistant State by Inhibiting NAD(P)H Oxidase Activity and Uncoupled Endothelial Nitric Oxide Synthase - Dependent Superoxide Production. J Cardiovasc Pharmacol, 2007, 49:122～130
21 Masamura K, Oida K, Kanehara K, et al. Pitavastatin –Induced Thrombomodulin Expression by Endothelial Cells Acts Via Inhibition of Small G Proteins of the Rho Family. Arterioscler Thromb Vasc Biol, 2003, 23: 512～517
22 Morikawa S, Takabe W, Mataki C, et al. The effect of statins on mRNA levels of genes related to inflammation: coagulation. J Atheroscler Thromb 2002, 9:178～183
23 Morikawa S, Takabe W, Mataki C, et al. The effect of statins on mRNA levels of genes to inflammation, coagulation, and vascular constriction in HUVEC. Human umbilical vein endothelial cells. J Atheroscler Thromb, 2002, 9:178～183
24 Han J, Zhou X, Yokoyama T, et al. Pitavastatin Downregulates Expression of the Macrophage Type B Scavenger Receptor, CD36. Circulation, 2004, 109:790～796
25 WANG J, Tokoro T, Higa S, et al. Anti-inflammatory effect of pitavastatin on NF-kappaB activated by TNF-alpha in hepatocellular carcinoma cells. Biol Pharm Bull, 2006,29:634～639
26 Tsubouchi H, Inoguchi T, Sonta T, et al. Statin attenuates high glucose-induced and diabetes-induced oxidative stress in vitro and in vivo evaluated by electron spin resonance measurement. Free Radic Biol Med, 2005, 39:444～452
27 Kohno M, Shinomiya K, Abe S, et al. Inhibition of migration and proliferation of rat vascular smooth muscle cells by a new HMG-CoA reductase inhibitor pitavastatin. Hypertens Res, 2002, 25:279～285
28 Tsujimoto A, Takemura G, Mikami A, et al. A Therapeutic Dose of the Lipophilic Statin Pitavastatin Enhances Oxidant- Induced Apoptosis in Human Vascular Smooth Muscle Cells. J Cardiovasc Pharmacol, 2006, 48:160～165
29 Jiang M, Bujo H, Zhu Y, et al. Pitavastatin attenuates the PDGF-induced LR11/uPA receptor-mediated migration of smooth muscle cells. Biochem Biophys Res Commun, 2006, 348:1367～1377
30 Takayuki Y, Katsumi M, Takeshi K, et al. Inhibitory efficacy of pitavastatin on the early inflammatory response and neointimal thickening in a porcine coronary after stenting. Atherosclerosis, 2004, 174:253～259
31 Saka M, Obata K, Ichihara S, et al. Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure.J Cardiovasc Pharmacol, 2006, 47: 770～779
32 Tounai H, Hayakawa N, Kato H, et al. Immunohist -ochemical Study on Distribution of NF-κB and p53 in Gerbil Hippocampus after Transient Cerebral Ischemia: Effect of Pitavastatin.Metab Brain Dis, 2007, 22:89～104
33 Nakazawa T, Takahashi H, Nishijima K, et al. Pitavastatin prevents NMDA-induced retinal ganglion cell death by suppressing leukocyte recruitment. J Neurochem, 2007, 100:1018～1031
2 王钟林.血脂与心血管病的流行病学研究.实用老年医学,1998, 12:201～202
3 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet, 1994, 344:1383～1389
4 Sacks FM, Pteffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med, 1996, 335:1001～1009
5 Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet, 2002, 360:1623～1630
6 Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS (Air Force/Texas Coronary Atheroscl -erosis Pre-vention Study)JAMA, 1998, 279: 1615～1662
7 Heart Protection Study Collaborative Group. MRC/BHFHeart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals:a randomized placebo-controlled trial. Lancet, 2002, 360:7～22
8 Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. N Engl J Med, 1998, 339:1349～1357
9 Schwartz G, Ezekowitz M, Olsson A, et al. Effect of atrovastatin on early recurrent ischemic events in acute coronary syndromes.The MIRACL study a randomized controlled trial. JAMA, 2001, 285:1711～1718
10 Spencer FA , Allegrone J, Goldberg RJ, et al. Association of statin therapy with outcomes of acute coronary syndrome: The GRACE study.Ann Intern Med, 2004, 140:857～866
11 Saito Y, Yamada N, Teramoto T, et al. Clinical efficacy of pitavastatin,a new 3- hydroxyl -3- methylglutaryl coenzyme a reductase inhibitor,in patients with hyperlipidemia. Dose-finding study using the double-blind, three-group parallel comparison. Arzneimittelforschung, 2002, 52:251～255
12 Kajinami K, Koizumi J, Ueda K, et al. Effects of NK-104,a new hydroxymethylglutarylcoenzyme reductase inhibitor, on low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia.Hokuriku NK-104 Study Group. Am J Cardiol, 2000, 85:178～183
13 Sone H, Takahashi A, Shimano H, et al. HMG-CoA reductase inhibitor decreases small dense low-density lipoprotein and remnant-like particle cholesterol in patients with type-2 diabetes. Life Sci, 2002, 71:2403～2412
14 Nissen SE,Tuzcu EM,Schoenhagen P,et al. Effect of intensive compared with moderate lipid-lowering therapy on progressionof coronary atherosclerosis: a randomized controlled trial. JAMA,2004,291:1071～1080
15 Cannon CP,Braunwald E,Mccabe CH,et al. Pravastatin or atorvastatin Evaluation and Infection Therapy 一Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med, 2004, 350:1495～1504
16 LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med, 2005, 352:1425～1435
17 Grundy SM, Cleeman JI, Merz CN, et al. Implications of recen tclinica ltrials for the National Cholesterol Education Program Adult Treat men Panel Ⅲ Guidelines. Circulation, 2004, 110:227～239
18 Olsson AG, Istad H, Luurila O, on behalf of the Rosuvastatin Investigators Group. Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia. Am Heart J 2002, 144: 1044～1051
19 Brown WV, Bays HE, Hassman DR, for the Rosuvastatin Study Group. Efficacy and safety of rosuvastatin comparedwith pravastatin and simvastatin in patients with hypercholesterolemia: a randomized, double-blind, 52-week trial. Am Heart J 2002, 44:1036～1043
20 Knopp RH. Drug treatment of lipid disorders. N Engl J Med, 1999, 341:498～511
21 Aoki T, Nishimura H, Nakagawa S, et al. Pharmacological profile of a novel synthetic inhibitor of 3– hydroxyl –3- methylglutaryl – coenzyme A reductase. Arzneimittelf -orschung. 1997, 47:904～909
22 Isley WL. Pitavastatin (NK-104), a new HMG-CoA reductase inhibitor.Drugs Today(Barc). 2001, 37:587～589
23 Saito Y, Yamada N, Teramoto T, et al. A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia. Atherosclerosis, 2002, 162:373～379
24 血脂治疗现状调查协作组,我国血脂异常治疗现状的调查.中华心血管病杂志,2001,29:15～17
25 徐成斌.血脂异常的药物治疗新进展.中华心血管病杂志,2001, 29:189～192
26 中国成人血脂异常防治指南制订联合委员会.中国成人血脂异常防治指南.中华心血管病杂志. 2007, 35: 390～413
27 Park S, Kang HJ, Rim SJ, et al. A Randomized, Open-Label Study to Evaluate the Efficacy and Safety of PitavastatinCompared with Simvastatin in Korean Patients with Hypercholesterolemia. Clin Ther, 2005, 27:1074～1082
28 Flores NA. Pitavastatin: Nissan/Kowa Yakuhin/ Novartis/ Sankyo. Curr Opin Invest Drugs, 2002, 3:1334～1341
29 Takayuki Yokoyama, Katsumi Miyauchi, Takeshi Kurata, et al. Inhibitory efficacy of pitavastatin on the early inflammatory response and neointimal thickening in a porcine coronary after stenting. Atherosclerosis, 2004, 174:253～259
30 Saka M, Obata K, Ichihara S, et al. Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. J Cardiovasc Pharmacol, 2006, 47: 770～779
1 Maejima T, Yamazaki H, Aoki T, et al. Effect of pitavastatin on apolipoprotein A-I production in HepG2 cell.Biochem Biophys Res Commun. 2004, 324:835～839
2 Nakagawa S, Tanabe S, Tamaki T, et al. Effect of NK-104,an HMG-CoA reductase inhibitor on lipid metabolism in HepG2 cells. Jpn pharmacol Ther, 2001, 29:1～56
3 Ooyen C, Zecca A, Bersino AM, et al. NK-104, a potent 3- hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor, decreases apolipoprotein B-100 ecretion from HepG2 cells. Atherosclerosis, 1999, 145:87～95
4 Kojima J, Ohshima T, Yoneda M, et al. Effect of biliary excretion on the pharmacokinetics of pitavastatin (NK-104) in dogs. Xenobiol Metab Dispos, 2001, 16:497～502
5 Suzuki H, Yamazaki H, Aoki T, et al. Lipid-lowering and antiatherosclerotic effect of NK-104, a potent 3-hydroxy -3- methylglutaryl coenzyme A reductase inhibitor, in Watanabe heritable hyperlipidemic rabbits. Arzneimittelforschung, 2000, 50:995～1003
6 Suzuki H, Yamazaki H, Aoki T, et al. Hypolipidemic effect of NK-104 and other 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors in guinea pigs. Arzneimittelfo -rschung, 2001, 51:38～45
7 Kajinami K, Takekoshi N, Saito Y. Pitavastatin: efficacyand safety profiles of a novel synthetic HMG-CoAreductase inhibitor.Cardiovasc Drug Rev, 2003, 21:199～215
8 Shibuta T, Kato Y, Akiba T, et al. Single dose toxicity studies of ( + )-monocalcium bis[(3R, 5S, 6E) -7- [2- cyclopropyl -4-(4-fluorophenyl)-3-quinolyl]-3, 5- dihydroxy
6-heptenoate](NK-104) in rats and dogs. Pharmacometrics, 1998, 56:67～72
9 Nishigaki K, Moriwaki T, Akiba T, et al. Reproductive and developmental toxicity studies of (1)- monocalcium bis [(3R,5S, 6E, 7- [2 –cyclopropyl – 4- (4-fluorophenyl)–3 -quinolyl]-3, 5- dihydroxy -6- heptenoate)(NK-104): 4. Perinatal and postnatal study in rats by oral administration. Pharmacometrics, 1998, 56:161～177
10 Nishigaki K, Moriwaki T, Akiba T, et al. Reproductive and developmental toxicity study of (1)-monocalcium bis[(3R, 5S,6E, 7- [2- cyclopropyl -4- (4-fluorophenyl) -3- quinolyl] -3, 5- dihydroxy -6- heptenoate)(NK-104): 3.Teratogenicity study in rabbits by oral administration. Pharmacometrics, 1998, 56:153～159
11 Saito Y, Yamada N, Teramoto T, et al. Clinical efficacy of pitavastatin, a new 3-hydroxy -3- methylglutaryl coenzyme a reductase inhibitor, in patients with hyperlipidemia. Dose- finding study using the double-blind, three-group parallel comparison. Arzneimittelforschung, 2002, 52:251～255
12 Teramoto T, Salto Y, Nakaya N, et al. Clinical evaluation of NK-104(pitavastatin) in long-term treatment of patientswith hyperlipidemia. Atheroselerosis, 2000, 151:53
13 Kajinami K, Koizumi J, Ueda K, et al. Effects of NK-104, a new hydroxymethylglutarylcoenzyme reductase inhibitor, on low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia.Hokuriku NK-104 Study Group. Am J Cardiol, 2000, 85:178～183
14 Noji Y, Higashikata T, Inazu A, et al. Long-term treatment with pitavastatin (NK-104), a new HMG-CoA reductase inhibitor, of patients with heterozygous familial hypercholes -terolemia. Atherosclerosis, 2002, 163:157～164
15 Sone H, Takahashi A, Shimano H, et al. HMG-CoA reductase inhibitor decreases small dense low-density lipoprotein and remnant-like particle cholesterol in patients with type-2 diabetes. Life Sci, 2002, 71:2403～2412
16 Saito Y,Yamada N,Teramoto T, et al. A randomized, double - blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholester -olemia. Atherosclerosis, 2002, 162:373～379
17 Park S, Kang HJ, Rim SJ, et al. A Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Pitavastatin Compared with Simvastatin in Korean Patients with Hypercholesterolemia.Clin Ther, 2005, 27:1074～1082
18 Yoshitomi Y, Ishii T, Kaneki M, et al. Efficacy of a low dose of pitavastatin compared with atorvastatin in primary hyperlipidemia: results of a 12-week, open label study. J Atheroscler Thromb, 2006, 13:108～113
19 Flores NA. Pitavastatin: Nissan/Kowa Yakuhin / Novartis /Sankyo. Curr Opin Invest Drugs, 2002, 3:1334～1341
20 Shinozaki K, Nishio Y, Ayajiki K, et al. Pitavastatin Restores Vascular Dysfunction in Insulin-Resistant State by Inhibiting NAD(P)H Oxidase Activity and Uncoupled Endothelial Nitric Oxide Synthase - Dependent Superoxide Production. J Cardiovasc Pharmacol, 2007, 49:122～130
21 Masamura K, Oida K, Kanehara K, et al. Pitavastatin –Induced Thrombomodulin Expression by Endothelial Cells Acts Via Inhibition of Small G Proteins of the Rho Family. Arterioscler Thromb Vasc Biol, 2003, 23: 512～517
22 Morikawa S, Takabe W, Mataki C, et al. The effect of statins on mRNA levels of genes related to inflammation: coagulation. J Atheroscler Thromb 2002, 9:178～183
23 Morikawa S, Takabe W, Mataki C, et al. The effect of statins on mRNA levels of genes to inflammation, coagulation, and vascular constriction in HUVEC. Human umbilical vein endothelial cells. J Atheroscler Thromb, 2002, 9:178～183
24 Han J, Zhou X, Yokoyama T, et al. Pitavastatin Downregulates Expression of the Macrophage Type B Scavenger Receptor, CD36. Circulation, 2004, 109:790～796
25 WANG J, Tokoro T, Higa S, et al. Anti-inflammatory effect of pitavastatin on NF-kappaB activated by TNF-alpha in hepatocellular carcinoma cells. Biol Pharm Bull, 2006,29:634～639
26 Tsubouchi H, Inoguchi T, Sonta T, et al. Statin attenuates high glucose-induced and diabetes-induced oxidative stress in vitro and in vivo evaluated by electron spin resonance measurement. Free Radic Biol Med, 2005, 39:444～452
27 Kohno M, Shinomiya K, Abe S, et al. Inhibition of migration and proliferation of rat vascular smooth muscle cells by a new HMG-CoA reductase inhibitor pitavastatin. Hypertens Res, 2002, 25:279～285
28 Tsujimoto A, Takemura G, Mikami A, et al. A Therapeutic Dose of the Lipophilic Statin Pitavastatin Enhances Oxidant- Induced Apoptosis in Human Vascular Smooth Muscle Cells. J Cardiovasc Pharmacol, 2006, 48:160～165
29 Jiang M, Bujo H, Zhu Y, et al. Pitavastatin attenuates the PDGF-induced LR11/uPA receptor-mediated migration of smooth muscle cells. Biochem Biophys Res Commun, 2006, 348:1367～1377
30 Takayuki Y, Katsumi M, Takeshi K, et al. Inhibitory efficacy of pitavastatin on the early inflammatory response and neointimal thickening in a porcine coronary after stenting. Atherosclerosis, 2004, 174:253～259
31 Saka M, Obata K, Ichihara S, et al. Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure.J Cardiovasc Pharmacol, 2006, 47: 770～779
32 Tounai H, Hayakawa N, Kato H, et al. Immunohist -ochemical Study on Distribution of NF-κB and p53 in Gerbil Hippocampus after Transient Cerebral Ischemia: Effect of Pitavastatin.Metab Brain Dis, 2007, 22:89～104
33 Nakazawa T, Takahashi H, Nishijima K, et al. Pitavastatin prevents NMDA-induced retinal ganglion cell death by suppressing leukocyte recruitment. J Neurochem, 2007, 100:1018～1031