辛伐他汀5mg与普伐他汀10mg治疗高胆固醇血症的比较

目的：探讨低剂量辛伐他汀治疗高胆固醇血症的临床疗效及耐受性。方法：低、中度原发性高胆固醇血症病人６２例，随机分为２组，Ａ组３１例（男性２６例，女性５例；年龄６４±ｓ１４ａ）采用辛伐他汀５ｍｇ，ｐｏ，ｑｄ。Ｂ组３１例（男性２５例，女性６例；年龄６１±１３ａ）采用普伐他汀１０ｍｇ，ｐｏ，ｑｄ。疗程均为４ｗｋ。结果：辛伐他汀组在降低ＴＣ，ＬＤＬ＿ｃｈ及提高ＨＤＬ＿ｃｈ的平均变化率上分别为１７％±９％，２５％±１２％（Ｐ＜０．０１）和１１％±１１％（Ｐ＞０．０５），与普伐他汀组疗效相当，组间比较，Ｐ值＞０．０５。２种药物治疗期间病人均无显著不良反应。结论：小剂量辛伐他汀疗效可与普伐他汀媲美，５ｍｇ／ｄ可作为治疗高胆固醇血症的起始剂量     

HPLC—MS法同时测定人血浆中普伐他汀及其主要代谢物3’α-异普伐他汀

目的:建立同时测定人血浆中普伐他汀及其主要代谢物3’α-异普伐他汀的HPLC—MS法,并研究普伐他汀钠片在人体内的药代动力学。方法:血浆样品中加入内标霉酚酸,用固相萃取柱进行提取。色谱柱为Discovery C_(18)柱(5μm,150mm×4.6 mm),流动相为甲醇-乙腈-6 mmol·L~(-1)乙酸铵溶液(20:30:50),流速为0.4 mL·min~(-1)。采用HPLC—ESI~--MS法,选择离子检测方式,用于定量分析的检测离子为m/z423.4(普伐他汀和3’α-异普伐他汀)和m/z 319.2(内标)。结果:血浆中内源性物质对样品测定无干扰。普伐他汀和3’α-异普伐他汀的线性范围均为1.25—200 ng·mL~(-1),最低定量浓度均为1.25 ng·mL~(-1),提取回收率均大于80%,日内、日间RSD均小于10%。结论:本法灵敏、准确,适用于普伐他汀及其主要代谢物3’α-异普伐他汀的药代动力学研究。     

Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction

OBJECTIVES

We tested to find out whether pravastatin restores the infarct size (IS)-limiting effect of ischemic preconditioning (IP) and if it has any effect on the IP-induced activation of adenosine producing enzyme ecto-5′-nucleotidase which plays a key role in the IP-induced cardioprotection.

BACKGROUND

The IS-limiting effect of IP is blunted by hypercholesterolemia. Recently, HMG-CoA reductase inhibitors are shown to have direct cytoprotective effects.

METHODS

Rabbits were fed with a normal or cholesterol (1%) added diet with or without pravastatin (5 mg/kg/day) treatment. Infarct size was measured after 30 min occlusion and 3 h reperfusion of circumflex coronary artery with or without the IP procedure (5 min occlusion and 10 min reperfusion). Additionally, ecto-5′-nucleotidase activities of ischemic and nonischemic myocardium were measured immediately after IP procedure.

RESULTS

This dose of pravastatin did not normalize the increased level of serum cholesterol. The IS-limiting effect of preceding IP (IS reduced from 36.7% to 9.6%, p < 0.001) was abolished by hypercholesterolemia (from 46.1% to 31.3%, p = NS) and restored by pravastatin treatment (from 35.2% to 9.4%, p < 0.001). Pravastatin treatment did not affect IS or the effect of IP under normocholesterolemia. The activation of ecto-5′-nucleotidase presented as the activity ratio of ischemic to nonischemic myocardium (3.1-fold in normocholesterolemia) was blunted by hypercholesterolemia (1.8-fold, p < 0.05) and restored by pravastatin treatment (2.9-fold).

CONCLUSIONS

Pravastatin, at the dose serum cholesterol was not normalized, restored the IS-limiting effect of IP and IP-induced ecto-5′-nucleotidase activation, which were both blunted by hypercholesterolemia. The activation of ecto-5′-nucleotidase may be worth further investigation as a possible mechanism for the hypercholesterolemia-induced retardation and pravastatin-mediated restoration of the cardioprotective effect of IP.     

Effects of Long-Term Pravastatin Treatment on Serum and Urinary Monocyte Chemoattractant Protein-1 Levels and Renal Function in Type 2 Diabetic Patients with Normoalbuminuria

To explore the renoprotective and anti-inflammatory effects of pravastatin, we analyzed the changes in renal function and urinary monocyte chemoattractant protein-1 (MCP-1) level as a renal tubulointerstitial inflammatory biomarker and serum MCP-1 level as a systemic inflammatory biomarker following the introduction of treatment with 10 mg/day of pravastatin in 10 hyperlipidemic type 2 diabetic patients with normoalbuminuria. Twelve months of the pravastatin treatment did not affect urinary levels of albumin, transferrin, N-acetylglucosaminidase, or MCP-1 in the hyperlipidemic diabetic patients, whereas the treatment significantly reduced serum levels of MCP-1 in the patients. The pravastatin treatment effectively lowered low-density lipoprotein cholesterol (LDL-C) levels in the hyperlipidemic diabetic patients to levels nearly to those in 11 non-hyperlipidemic type 2 diabetic patients with normoalbuminuria. Interestingly, serum MCP-1 levels were significantly lower in the hyperlipidemic patients treated with pravastatin than in the non-hyperlipidemic patients. No significant correlation was observed between serum LDL-C and MCP-1 levels in all the data in the hyperlipidemic patients before and after the pravastatin treatment and in the non-hyperlipidemic patients. These results collectively indicate that pravastatin may ameliorate systemic vascular inflammation rather than local renal inflammation in hyperlipidemic type 2 diabetic patients with normoalbuminuria, independent of its cholesterol-lowering effects.     

The Effects of High Dose Pravastatin and Low Dose Pravastatin and Ezetimibe Combination Therapy on Lipid,Glucose Metabolism and Inflammation

Objective Coronary artery disease (CAD) is presently the major cause of mortality and morbidity. Anti-hyperlipidemic treatment is one of the main treatment steps in the management of CAD. Statins are the cornerstones in this treatment. Ezetimibe can be reliably used, when statins prove ineffective in treatment, or to reduce their side effects. In the present study we examined the effects of high-dose pravastatin (40 mg) and low-dose pravastatin (10 mg) + ezetimibe (10 mg) combination therapy on lipid and glucose mechanism, as well as inflammation. Methods This study registered 100 cases. Of the cases, 50 [57.1 ± 11.1 years (24 (48%) females and 26 (52%) males)] were administered 40 mg/day pravastatin (group 1) and 50 [53.2 ± 12.2 years (27 (54%) females and 23 (46%) males)] were administered 10 mg pravastatin + 10 mg ezetimibe (group 2). Results In group 1, total cholesterol fell from 231.1 ± 83.5 mg/dl to 211.3 ± 37.2 mg/dl (p = 0.03), triglyceride from 243.5 ± 96.8 mg/dl to 190.9 ± 55.2 mg/dl (p = 0.003), and LDL cholesterol from 165.7 ± 29.7 mg/dl to 133.4 ± 26.6 mg/dl (p = 0.02). In group 2, total cholesterol dropped from 250.9 ± 51.8 mg/dl to 187.9 ± 34.9 mg/dl (p = 0.001), triglyceride from 270.3 ± 158.9 mg/dl to 154.6 ± 60.7 mg/dl (p = 0.001), and LDL cholesterol from 158.1 ± 47.5 mg/dl to 116.9 ± 26.4 mg/dl (p = 0.001). Insulin resistance decreased from 4.05 ± 2.31 to 3.16 ± 1.90 (p = 0.07) in group 1 and from 2.96 ± 1.50 to 2.05 ± 0.55 (p = 0.009) in group 2. High sensitive C-reactive protein fell from 6.69 ± 6.11 mg/l to 3.02 ± 1.70 mg/l (p = 0.01) in group 1 and from 6.36 ± 2.06 mg/l to 2.68 ± 1.69 mg/l (p = 0.001) in group 2. Conclusion Both therapy regimes are effective. However, we found that low-dose pravastatin and ezetimibe combination therapy is more effective than high-dose pravastatin therapy on lipid metabolism, glucose metabolism and inflammation.     

临床药师参与1例普伐他汀致肌炎的药学实践

目的:通过本例案例报道,提示临床规范和合理用药。方法:通过药学查房,对患者用药史的详细询问及后期循证取证,判断药物相关性不良反应的可能性及停用可疑药物,以减轻患者的不良反应症状及分析不良事件的原因。结果:停用可疑药物6d后患者全身肌痛减轻,实验室检查值逐步恢复正常。结论:对于初次使用他汀类药物的患者,初始剂量应从小剂量开始,且密切关注息者的肝功能和血肌酸激酶水平。     

普伐他汀对培养巨噬细胞表达基质金属蛋白酶活性的影响

目的　探讨普伐他汀对基质金属蛋白酶 (matrixmetalloproteinases ,MMPs)活性的影响及其与粥样斑块稳定性的关系。方法　从SD大鼠腹腔取巨噬细胞体外培养 ,接种于 2 4孔板中 ,逐孔加入普伐他汀 ,终浓度分别为 10 - 3、10 - 4及 10 - 5mol L ,每种浓度 3孔 ,分别在 2 4、4 8及 72h收集上清液 ,未加药孔为空白对照 ,采用酶谱分析法测量上清液中MMPs的活性。结果　巨噬细胞上清液中有MMP 2及MMP 9的活性表达 ,以 2 4h时活性最强。普伐他汀可以降低其活性 ,随着浓度的增加 ,抑制作用越明显。结论　普伐他汀可以使巨噬细胞产生的MMPs活性降低 ,可能使纤维帽中胶原的降解减少 ,从而增加粥样斑块的稳定性     

Compliance and adverse event withdrawal: their impact on the West of Scotland Coronary Prevention Study

AIMS: To assess the additional benefit gained from high compliancein the West of Scotland Coronary Prevention Study and to examinecases where withdrawal from trial medication was due to an adverseevent. METHODS: The incidence of definite coronary heart disease or non-fatalmyocardial infarction, cardiovascular mortality, definite orsuspect coronary heart disease death or non-fatal myocardialinfarction, the need for coronary revascularization procedures,all-cause mortality and incident cancers were measured in theentire cohort and compared with the high compliance group. Theadverse events associated with withdrawal were coded by bodysystem. RESULTS: In subjects with compliance 75%, treatment with pravastatinresulted in a 38% risk reduction for definite coronary heartdisease death or non-fatal myocardial infarction and for cardiovascularmortality, a 46% reduction in risk or coronary revascularizationand a 32% risk reduction (P=0·015) for all-cause mortality. CONCLUSION: The analysis of the effect of pravastatin in the subgroup ofhigh compliers to randomized medication demonstrated a substantialincrease in the estimated risk reductions in comparison withthat achieved in the intention-to-treat analysis. This resulthas significant implications for the motivation of high complianceamong patients and for the assessment of the cost-effectivenessof treatment.     

普拉固对兔激素性股骨头坏死骨细胞凋亡的干预研究

目的:采用激素(地塞米松,Dexamethasone)制作成兔股骨头坏死(Steroid-induced Femoral Head Necrosis, SIFHN) 模型,探讨普拉固(Pravastatin)是否能干预SIFHN中骨细胞凋亡.方法:12～18周龄日本大白兔34只,雌雄不限,体重(2.5±0.6) kg,随机分为3组:对照组(A组):6只,单纯标准饲料及草料喂养.实验组(B组):14只,Dexamethasone 2.5 mg/kg·d-1 肌注.干预组(C组):14只,Dexamethasone 2.5 mg/kg·d-1肌注 普拉固2.5 mg/kg·d-1口服.期间每组均予青霉素80万单位/只,肌注,链霉素1.0 g/只,肌注,2次/周,防止感染.分别于6、8、10、12周处死每组兔子各3只,实验开始及处死前均检查血脂、血Prothrombin Time(PT)、tissue plasminogen(t-PA),处死后行光镜下细胞凋亡分析.结果:C组的兔血脂较B均降低(P<005),PT较实验组均降低 (P<0.05),t-PA较B组升高(P<0.01).与B组比较,光镜示细胞凋亡分析指数减少(P<0.01).结论:地塞米松能在兔体内成功造成股骨头坏死模型,而他汀类药物普拉固能有效干预SIFHN中骨细胞凋亡,其作用机制可能与降脂、抗凝、调控凋亡基因表达等因素有关.     

Primary and secondary prevention of heart failure with statins

Statins are effective in the prevention of coronary heart disease (CHD), a leading cause of heart failure (HF). Secondary analyses from 11 randomized clinical trials of patients with high-risk acute or stable coronary heart disease, but without HF, suggest that statins may prevent new-onset HF or HF-related hospitalization. In persons with established HF, several cohort studies found an approximate 35% relative risk reduction in all-cause mortality. While ongoing randomized clinical trials will help to determine the efficacy of statins in persons with established HF, it is reasonable to consider this class of medications in patients with a history of cardiovascular disease, dyslipidemia or diabetes mellitus, and who have either developed, or who remain at risk of, HF.