匹伐他汀临床应用的最新进展

匹伐他汀(pitavastatin)是新一代人工合成的降血脂类药物。该药是新一代HMG-COA还原酶抑制剂,用于治疗原发型高脂血症和混合型血脂障碍,能够显著降低LDL、TC、TG、及升高HDL-C。药物动力学性质优良,具有肝细胞选择性,并且毒性低,安全性好,具有抗动脉粥样硬化、促进血管生成和抗炎作用。本文就匹伐他汀的临床研究进展进行综述。     

匹伐他汀对Klotho基因敲除杂合子小鼠血管新生的促进作用

目的：探讨匹伐他汀对Klotho基因敲除杂合子小鼠血管新生的促进作用及其作用机制。方法：建立Klotho基因敲除杂合子小鼠（hetero kl＋／-）和同窝出生野生型小鼠（wild kl＋／＋）下肢缺血模型并分为4组：①hetero正常组;②hetero匹伐他汀组;③wild正常组;④wild匹伐他汀组。使用激光多普勒血流测定仪测定klotho（kl＋／-,kl＋／＋）小鼠投药前、下肢缺血手术后双下肢血流。免疫荧光组化SP法计数Klotho（kl＋／-,kl＋／＋）小鼠缺血肢毛细血管数。免疫酶组化直接法计数Klotho（kl＋／-,kl＋／＋）小鼠缺血肢磷酸化Akt阳性细胞数。蛋白印迹杂交方法检测Klotho（kl＋／-）小鼠缺血肢VEGF蛋白表达。结果：匹伐他汀使Klotho（kl＋／-,kl＋／＋）小鼠术后缺血肢血流恢复明显,缺血肢与非缺血肢血流面积比明显增加;匹伐他汀使Klotho（kl＋／-、kl＋／＋）小鼠缺血肢毛细血管密度增加、p-Akt阳性细胞数明显增加;匹伐他汀使Klotho（kl＋／-）缺血肢VEGF蛋白表达增强。结论：匹伐他汀有促进Klotho基因敲除杂合子小鼠血管新生的作用。其作用机制可能是通过VEGF—p—Akt—NO径路实现的。     

Characterization of interactions of simvastatin,pravastatin, fluvastatin,and pitavastatin with bovine serum albumin: multiple spectroscopic and molecular docking

The binding interactions of simvastatin (SIM), pravastatin (PRA), fluvastatin (FLU), and pitavastatin (PIT) with bovine serum albumin (BSA) were investigated for determining the affinity of four statins with BSA through multiple spectroscopic and molecular docking methods. The experimental results showed that SIM, PRA, FLU, and PIT statins quenched the intrinsic fluorescence of BSA through a static quenching process and the stable stains–BSA complexes with the binding constants in the order of 10⁴ M^?1 at 298 K were formed through intermolecular nonbond interaction. The values of ΔH⁰, ΔS⁰ and ΔG⁰ in the binding process of SIM, PRA, FLU, and PIT with BSA were negative at the studied temperature range, suggesting that the binding process of four statins and BSA was spontaneous and the main interaction forces were van der Waals force and hydrogen-bonding interactions. Moreover, the binding of four statins with BSA was enthalpy-driven process due to |ΔH°|>|TΔS°| under the studied temperature range. From the results of site marker competitive experiments and molecular docking, subdomain IIIA (site II) was the primary binding site for SIM, PRA, FLU, and PIT on BSA. The results of UV–vis absorption, synchronous fluorescence, 3D fluorescence and FT-IR spectra proved that the slight change in the conformation of BSA, while the significant changes in the conformation of SIM, PRA, FLU, and PIT drug in statin–BSA complexes, indicating that the flexibility of statin molecules plays an important role in increasing the stability of statin–BSA complexes.     

Statin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia

The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride (−41%), remnant cholesterol (−55%), and LDL-cholesterol (−39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D.