Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
J Lipid Res. 2011 Feb;52(2):361-73. doi: 10.1194/jlr.M011098. Epub 2010 Nov 10.
L-4F, an apolipoprotein A-I (apoA-I) mimetic peptide (also known as APL180), was administered daily by either intravenous (IV) infusion for 7 days or by subcutaneous (SC) injection for 28 days in patients with coronary heart disease in two distinct clinical studies. L-4F was well tolerated at all doses tested. Despite achieving plasma levels (mean maximal plasma concentration of 2,907 ng/ml and 395 ng/ml, following IV infusion and SC injection, respectively), that were effective in previously published animal models, treatment with L-4F, as assessed by biomarkers of HDL function such as HDL-inflammatory index (HII), and paraoxonase activity, did not improve. Paradoxically, there was a 49% increase in high-sensitivity C-reactive protein (hs-CRP) levels after seven IV infusions of 30 mg L-4F (P < 0.05; compared with placebo) and a trend for hs-CRP increase in subjects receiving 30 mg SC injection for 28 days. In a subsequent, ex vivo study, addition of L-4F at concentrations of 150, 375, or 1,000 ng/ml to plasma from subjects prior to L-4F treatment resulted in significant dose-dependent HII improvement. In conclusion, in vivo L-4F treatment, delivered by either SC injection or IV infusion, did not improve HDL functional biomarkers despite achieving plasma levels that improved identical biomarkers ex vivo and in animal models.
L-4F 是一种载脂蛋白 A-I（apoA-I）模拟肽（也称为 APL180），在两项不同的临床研究中，患有冠心病的患者每日通过静脉内（IV）输注 7 天或通过皮下（SC）注射 28 天进行给药。在所有测试剂量下，L-4F 的耐受性都很好。尽管达到了有效的血浆水平（静脉输注后平均最大血浆浓度为 2907ng/ml 和 395ng/ml，SC 注射后），与之前发表的动物模型中的水平一致，但用 L-4F 治疗，如通过 HDL 功能的生物标志物（如 HDL-炎症指数（HII）和对氧磷酶活性）评估，并没有改善。矛盾的是，在接受 30mg L-4F 静脉输注 7 次后，高敏 C 反应蛋白（hs-CRP）水平升高了 49%（P<0.05；与安慰剂相比），而接受 30mg SC 注射 28 天的受试者也有升高 hs-CRP 的趋势。在随后的体外研究中，在给予 L-4F 治疗之前，将 L-4F 以 150、375 或 1000ng/ml 的浓度添加到受试者的血浆中，导致 HII 显著剂量依赖性改善。总之，尽管体内 L-4F 治疗达到了改善体外和动物模型中相同生物标志物的血浆水平，但并未改善 HDL 功能生物标志物。
