Statin-Berberine Combination Therapy in Hyperlipidemia

他汀类药物与小檗碱联合治疗高脂血症

基本信息

批准号：
7586203
负责人：
JINGWEN LIU
金额：
$ 17.5万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586203
关键词：
Address Adverse effects Affect Americas Animal Feed Animal Model Animals Apolipoproteins B Area Atherosclerosis Berberine Berberine Alkaloids Biological Assay Biological Factors Cardiovascular system Cell Line Cells Chinese Herbs Chinese People Cholesterol Clinic Clinical Research Combined Modality Therapy Common Cold Coronary Arteriosclerosis Coronary heart disease Crude Extracts Cytochrome P450 Development Diarrhea Diet Dose Drug Interactions Drug Kinetics Drug Prescriptions Effectiveness Enzymes Event Fatty acid glycerol esters Feedback Fibrates Genetic Transcription Goldenseal Half-Life Hamsters Heart Hepatic Hepatocyte Herbal Medicine Human Hydroxymethylglutaryl-CoA Reductase Inhibitors Hyperlipidemia In Vitro Individual Investigation LDL Cholesterol Lipoproteins Light Lipids Liver Lovastatin Low Density Lipoprotein Receptor Measures Mediating Medicinal Plants Messenger RNA Morbidity - disease rate Mus Muscle Weakness Myalgia Nonesterified Fatty Acids Oral Administration Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Placebo Control Placebos Plant Extracts Plasma Population Prevention Primary carcinoma of the liver cells Problem Solving Process Receptor Gene Regulation Regulatory Element Research Risk Risk Factors SRE-1 binding protein Serum Simvastatin Skeletal Muscle Sterols Symptoms Therapeutic Agents Time Toxic effect Transaminases Transgenic Mice Triglycerides Up-Regulation Upper Respiratory Infections Work base feeding fluvastatin huanglian hypercholesterolemia improved in vivo innovation mRNA Expression mRNA Stability mortality novel prevent protein expression receptor expression success uptake

项目摘要

DESCRIPTION (provided by applicant): Currently, HMG-CoA reductase inhibitors (statins) are the primary drugs to treat hypercholesterolemia. This class of drugs potently lowers serum LDL-cholesterol mainly through increased hepatic LDL receptor (LDLR) expression by activation of LDLR transcription. Statins effectively reduce elevated LDL-c and lessen the risk of coronary heart disease and related cardiovascular events. However, despite the success with statin treatments, a significant number of hypercholesterolemic patients do not achieve an acceptable plasma cholesterol level by a single drug therapy, and some patients do not tolerate statins owing to symptoms of muscle pain and muscle weakness caused by statins dose-dependently. Thus, in these cases, combination therapy by two agents with different modes of action might result in a better cholesterol-lowering effect with an improved efficacy of statins. We have identified Berberine (BBR), a compound originally isolated from the Chinese herb Hunglian as a novel upregulator of hepatic LDLR. We demonstrated that BBR strongly increased the hepatic LDLR expression by increasing the LDLR mRNA stability. We also demonstrated the effectiveness of BBR in reducing plasma cholesterol and LDL-c in hypercholesterolemic patients without side effects in a placebo-controlled clinical study. Recently, we have further identified that the BBR-containing medicinal plant extract goldenseal is a potent lipid-lowering natural product. Goldenseal strongly increases LDLR expression in HepG2 cells and effectively lowers plasma cholesterol and LDL-c in hyperlipidemic hamsters. Based upon these mechanistic and clinical studies, we hypothesize that BBR and its natural product goldenseal are promising candidates for statin combination therapy in treating hypercholesterolemic patients. The overall objectives of this new R21 proposal are to explore potential applications of the pure compound BBR and the crude extract goldenseal in combination therapy with current cholesterol lowering drug statins. The specific aims of this new proposal are to: 1) Use the human ApoB/CETP double trasnsgenic mice, which have a lipid profile similar to humans, as an vivo animal model to determine if the herbal medicine goldenseal or the pure compound BBR is capable of potentiating the lipid lowering effects of fluvastatin and ameliorating the side effects of fluvastatin in damaging hepatic functions; and 2) We will examine the effects of BBR and goldenseal on fluvastatin pharmacokinetics to determine whether drug interactions occur in animals co-administered with statin and BBR. These proposed studies are exploratory and highly innovative. The success of these studies will ultimately benefit patients by offering more choices for their individual needs in reducing plasma cholesterol levels to prevent atherosclerotic cardiovascular disease.

说明书（申请人提供）：目前，HMG-CoA还原酶抑制剂（他汀类药物）是治疗高胆固醇血症的主要药物。此类药物主要通过激活 LDLR 转录来增加肝脏 LDL 受体 (LDLR) 的表达，从而有效降低血清 LDL 胆固醇。他汀类药物可有效降低升高的低密度脂蛋白胆固醇，降低冠心病和相关心血管事件的风险。然而，尽管他汀类药物治疗取得了成功，但仍有相当多的高胆固醇血症患者通过单一药物治疗未能达到可接受的血浆胆固醇水平，并且一些患者由于他汀类药物剂量引起的肌肉疼痛和肌无力症状而不能耐受他汀类药物。依赖。因此，在这些情况下，两种不同作用方式的药物联合治疗可能会产生更好的降胆固醇效果，同时提高他汀类药物的疗效。我们已经鉴定出小檗碱 (BBR)，一种最初从中药红莲中分离出来的化合物，是一种新型的肝脏 LDLR 上调剂。我们证明，BBR 通过增加 LDLR mRNA 的稳定性来强烈增加肝脏 LDLR 的表达。我们还在一项安慰剂对照临床研究中证明了 BBR 在降低高胆固醇血症患者血浆胆固醇和 LDL-c 方面的有效性，且没有副作用。最近，我们进一步鉴定出含有BBR的药用植物提取物白毛茛是一种强效的降脂天然产物。 Goldenseal 强烈增加 HepG2 细胞中 LDLR 的表达，并有效降低高脂仓鼠的血浆胆固醇和 LDL-c。基于这些机制和临床研究，我们假设 BBR 及其天然产物白毛茛是治疗高胆固醇血症患者的他汀类联合疗法的有希望的候选者。这项新的 R21 提案的总体目标是探索纯化合物 BBR 和金毛草粗提物与现有降胆固醇药物他汀类药物联合治疗的潜在应用。该新提案的具体目标是： 1) 使用具有与人类相似的脂质谱的人类 ApoB/CETP 双转基因小鼠作为体内动物模型，以确定草药金毛草或纯化合物 BBR 是否具有能力增强氟伐他汀的降脂作用，改善氟伐他汀损害肝功能的副作用； 2) 我们将检查 BBR 和白毛茛对氟伐他汀药代动力学的影响，以确定在与他汀类药物和 BBR 共同给药的动物中是否发生药物相互作用。这些拟议的研究具有探索性和高度创新性。这些研究的成功将最终使患者受益，为患者在降低血浆胆固醇水平以预防动脉粥样硬化性心血管疾病方面的个人需求提供更多选择。