The Effect of a PPAR Alpha Agonist on CYP Monooxygenase Activity in Humans
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 75
- 试验地点
- 1
- 主要终点
- Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment
研究概览
简要总结
The hypothesis is to test to see if the drug fenofibrate will increase important chemicals in the body and specifically in the kidney, help to rid the body of salt by the kidneys, decrease blood pressure and improve insulin sensitivity during high-salt intake in individuals with hypertension.
详细描述
Hypertension affects 73 million people in the United States and a billion people worldwide and contributes to death due to stroke, myocardial infarction, end-stage kidney disease and congestive heart failure. Fifty to 60% of individuals with hypertension have "salt-sensitive" hypertension, characterized by an exaggerated blood pressure response to increased salt intake. Salt-sensitive hypertension is associated with increased mortality due to cardiovascular disease.
This study will test the hypothesis that administration of a PPARa agonist, an intervention increases renal tubular Cyp2c and 4a expression in rodents, will increase urinary excretion of 20-hydroxyeicosatetraenoic acid(HETE) and epoxyeicosatrienoic acids(EET)s, induce natriuresis, decrease blood pressure, and improve insulin sensitivity during high-salt intake in individuals with hypertension.
Metabolites of the P450 arachidonic acid monooxygenases play an important role in the regulation of blood pressure in rodent models.
Targeted disruption of murine Cyp4a genes provides insight into the roles of renal monooxygenases and epoxygenases in the regulation of salt excretion and blood pressure.
PPARa agonists induce the expression of renal tubular monoxygenases and epoxygenases and decrease blood pressure in both Ang II- dependent and salt-sensitive rodent models of hypertension.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Ambulatory subjects, 18-70 years of age, inclusive
- •For female subjects, the following conditions must be met Postmenopausal status for at least 1 year, or Status post surgical sterilization, or If of childbearing potential, utilization of adequate birth control and willingness to undergo urine beta-hcg testing prior to drug treatment and on every study day
排除标准
- •Secondary causes of hypertension
- •Diabetes type 1 or type 2 as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication
- •Use of hormone replacement therapy
- •Statin or fibrate therapy
- •A seated systolic blood pressure(SBP) greater than 179 mmHg or a seated diastolic blood pressure(DBP) greater than 110 mmHg
- •Pregnancy
- •Breast-feeding
- •Cardiovascular disease such as history of myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure, (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
- •Treatment with anticoagulants
- •History of serious neurologic diseases such as cerebral hemorrhage,stroke, or transient ischemic attack
- •History or presence of immunological or hematological disorders
- •Diagnosis of asthma
- •Clinically significant gastrointestinal impairment that could interfere with drug absorption
- •Impaired hepatic function (aspartate aminotransferase [AST] and or alanine aminotransferase [ALT] > 2.0 x upper range)
- •Known preexisting gallbladder disease
- •Impaired renal function (eGFR < 60 ml/min/1.73M2)
- •Hematocrit < 35%
- •Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
- •Treatment with a glucocorticoid therapy
- •Treatment with lithium salts
- •History of of alcohol or drug abuse
- •Treatment with any investigational drug in the 1 month preceding the study
- •Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
- •Inability to comply with the protocol, e.g uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
研究组 & 干预措施
Placebo, then fenofibrate
Randomized study of fenofibrate versus placebo during high salt diet
干预措施: fenofibrate (Drug)
Placebo, then fenofibrate
Randomized study of fenofibrate versus placebo during high salt diet
干预措施: Placebo (Drug)
Fenofibrate, then placebo
Randomized study of fenofibrate versus placebo during high salt intake.
干预措施: fenofibrate (Drug)
Fenofibrate, then placebo
Randomized study of fenofibrate versus placebo during high salt intake.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment
时间窗: pressure measured on day 6 of high salt fenofibrate minus pressure measured on day 6 of high salt placebo
Difference in blood pressure (mean arterial pressure) measured on the last day of high salt intake and fenofibrate treatment minus blood pressure (mean arterial pressure) measured during high salt intake and placebo treatment in participants classified as being salt-sensitive versus salt-resistant. Participants were classified as salt-sensitive if the average study day mean arterial pressure (MAP) was at least 5 mmHg higher during the high salt placebo arm than during low salt intake.
次要结局
- HDL-cholesterol Measured During High Salt Fenofibrate in Salt-resistant and Salt-sensitive Hypertension(Measured on day 6 of high salt intake and fenofibrate treatment)
研究者
Nancy J. Brown
Professor of Medicine
Vanderbilt University