Effects of Tetrahydrobiopterin on Blood Pressure
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Evaluate the effects of BH4 on BP
研究概览
简要总结
Tetrahydrobiopterin (BH4) is a cofactor for the nitric oxide (NO) synthase enzymes, such that its insufficiency results in uncoupling of the enzyme, leading to release of superoxide rather than NO in disease states, including hypertension. We hypothesized that oral BH4 will reduce arterial blood pressure (BP) and improve endothelial function in hypertensive subjects. Oral BH4 was given to subjects with poorly controlled hypertension (BP >135/85 mm Hg) and weekly measurements of BP and endothelial function made. In Study 1, 5 or 10 mg kg-1 day-1 of BH4 (n=8) was administered orally for 8 weeks, and in Study 2, 200 and 400 mg of BH4 (n=16) was given in divided doses for 4 weeks
详细描述
Problem of Interest:
Blood vessels are lined by a single layer of cells called the endothelium. These cells actively release substances that influence a variety of functions including blood flow in the arteries. Nitric oxide (NO) is among the most important of these substances. Decrease in NO reduces blood vessel size and increases blood pressure (BP). Subjects with hypertension (high blood pressure) and those with a strong family history of hypertension but without high blood pressure also exhibit endothelial dysfunction and decreased NO activity. This abnormality predisposes individuals with high blood pressure to an increased long term risk of adverse cardiovascular events such as heart attack and stroke.
NO is produced in cells by a reaction mediated by the enzyme endothelial nitric oxide synthase (eNOS). Experimental studies performed at Emory University have shown that tetrahydrobiopterin (BH4), a naturally produced substance, is an essential factor for eNOS to be normally active, because in the event of BH4 deficiency, eNOS switches from producing NO to generating oxygen free radicals that increase oxidant stress in blood vessels leading to vascular damage. Moreover, studies have shown that administration of BH4 to animals with hypertension decreases blood pressure.
A recently completed study performed by the researchers at Emory University showed that BH4 pills given twice a day to 8 patients with poorly controlled high blood pressure for eight weeks improved endothelial function and decreased blood pressure without any significant side effects. After stopping BH4, the blood pressure and endothelial function returned to baseline.
Hypertension has also been linked with diastolic heart failure, a condition where the squeeze of the heart is normal but it relaxes abnormally causing shortness of breath, edema and fatigue. Up to one half of cases of heart failure are caused by diastolic heart failure. Recent evidence shows that the lining cells of the heart also produce NO and that this promotes relaxation of the heart. In addition, studies here at Emory have shown that in animals with high blood pressure, NO production in the heart is reduced compared to normals.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female patients without childbearing potential between the ages of 18 and 75 years
- •History of documented essential hypertension or newly diagnosed hypertension (BP >140 mmHg systolic and/or 90 mmHg diastolic measured on 2 separate occasions)
- •Patients on conventional anti-hypertensive therapy with poorly controlled hypertension (BP >135/85 mmHg). Their anti-hypertensive regimen will remain unchanged throughout the study period. Patients will not need to stop taking their prescribed anti-hypertensives.
- •Controls will be recruited for part 2 of the study. These will be patients who meet the age and childbearing criteria above, who have no history of hypertension, arterial BP of <130 systolic and <85 diastolic, no evidence of diabetes mellitus, total cholesterol <240 and be non-smoking for at least six months.
- •Patients can be at any stage of hypertension. They can be at any performance status. The only requirement will be that they be able to come to scheduled follow up visits either by themselves or with assistance. Patients will need to be able to give informed consent.
排除标准
- •Female subjects with childbearing potential.
- •History of symptomatic coronary or peripheral vascular disease.
- •Known secondary causes for hypertension
- •Severe uncontrolled hypertension (BP >180 mmHg systolic and /or 110 mmHg diastolic).
- •Severe co-morbid conditions which would limit life expectancy to less than 6 months.
- •Patients unable to give informed consent or adhere to the protocol.
- •Patients participating in another study protocol.
- •Patients with organ failure, creatinine >2.5 mg/dL or hepatic enzymes >2X normal
- •Recent (within 6 weeks) alteration of any concomitant therapy.
- •Presence of intercurrent illness
- •Bleeding disorders
研究组 & 干预措施
Dose-response of oral BH4
Eight subjects received 100 mg of oral BH4 twice a day and 8 received 200 mg twice daily.
干预措施: Tetrahydrobiopterin (Drug)
Onset & duration of action of oral BH4
Eight hypertensive subjects were assigned to either 5 mg kg-1 day-1 (n=4) or 10 mg kg-1 day-1 (n=4) of BH4, given in two divided doses orally for 8 weeks.
干预措施: Tetrahydrobiopterin (Drug)
结局指标
主要结局
Evaluate the effects of BH4 on BP
次要结局
- Evaluate the effects of BH4 on vascular function
研究者
Arshed A. Quyyumi
Professor
Emory University