Differential Effects of Uric Acid and Xanthine Oxidoreductase on Endothelial Function and Oxydative Stress
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 53
- 试验地点
- 1
- 主要终点
- Cutaneous perfusion by Laser Doppler (perfusion unit)
研究概览
简要总结
Cardiovascular disease is the leading cause of mortality worldwide. Endothelial dysfunction (ED) is the main mechanism which leads to atherosclerosis, where the balance between pro and antioxidant factors results in a decreased nitric oxide (NO) bioavailability. Xanthine OxidoReductase (XOR) is one of the main generators of reactive oxygen species (ROS). Uric acid (UA), a major antioxidant in human plasma and end product of purine metabolism, is associated with cardiovascular diseases since many years; however the precise mechanisms which relate UA to ED are still not well understood.
The purpose of this study is to unravel the XOR and UA pathways involved in ED. Three groups of participants (young (< 40 y) male healthy participants [1] ; male and female helthy participants (40 to 65 y) [2] and patients with primary hypertension [3]) will be exposed to febuxostat (a strong and selective XOR inhibitor), or recombinant uricase (which oxidizes UA into allantoin) to vary UA levels and concomitantly control for confounding changes in XOR activity. Oxidative stress will be estimated by several markers. Endothelial function will be assessed by a laser Doppler imager in the presence of hyperthermia and endothelium stimulators. This study is specifically designed to untie the respective effects of UA and XOR pathways on oxidative stress and endothelial function in humans.
The investigators will test the following hypothesis:
- An extremely low level of uric acid after uricase administration induces endothelial dysfunction and oxydative stress,
- A specific XO inhibitor limits unfavourable effects of the serum UA reduction elicited by uricase administration,
- Endothelial function and oxydative stress are further improved with febuxostat as compared to placebo,
- All these observations are more marked in hypertensives then in older participants than in young healthy subjects.
详细描述
The goals of the research protocol are to clearly untie the respective roles of uric acid (UA) and xanthine oxidoreductase (XOR) pathways on endothelial function and oxidative stress in humans.
UA represents the end-product of purine metabolism due to the loss of uricase 15 million years ago in humans. The selective advantage of this mutation could be the strong antioxidant effect of UA (which represents more than 60% of the antioxidant plasmatic capacity). Many recent epidemiological studies have showed a J-shape association between UA levels and cardiovascular risk. An UA level lower than 3 mg/dl could be damageable due to the loss of the antioxidant properties of UA. In contrast, hyperuricemia is associated with an increased inflammation, insulin resistance, ED, platelet aggregation, left ventricle hypertrophy, arterial vasodilatation impairment, aortic stiffness and intima-media thickness. However, the association between UA and cardiovascular disease remains controversial because whether UA is an independent risk factor for these illnesses is unclear.
Interventional studies:
Because the above-mentioned associations do not prove causation, several authors designed interventional studies with the purpose to modify UA levels and determine if this affected endothelial function and oxidative stress. The main limitation of these studies is that they were unable to untie the effects of the synthesis of UA, of UA itself and of the activity of XOR, on ROS production and endothelial function in humans.
This is because:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
Febuxostat and Rasburicase will be prepared by an independant pharmacist.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age between 18 and 40 years
- •Healthy volunteers
- •Non smoker for at least 6 months
- •Uric acid level in normal range (normouricemic group)
排除标准
- •Any diseases of one of the following systems: cardiovascular, digestive, hormonal, urinary, pulmonary, rheumatic or immune.
- •Smoker, alcoholic
- •Participants should not take any chronic medicine nor vitamins or other antioxidants.
- •A G6PD deficit will be excluded as this is a contraindication to uricase administration (hemolytic anemia).
- •Inclusion Criteria:
- •Age between 40 and 65 years
- •Male or female (menopaused)
- •Healthy volunteers
- •Non smoker for at least 6 months
- •Uric acid level in normal range (normouricemic group)
- •Exclusion Criteria:
- •Any diseases of one of the following systems: cardiovascular, digestive, hormonal, urinary, pulmonary, rheumatic or immune.
- •Smoker, alcoholic
- •Participants should not take any chronic medicine nor vitamins or other antioxidants.
- •A G6PD deficit will be excluded as this is a contraindication to uricase administration (hemolytic anemia).
- •Inclusion Criteria:
- •Age between 40 and 65 years
- •History of hypertension for more than 6 months
- •Non smoker or smoke stopped for at least for 6 months
- •Exclusion Criteria:
- •Acute coronary syndrome
- •Heart failure (LVEJ < 40%)
- •Active smoking
- •Chronic kidney disease stage superior to 3a
- •History of cerebrovascular thrombosis
- •Cirrhosis
- •Alcohol consumption more than 3 units/day
- •Participants should not take any chronic medicine nor vitamins or other antioxidants.
- •A G6PD deficit will be excluded as this is a contraindication to uricase administration (hemolytic anemia).
- •The populations of phases 2 and 3 will be enrolled and studied together with subgroups analyses of the results for the status of hypertension, of treatment, age and gender.
研究组 & 干预措施
Placebos PO and IV
PO : per os IV : intraveinously
干预措施: Placebos (Drug)
Febuxostat PO and Placebo IV
240 mg a day for 3 days
干预措施: Placebos (Drug)
Febuxostat PO and Placebo IV
240 mg a day for 3 days
干预措施: Febuxostat (Drug)
Febuxostat PO And Rasburicase IV
Febuxostat : 240 mg a day for 3 days. Uricase : 3 mg once.
干预措施: Febuxostat (Drug)
Febuxostat PO And Rasburicase IV
Febuxostat : 240 mg a day for 3 days. Uricase : 3 mg once.
干预措施: Rasburicase (Drug)
Placebo PO And Rasburicase IV
Placebo : for 3 days. Uricase : 3 mg once.
干预措施: Placebos (Drug)
Placebo PO And Rasburicase IV
Placebo : for 3 days. Uricase : 3 mg once.
干预措施: Rasburicase (Drug)
结局指标
主要结局
Cutaneous perfusion by Laser Doppler (perfusion unit)
时间窗: 24 hours after infusion of Uricase or Placebo
Perfusion unit (Laser Doppler Imager + iontophoresis of (ACh and SNP and hyperemia with ou without L-NAME). Assessment of endothelial function.
次要结局
- Arterial stiffness(24 hours after infusion of Uricase or Placebo)
- Change in Oxydative stress biomarkers from baseline to 30 min or 24 hours after infusion of Uricase or Placebo(Baseline, 30 minutes and 24 hours after infusion of Uricase or Placebo)
- Change in enzymes activity(30 min and 24 hours after infusion of Uricase or Placebo)
- Blood pressure (mmHg)(24 hours after infusion of Uricase or Placebo)
- Cardiac output (l-min)(24 hours after infusion of Uricase or Placebo)
- Change in enzymes expression(30 min and 24 hours after infusion of Uricase or Placebo)
- Change in urinary excretion of sodium(Baseline, 30 minutes and 24 hours after infusion of Uricase or Placebo)
- Change in proteomic or metabolomic analysis(30 min and 24 hours after infusion of Uricase or Placebo)
- Change in renin-angiotensin activity(Baseline, 30 minutes and 24 hours after infusion of Uricase or Placebo)
研究者
Benjamin De Becker
Investigator, Clinical Research
Erasme University Hospital