Uric Acid Effects on Endothelium and Oxydative Stress

• Status: Completed
• Trial end date: 2020-02-27
• Target enrollment: 0
• Participant gender: All

Summary

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:

1. An extremely low level of uric acid after uricase administration induces endothelial dysfunction and oxydative stress,

2. A specific XO inhibitor limits unfavourable effects of the serum UA reduction elicited by uricase administration,

3. Endothelial function and oxydative stress are further improved with febuxostat as compared to placebo,

4. All these observations are more marked in hypertensives then in older participants than in young healthy subjects.

• Phase: N/A
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Erasme University Hospital
• Collaborators: Fonds Erasme; Fonds National de la Recherche Scientifique
• Treatments: Febuxostat; Rasburicase

Criteria

Phase 1 :

Inclusion Criteria:

• Age between 18 and 40 years

• Male

• 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).

Phase 2 :

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).

Phase 3 :

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%)

• Diabetes

• Active smoking

• Gout

• 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.