Uric Acid Effects on Endothelium and Oxydative Stress

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.

Conditions

• Oxidative Stress
• Endothelial Function
• Cardiovascular System
• Hypertension

Interventions

DRUG

Placebos

Lactose placebo for pills and saline for perfusion.

DRUG

Febuxostat

Febuxostat tablet.

DRUG

Rasburicase

Rasburicase injectable solution.

Sponsors & Collaborators

• Fonds Erasme

  collaborator UNKNOWN

• Fonds National de la Recherche Scientifique

  collaborator OTHER

• Erasme University Hospital

  lead OTHER

Principal Investigators

• Philippe van de Borne · Erasme hospital

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2018-01-03

Primary Completion

2019-12-31

Completion

2020-02-27

Countries

• Belgium

Study Locations