Xanthine Oxidase Inhibition for the Prevention of Recurrent Stroke

Allopurinol, a commonly used drug for gout, a form of arthritis may reduce risk of stroke and be a useful treatment for angina and heart failure. We are performing clinical trials of the effect of allopurinol on blood vessels in patients who have suffered stroke and are moving towards a large study where we measure the effect of allopurinol on rate of stroke.

Novel preventative strategies are needed after stroke and allopurinol may be such a measure. Allopurinol inhibits activity of xanthine oxidase leading to reduction in both serum uric acid (UA) level and oxidative stress via reduced superoxide anion production. Higher serum UA is associated with increased risk of cardiovascular disease, adverse outcomes after ischaemic stroke and with cognitive impairment. Allopurinol reduces UA by as much as 60% in patients with cardiovascular disease and without serious adverse effects and may deliver benefits independent of uric acid reduction. We have shown that allopurinol 300 mg per day improves cerebral nitric oxide bioavailability in patients with type 2 diabetes, reduces markers of inflammation after ischaemic stroke and have just completed a one year pilot randomised double blind placebo-controlled study of allopurinol 300 mg per day in 80 patients with ischaemic stroke. This measured the effect of allopurinol on carotid intima media thickness and gave promising results.
We have also completed a systematic review and meta-analysis which aimed to identify all studies of xanthine oxidase inhibition that evaluated a measure of cardiovascular function or health. Thirty-six manuscripts (a total of 38 studies) were identified and on meta-analysis and allopurinol significantly improved a variety of endpoints including brachial artery flow mediated dilatation, a measure of endothelial function.
Other groups have shown allopurinol causes regression of left ventricular hypertrophy in patients with diabetes, renal impairment and angina and that it reduces myocardial ischaemia in patients with angina, reduces augmentation index and has a small effect on lowering arterial blood pressure.
The next step is to confirm these benefits are sustained and that benefit is seen on more robust long term markers of cardiovascular disease and that allopurinol lowers risk of stroke.

Publications

1. Higgins P, Dawson J, Lees KR, McArthur K, Quinn TJ, Walters MR. Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. Cardiovascular Therapeutics 2011. Published on –line June 2011.
2. Dawson J, Quinn TJ, Harrow C, Lees KR, Walters MR. The effect of allopurinol on the cerebral vasculature of patients with subcortical stroke; a randomized trial. British Journal of Clinical Pharmacology 2009;68:662-668
3. Dawson J, Lees KR, Weir CJ et al. Baseline Serum Urate and 90-Day Functional Outcomes Following Acute Ischemic Stroke. Cerebrovascular Diseases 2009;28:202-203
4. Dawson J, Quinn TJ, Harrow C, Lees KR, Weir CJ, Cleland SJ, Walters MR. Allopurinol and nitric oxide activity in the cerebral circulation of those with diabetes. Diabetes Care 2009;32:135-37
5. Muir S, Harrow C, Dawson J, Lees KR, Weir CJ, Sattar N, Walters MR. Allopurinol Use Yields Potentially Beneficial Effects on Inflammatory Indices In Those With Recent Ischemic Stroke; a Randomised, Double Blind Placebo Controlled Trial. Stroke 2008;39:3303-3307.
6. Dawson J, Quinn TQ, Walters MR. Xanthine Oxidase Inhibition – A New Paradigm in Management of Cardiovascular Risk. Current Medicinal Chemistry 2007;14:1879-86.
7. Dawson J, Walters MR. Uric Acid and Xanthine Oxidase: Future Therapeutic Targets in the Prevention of Cardiovascular Disease? BJCP 2006;62:633-644.