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Allopurinol: novel indications in cardiovascular disease
  1. Allan Struthers,
  2. Fiona Shearer
  1. Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, UK
  1. Correspondence to Professor Allan Struthers, Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee DD1 9SY, UK; a.d.struthers{at}dundee.ac.uk

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Introduction

Allopurinol has been used for the treatment of gout for the last 40 years, but it is only in the last 15 years that there has been a gathering realisation of its potential benefits in cardiovascular disease. In order to explain its potential clinical benefits, it is best to first review its pharmacology and clinical pharmacology.

Pharmacology/clinical pharmacology

The culprit in gout is the accumulation of uric acid in joints. Uric acid is formed mainly by the enzyme, xanthine oxidase, which converts hypoxanthine and oxygen into uric acid and superoxide and other oxidative free radicals. (figure 1)

Figure 1

Pharmacology of xanthine oxidase.

From the above it is clear that inhibiting xanthine oxidase would reduce uric acid and, thereby, the tendency to gout. Allopurinol is an inhibitor of xanthine oxidase (XO) and, hence, is very effective in the prophylaxis of gout. However, as can be seen from figure 1, allopurinol will exert other key effects which might translate into clinical benefit. The other key effects of allopurinol are, first, to reduce superoxide anions and other free radicals which exert oxidative stress (OS); second, to increase tissue oxygen, and third, to increase hypoxanthine. Each of these three effects could exert extra clinical benefits (box 1).

Box 1

Potential pharmacological benefits of xanthine oxidase inhibitors

  • Improves endothelial/vascular dysfunction.

  • Reduces vascular tissue oxidative stress.

  • Increases ATP/energy in ischaemic tissue.

  • Reduces exercise induced myocardial ischaemia.

  • Increases tissue oxygen in ischaemic tissue.

The first effect mentioned above is to reduce OS. OS is thought to exert many harmful effects, such as inactivating nitric oxide, forming harmful peroxynitrite and perhaps, encouraging plaque rupture. A major caveat in the whole OS story is, of course, that in large multicentre trials, antioxidant vitamins did not reduce CV events. This may well be because the doses of antioxidant …

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