Arginine Protects Against NSAID-Induced Gastrointestinal Toxicity

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 8 No. 1 • January 2005

Arginine Protects Against NSAID-Induced Gastrointestinal Toxicity

One of the reasons that selective COX-2 inhibitors were developed is that nonsteroidal anti-inflammatory drugs such as ibuprofen or aspirin can cause gastric mucosal injury, including bleeding, because they inhibit COX-1. About 16,000 Americans die each year from NSAID-induced gut hemorrhage. The COX-2 inhibitors celecoxib, rofecoxib, and valdecoxib were approved by the FDA on the basis of trials lasting typically three to six months that had as their end point endoscopically visualized gastric ulcerations.1 Hence, the focus was on gastric injury, even though early trials (e.g., Vigor® with Vioxx) noted a significant increase by a factor of five in the incidence of heart attack, while serious gastrointestinal events among those receiving rofecoxib were half that of those receiving the traditional NSAID naproxen (Aleve®).1

Two recent papers report on the protective effects of arginine against the gastric lesions induced by NSAIDs. In the first,2 the authors note that nitric oxide (NO) is a potent inhibitor of white cell adhesion to the microvasculature, an early event in the initiation of many types of gut injury, including that of NSAIDs. They note that many NO-releasing drugs used as vasodilators (such as glyceryl trinitrate, isoamyl nitrate, and nitroprusside) are protective against acute hemorrhagic mucosal injury caused by topical irritants. Transdermal application of nitroglycerin prevented mucosal damage that would otherwise have been caused by the NSAID indomethacin via effects on blood flow and leukocyte adhesion.

The second paper3 found that arginine, the amino acid precursor of nitric oxide, was protective against gastric injury induced by the NSAID ibuprofen. Male Wistar rats were the unfortunate subjects. Rats receiving oral administration of 100 mg/kg of ibuprofen suffered severe damage to the gastric mucosa, accompanied by a significant increase in myeloperoxidase activity, indicating increased neutrophil activation. Treatment with equimolar doses of arginine* along with the ibuprofen resulted in considerably reduced number and intensity of lesions. Arginine also significantly decreased the hemorrhagic score. The activity of xanthine oxidase, a major source of oxidative stress that the authors believe may be involved in NSAID-induced gastric lesions, was significantly inhibited by arginine.

*This is a very small amount; the amount of arginine in a dietary supplement is far larger than the usual human dose of ibuprofen.

The authors2 note that a conservative estimate for those using NSAIDs suffering digestive complications at some time is 20–50% and that 1–2% of those using NSAIDs continuously are hospitalized each year. Hence, these results suggest that use of arginine concurrently with ibuprofen or other COX-1 inhibiting NSAIDs might prevent many of these complications and even hospitalizations.

  1. FitzGerald. Coxibs and cardiovascular disease. New Engl J Med 351(17):1709-11 (2004).
  2. Whittle. Nitric oxide and the gut injury induced by non-steroidal anti-inflammatory drugs. Inflammopharmacol 11(4-6):415-22 (2003).
  3. Jimenez et al. Role of L-arginine in ibuprofen-induced oxidative stress and neutrophil infiltration in gastric mucosa. Free Rad Res 38(9):903-11 (2004).

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