COX 2 inhibitors can affect the stomach lining

BMJ 1999; 319 doi: (Published 11 December 1999) Cite this as: BMJ 1999;319:1518
  1. Deborah Josefson
  1. San Francisco

    A new class of analgesics designed to be less ulcerogenic than traditional non-steroidal anti-inflammatory drugs may not protect the gastric lining after all, according to a University of California study (Nature Medicine 1999;5:1415-23, 1348-9).

    Their ulcerogenic effect may stem from their antiangiogenic properties, and as such they may be useful anticancer drugs.

    The analgesics, agents known as selective cyclo-oxygenase-2 (COX 2) inhibitors, were specifically designed to be less harmful to the gastric mucosal lining than traditional non-steroidal anti-inflammatory medications such as aspirin, indomethacin, and ibuprofen, which block the activity of both cyclo-oxygenase-1 (COX 1) and COX 2 to some extent.

    The cyclo-oxygenases are enzymes that catalyse various reactions in prostaglandin synthesis. Previously, COX 1 was thought to be solely responsible for catalysing reactions that produced protective prostaglandins—such as those involved in maintaining the integrity of the gastric lining, regulating renal blood flow by keeping the renal blood vessels open, and maintaining platelet function. Inhibition of COX 1 could therefore produce deleterious as well as anti-inflammatory side effects

    COX 2, meanwhile, was thought to catalyse the synthesis of painful prostaglandins such as those mediating inflammation. The theory was that selective inhibition of COX 2 would yield a safer anti-inflammatory agent.

    Non-steroidal anti-inflammatory drugs are widely used for headache, menstrual cramps, musculoskeletal pain syndromes, and arthritis. Additionally, they are widely prescribed for both primary and secondary prevention of both heart attack and stroke. Recently they have received attention as useful agents in decreasing the severity of Alzheimer's disease as well as in possibly preventing the formation of adenomatous polyps and colon cancer.

    Up to a quarter of patients taking these drugs, however, experience side effects such as gastroduodenal ulcers, delayed wound healing, bleeding, and perforated ulcers.

    Researchers led by Dr Michael Jones of the Veterans Affairs Medical Center in Long Beach, California, compared the antiangiogenic properties of a selective COX 2 inhibitor, NS-398, with those of a non-selective non-steroidal anti-inflammatory drug, indomethacin, in in vitro assays of angiogenesis using aortic endothelial cells from rats, human dermal microvascular cells, and endothelial cells from the human umbilical vein.

    Both indomethacin and NS-398 substantially inhibited angiogenesis in all cell lines studied. The extent of inhibition was similar for both.

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