Effect of Drugs on Colonic Eicosanoid Accumulation in Active Ulcerative Colitis

Abstract

The effect of immunosuppressive drugs, 4-aminosalicylic acid (4-ASA), acetyl 5-aminosalicylic acid (S-ASA), and ketotifen on human colonic eicosanoid accumulation was evaluated in view of enhanced accumulation in patients with active ulcerative colitis. Azathioprine (100 üg/ml), cyclosporin (100 üg/ml), and methotrexate (100 üg/ml) significantly inhibited, by 25–35%, prostaglandin E, (PGE,) accumulation by organ-cultured colonic mucosa of ulcerative colitis patients. Methotrexate was the only immunosuppressive drug that inhibited leukotriene B₄ (LTB₄) accumulation (50%), whereas azathioprine inhibited the accumulation of leukotriene C₄ (LTC,) (25%). 5-ASA and its metabolite, acetyl 5-ASA, inhibited by 20–70% PGE₂, LTB, and LTC₄ accumulation in the culture, supporting the contention that acetyl 5-ASA is as active as 5-ASA in these respects. 4-ASA had no effect on any of the eicosanoids. Ketotifen, a mast cell stabilizer, significantly inhibited the accumulation of PGE₂, LTB₄, and LTC₄ by 33–60%. These results suggest a potential, new, unrecognized mode by which the immuno-modulators induce part of their therapeutic effects in inflammatory bowel disease and support the contention that acetyl 5-ASA is as active as 5-ASA. The results obtained also indicate that ketotifen, used effectively in the prevention of bronchial asthma, inhibits the accumulation of colonic eicosanoids and, thus, may be of value in the treatment of inflammatory bowel disease.

Key Words:

• Acetyl 5-aminosalicylic acid
• 4-aminosalicylic acid
• 5-aminosalicylic acid
• azathioprine
• chloroquine
• cyclosporin
• ketotifen
• methotrexate
• ulcerative colitis