Blockade of leukotriene production by a single oral dose of MK-0591 in active ulcerative colitis.

Abstract

BACKGROUND:

5-Lipoxygenase products of arachidonic acid metabolism are thought to play a central role in the secondary amplification of the inflammatory response in a number of human inflammatory diseases, such as ulcerative colitis. MK-0591 (3-(1((4-chlorophenyl)methyl)-3((1,1-dimethyl-ethyl)thio)-5(quinolin+ ++-2ylmethyl-oxy)-1H-indol-2yl)-2,2-dimethyl-propanoate) exerts its effect by binding to the 5-lipoxygenase activating protein, thereby inhibiting the translocation and activation of 5-lipoxygenase.

METHODS:

Concentrations of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in rectal dialysis fluid, ex vivo biosynthesis of LTB4 in whole blood, and urinary excretion of leukotriene E4 (LTE4) from 16 patients with mild to moderately active distally located ulcerative colitis were measured by use of radioimmunoassays in a double-blind, placebo-controlled parallel-design study before and after oral administration of a 250 mg dose of MK-0591 or placebo.

RESULTS:

The mean LTB4 concentration in rectal dialysis fluid was lowered after MK-0591 by > 90% (p < 0.05) from 4 to 8 hours, with a maximum inhibition of 97.5% +/- 3.4% (mean +/- SD) at 20 to 24 hours after dosing, whereas PGE2 was unchanged. In whole blood, MK-0591 decreased ex vivo biosynthesis of LTB4 (p < 0.01), with a maximum inhibition of 96.4% +/- 2.1% at 4 hours after dosing. Urinary excretion of LTE4 was reduced by more than 85% (p < 0.001) from 4 to 48 hours. No adverse events were observed.

CONCLUSION:

These findings show that a single oral 250 mg dose of MK-0591 results in nearly complete blockade of systemic leukotriene production and LTB4 formation in the target tissue of inflammation (the rectum). Controlled multiple-dose trials to assess the clinical efficacy of this novel 5-lipoxygenase-activating protein inhibitor seem to be worthwhile.

• Authors: J Hillingsø, J Kjeldsen, L S Laursen, K Lauritsen, S von Spreckelsen, M Depré, B S Friedman, K Malmström, S Shingo, K Bukhave
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 57 Issue 3 Pg. 335-41 (Mar 1995) ISSN: 0009-9236 [Print] United States
• PMID: 7697951 (Publication Type: Clinical Trial, Controlled Clinical Trial, Journal Article, Randomized Controlled Trial)

Chemical References

• Indoles
• Quinolines
• MK 0591
• Leukotriene B4
• Dinoprostone

Topics

• Acute Disease
• Administration, Oral
• Adult
• Colitis, Ulcerative (metabolism)
• Dinoprostone (antagonists & inhibitors, biosynthesis)
• Double-Blind Method
• Female
• Humans
• Indoles (administration & dosage, pharmacology)
• Leukotriene B4 (antagonists & inhibitors, biosynthesis)
• Male
• Middle Aged
• Quinolines (administration & dosage, pharmacology)