J Van Schoor, GF Joos, JC Kips, JF Drajesk, PJ Carpentier and RA Pauwels
Department of Respiratory Diseases, University Hospital, Ghent, Belgium.

Leukotrienes have been implicated in the bronchoconstriction caused by indirect stimuli. In the present study we examined the effect of oral ABT-761, a novel 5-lipoxygenase (5-LO) inhibitor, on exercise- and adenosine (AMP)-induced bronchoconstriction in nine asthmatics. At the four 1-d, single-dose treatment periods, ABT-761 (200 mg) or placebo (P) was ingested 5 h before challenge in a double-blind, crossover fashion. At study periods 1 and 2 the subjects performed an exercise challenge and at study periods 3 and 4 an AMP challenge. Pretreatment with ABT-761 caused a significant inhibition of the maximal percentage fall of FEV1 from baseline (p = 0.037) and a reduction of the percentage fall in FEV1 (area under the curve, AUC) of 61.4 +/- 14.1% (mean +/- SEM) after exercise challenge (p = 0.021). Although pretreatment with ABT-761 did not significantly inhibit the maximal fall of FEV1 after AMP challenge (p = 0.134), the overall bronchoconstriction was significantly inhibited, the AUC being reduced by a mean (+/- SEM) of 82.7 +/- 7.2% (p = 0.012). There was no significant correlation between the protective effect against exercise and that against AMP for individual patients. The percentage change in urinary leukotriene E4 (LTE4) excretion at exercise was + 18.1 +/- 10.9% on placebo and -44.8 +/- 6.2% after ABT-761 (p = 0.017); changes at adenosine were + 38.5 +/- 27.0% on placebo and -36.7 +/- 9.8% after ABT-761 (p = 0.028). On placebo, exercise produced a marked stimulation of the ex vivo LTB4 production, whereas adenosine was associated with only a minor increase; ABT-761 caused a greater than 90% inhibition (p < 0.05 for both challenges). We conclude that ABT-761 is a potent and long-acting 5-LO inhibitor which significantly attenuates exercise- and adenosine-induced bronchoconstriction, indicating that leukotrienes are important mediators in both challenges.

This article has been cited by other articles:

				L. Prieto, I. Reig, R. Rojas, A. Ferrer, and J. Domenech The effect of challenge method on sensitivity and reactivity to adenosine 5'-monophosphate in subjects with suspected asthma. Chest, November 1, 2006; 130(5): 1448 - 1453. [Abstract] [Full Text] [PDF]

				Z. Csoma, E. Huszar, E. Vizi, G. Vass, Z. Szabo, I. Herjavecz, M. Kollai, and I. Horvath Adenosine level in exhaled breath increases during exercise-induced bronchoconstriction Eur. Respir. J., May 1, 2005; 25(5): 873 - 878. [Abstract] [Full Text] [PDF]

				L. Prieto, L. Bruno, V. Gutierrez, S. Uixera, C. Perez-Frances, A. Lanuza, and A. Ferrer Airway Responsiveness to Adenosine 5'-Monophosphate and Exhaled Nitric Oxide Measurements: Predictive Value as Markers for Reducing the Dose of Inhaled Corticosteroids in Asthmatic Subjects Chest, October 1, 2003; 124(4): 1325 - 1333. [Abstract] [Full Text] [PDF]

				H. Zhong, S. G. Shlykov, J. G. Molina, B. M. Sanborn, M. A. Jacobson, S. L. Tilley, and M. R. Blackburn Activation of Murine Lung Mast Cells by the Adenosine A3 Receptor J. Immunol., July 1, 2003; 171(1): 338 - 345. [Abstract] [Full Text] [PDF]

				G.F. Joos and B. O'Connor Indirect airway challenges Eur. Respir. J., June 1, 2003; 21(6): 1050 - 1068. [Abstract] [Full Text] [PDF]

				L. Prieto, S. Uixera, V. Gutierrez, and L. Bruno Modifications of Airway Responsiveness to Adenosine 5'-Monophosphate and Exhaled Nitric Oxide Concentrations After the Pollen Season in Subjects With Pollen-Induced Rhinitis* Chest, September 1, 2002; 122(3): 940 - 947. [Abstract] [Full Text] [PDF]

				R. Polosa Adenosine-receptor subtypes: their relevance to adenosine-mediated responses in asthma and chronic obstructive pulmonary disease Eur. Respir. J., August 1, 2002; 20(2): 488 - 496. [Abstract] [Full Text] [PDF]

				R Polosa, S Rorke, and S T Holgate Evolving concepts on the value of adenosine hyperresponsiveness in asthma and chronic obstructive pulmonary disease Thorax, July 1, 2002; 57(7): 649 - 654. [Abstract] [Full Text] [PDF]

				L. Prieto, V. Gutierrez, and S. Uixera Exhaled Nitric Oxide and Bronchial Responsiveness to Adenosine 5'-Monophosphate in Subjects With Allergic Rhinitis* Chest, June 1, 2002; 121(6): 1853 - 1859. [Abstract] [Full Text] [PDF]

				S Rorke, S Jennison, J A Jeffs, A P Sampson, H Arshad, and S T Holgate Role of cysteinyl leukotrienes in adenosine 5`-monophosphate induced bronchoconstriction in asthma Thorax, April 1, 2002; 57(4): 323 - 327. [Abstract] [Full Text] [PDF]

				B. Dahlen, P.M. O'Byrne, R.M. Watson, A. Roquet, F. Larsen, and M.D. Inman The reproducibility and sample size requirements of exercise-induced bronchoconstriction measurements Eur. Respir. J., April 1, 2001; 17(4): 581 - 588. [Abstract] [Full Text] [PDF]

				A. N. Freed, S. McCulloch, and Y. Wang Eicosanoid and muscarinic receptor blockade abolishes hyperventilation-induced bronchoconstriction J Appl Physiol, November 1, 2000; 89(5): 1949 - 1955. [Abstract] [Full Text] [PDF]

				A. N. Freed, Y. Wang, S. McCulloch, T. Myers, and R. Suzuki Mucosal injury and eicosanoid kinetics during hyperventilation-induced bronchoconstriction J Appl Physiol, November 1, 1999; 87(5): 1724 - 1733. [Abstract] [Full Text] [PDF]