Short paper Effect of a novel 5-lipoxygenase activating protein inhibitor, BAYx 1005, on asthma induced by cold dry air

the eucapnic hyperventilation of cold dry air. The precise mechanism of this effect, including Background – Leukotrienes have been imthe role of biochemically active mediators, is plicated in the mediation of airway obunknown. The cysteinyl leukotrienes (LTC4, struction induced by hyperventilation of LTD4, and LTE4) are potent mediators of cold dry air in asthmatic subjects. The bronchoconstriction that possess proinflameffect of a novel inhibitor of 5-lipoxygenase matory properties. They have been implicated activating protein, BAYx 1005, on the in the pathobiology of asthma, including bronchospastic response to cold dry air asthma induced by cold dry air. 2 hyperventilation was investigated in asthThe first dedicated step in the biosynthesis matic patients. of the cysteinyl leukotrienes is the introduction Methods – After a screening cold dry air of molecular oxygen into arachidonic acid hyperventilation challenge to document which results in the formation of 5-hydrocold air responsiveness, 16 asthmatic subperoxyeicosatetraenoic acid, which in turn is jects (baseline forced expiratory volume further metabolised to leukotriene A4; both in one second (FEV1) >60% of predicted) reactions are catalysed by the enzyme 5-lipunderwent cold air challenge three hours oxygenase (5-LO) in the presence of 5-LO after receiving 750 mg of BAYx 1005 or activating protein (FLAP). Medications that placebo using a randomised, double blind, antagonise cysteinyl leukotriene receptors and Combined Program in crossover design. Leukotriene synthesis Pulmonary inhibitors of 5-LO have been shown to blunt inhibition was estimated by measuring the and Critical Care the bronchospasm elicited by exercise, allergen, Medicine, concentration of leukotriene B4 in whole or aspirin. Bronchospasm induced by cold Beth Israel and blood stimulated with calcium ionophore dry air has been blunted by inhibitors of 5Brigham A21387. and Women’s LO and antagonists of cysteinyl leukotriene Hospitals, Results – Treatment with BAYx 1005 proreceptors. 6 FLAP inhibitors have been shown Harvard Medical duced a 34% (95% CI 11 to 63) increase in to blunt antigen-induced responses 8 but have School, the amount of cold air minute ventilation not been tested against the stimulus of cold Boston, Massachusetts, USA required for a 10% decrease in FEV1 dry air. We investigated the potency of a novel A R Fischer (PD10V̇) compared with placebo (mean inhibitor of FLAP, BAYx 1005, on the response M A Rosenberg to bronchoprovocation with cold dry air. (SE) 37.6 (1.12) l/min compared with 28.0 M Roth E Israel (1.13) l/min, p<0.006). The PD20V̇ increased 19% (95% CI 8 to 31) after treatPharmaceutical Methods ment with BAYx 1005 compared with Division,  placebo (57.3 (1.10) l/min versus 48.1 (1.10) Bayer Corporation (formerly Miles Inc), Asthmatic subjects aged 18–60 with baseline l/min, p<0.002). Treatment with BAYx 1005 West Haven, forced expiratory volume in one second (FEV1) produced a 15.4% decrease in ionophoreConnecticut, USA >60% of predicted and a >20% decrease in stimulated LTB4 production, while treatM Loper FEV1 after a screening challenge with cold dry S Jungerwirth ment with placebo produced a 7.1% inair were eligible to participate. Each subject crease in ex vivo LTB4 (p<0.02). Correspondence to: was a non-smoker (<5 pack years) previously Dr E Israel, Conclusions – Treatment with BAYx 1005, Respiratory Division, treated with inhaled b2 agonists alone. All forms a novel inhibitor of leukotriene synthesis, Brigham and Women’s of corticosteroids were prohibited for eight weeks Hospital, produced a significant blunting of cold dry 75 Francis Street, and disodium cromoglycate or nedocromil use air responsiveness consistent with the Boston, Massachusetts was prohibited for two weeks before entry to the 02115, USA. hypothesis that leukotrienes mediate part study. All subjects gave their written informed of the bronchoconstriction induced by Presented (in part) at the consent to participate in the protocol which was annual meeting of the hyperventilation of cold dry air. approved by the Committee on Clinical InAmerican Thoracic Society, (Thorax 1997;52:1074–1077) Boston, MA, May 1994. vestigations of the Beth Israel Hospital. Received 4 November 1996