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Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects.
Am J Respir Crit Care Med. 1995 Oct; 152(4 Pt 1):1203-7.AJ

Abstract

The leukotrienes are known bronchoactive agonists with potential proinflammatory effects that may be involved in mediating airway hyperresponsiveness. We investigated the effects of zileuton, an inhibitor of 5-lipoxygenase (5-LO), on airway responsiveness to cold, dry air in patients with moderate asthma. A group of 10 asthmatic patients underwent cold, dry air hyperventilation challenge; challenges were performed before drug treatment and 1 to 10 d after the completion of treatment with study drugs. The cold air minute ventilation required to cause a 15% decrease in FEV1 (PD15 VE) increased by 58% compared with the response before treatment, 1 to 10 d after the completion of 13 wk of treatment with zileuton. The geometric mean (geometric mean/SEM and geometric mean x SEM) PD15 VE increased from 24.5 (20.4, 29.5) L/min to 38.8 (34.7, 43.7) L/min (p = 0.01). Zileuton treatment inhibited 5-LO as measured ex vivo by ionophore-stimulated LTB4 levels in whole blood. In four of seven subjects, LTB4 levels before zileuton ingestion fell from 110.88 +/- 25.42 to 5.40 +/- 1.95 ng/ml 2 h post-zileuton dosing (p = 0.02, pre- versus 2 h postzileuton ingestion). Consistent with the short half-life of zileuton, 6 h postzileuton dosing the ionophore-stimulated, LTB4 levels in whole blood had increased to 89.68 +/- 35.54 ng/ml (p = 0.41, pre- versus 6 h postzileuton ingestion). Based on the first-order kinetics of zileuton, its effect on 5-LO activity should have been dissipated less than 16 h postingestion. Thus, chronic zileuton treatment decreased airway hyperresponsiveness as determined by reactivity to cold, dry air.(

ABSTRACT

TRUNCATED AT 250 WORDS)

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Authors+Show Affiliations

Fischer AR
Combined Program in Pulmonary and Critical Care Medicine, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts, USA.
McFadden CA
No affiliation info available
Frantz R
No affiliation info available
Awni WM
No affiliation info available
Cohn J
No affiliation info available
Drazen JM
No affiliation info available
Israel E
No affiliation info available

MeSH

AdultArachidonate 5-LipoxygenaseAsthmaBronchial HyperreactivityBronchial Provocation TestsCold TemperatureDouble-Blind MethodFemaleForced Expiratory VolumeHumansHydroxyureaLipoxygenase InhibitorsMaleSingle-Blind MethodTime Factors

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

7551371

Citation

Fischer, A R., et al. "Effect of Chronic 5-lipoxygenase Inhibition On Airway Hyperresponsiveness in Asthmatic Subjects." American Journal of Respiratory and Critical Care Medicine, vol. 152, no. 4 Pt 1, 1995, pp. 1203-7.
Fischer AR, McFadden CA, Frantz R, et al. Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects. Am J Respir Crit Care Med. 1995;152(4 Pt 1):1203-7.
Fischer, A. R., McFadden, C. A., Frantz, R., Awni, W. M., Cohn, J., Drazen, J. M., & Israel, E. (1995). Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects. American Journal of Respiratory and Critical Care Medicine, 152(4 Pt 1), 1203-7.
Fischer AR, et al. Effect of Chronic 5-lipoxygenase Inhibition On Airway Hyperresponsiveness in Asthmatic Subjects. Am J Respir Crit Care Med. 1995;152(4 Pt 1):1203-7. PubMed PMID: 7551371.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects. AU - Fischer,A R, AU - McFadden,C A, AU - Frantz,R, AU - Awni,W M, AU - Cohn,J, AU - Drazen,J M, AU - Israel,E, PY - 1995/10/1/pubmed PY - 1995/10/1/medline PY - 1995/10/1/entrez SP - 1203 EP - 7 JF - American journal of respiratory and critical care medicine JO - Am J Respir Crit Care Med VL - 152 IS - 4 Pt 1 N2 - The leukotrienes are known bronchoactive agonists with potential proinflammatory effects that may be involved in mediating airway hyperresponsiveness. We investigated the effects of zileuton, an inhibitor of 5-lipoxygenase (5-LO), on airway responsiveness to cold, dry air in patients with moderate asthma. A group of 10 asthmatic patients underwent cold, dry air hyperventilation challenge; challenges were performed before drug treatment and 1 to 10 d after the completion of treatment with study drugs. The cold air minute ventilation required to cause a 15% decrease in FEV1 (PD15 VE) increased by 58% compared with the response before treatment, 1 to 10 d after the completion of 13 wk of treatment with zileuton. The geometric mean (geometric mean/SEM and geometric mean x SEM) PD15 VE increased from 24.5 (20.4, 29.5) L/min to 38.8 (34.7, 43.7) L/min (p = 0.01). Zileuton treatment inhibited 5-LO as measured ex vivo by ionophore-stimulated LTB4 levels in whole blood. In four of seven subjects, LTB4 levels before zileuton ingestion fell from 110.88 +/- 25.42 to 5.40 +/- 1.95 ng/ml 2 h post-zileuton dosing (p = 0.02, pre- versus 2 h postzileuton ingestion). Consistent with the short half-life of zileuton, 6 h postzileuton dosing the ionophore-stimulated, LTB4 levels in whole blood had increased to 89.68 +/- 35.54 ng/ml (p = 0.41, pre- versus 6 h postzileuton ingestion). Based on the first-order kinetics of zileuton, its effect on 5-LO activity should have been dissipated less than 16 h postingestion. Thus, chronic zileuton treatment decreased airway hyperresponsiveness as determined by reactivity to cold, dry air.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 1073-449X UR - https://www.unboundmedicine.com/medline/citation/7551371/Effect_of_chronic_5_lipoxygenase_inhibition_on_airway_hyperresponsiveness_in_asthmatic_subjects_ L2 - https://www.atsjournals.org/doi/10.1164/ajrccm.152.4.7551371?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -