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The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air.
N Engl J Med. 1990 Dec 20; 323(25):1740-4.NEJM

Abstract

BACKGROUND

The enzyme 5-lipoxygenase catalyzes the metabolism of arachidonic acid to form products that have been implicated in the airway obstruction of asthma. We hypothesized that if products of the 5-lipoxygenase pathway are important in mediating this obstruction, then prevention of their formation should decrease the severity of an induced asthmatic response.

METHODS

In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of A-64077, a 5-lipoxygenase inhibitor, on the bronchoconstriction induced by hyperventilation of cold, dry air in 13 patients with asthma. The completeness of 5-lipoxygenase inhibition was confirmed by examining the profile of eicosanoids produced in whole blood ex vivo after activation with the calcium ionophore A-23187.

RESULTS

A-64077 decreased the mean (+/- SEM) ionophore-induced synthesis of leukotriene B4, a 5-lipoxygenase product, by 74 percent (from 265.3 +/- 30.3 to 69.5 +/- 21.5 ng per milliliter, P less than 0.001), but it did not affect the ionophore-induced synthesis of thromboxane B2, a cyclooxygenase metabolite of arachidonic acid (80.0 +/- 17.1 ng per milliliter before A-64077 vs. 75.8 +/- 14.3 ng per milliliter after A-64077). In concert with the selective inhibition of 5-lipoxygenase by A-64077, the amount of cold, dry air (expressed as respiratory heat exchange) required to reduce the forced expiratory volume in one second by 10 percent was increased by 47 percent after A-64077 (3.0 kJ per minute for placebo vs. 4.4 kJ per minute for A-64077, P less than 0.002). Similar results were obtained when minute ventilation was used as an indicator of outcome (27.5 liters per minute for placebo vs. 39.8 liters per minute for A-64077, P less than 0.005).

CONCLUSIONS

Selective inhibition of 5-lipoxygenase by A-64077 is associated with a significant amelioration of the asthmatic response to cold, dry air, suggesting that 5-lipoxygenase products are involved in this response. This approach may be useful in the treatment of asthma.

Authors+Show Affiliations

Department of Medicine, Beth Israel Hospital, Boston, MA 02215.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

2247106

Citation

Israel, E, et al. "The Effects of a 5-lipoxygenase Inhibitor On Asthma Induced By Cold, Dry Air." The New England Journal of Medicine, vol. 323, no. 25, 1990, pp. 1740-4.
Israel E, Dermarkarian R, Rosenberg M, et al. The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N Engl J Med. 1990;323(25):1740-4.
Israel, E., Dermarkarian, R., Rosenberg, M., Sperling, R., Taylor, G., Rubin, P., & Drazen, J. M. (1990). The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. The New England Journal of Medicine, 323(25), 1740-4.
Israel E, et al. The Effects of a 5-lipoxygenase Inhibitor On Asthma Induced By Cold, Dry Air. N Engl J Med. 1990 Dec 20;323(25):1740-4. PubMed PMID: 2247106.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. AU - Israel,E, AU - Dermarkarian,R, AU - Rosenberg,M, AU - Sperling,R, AU - Taylor,G, AU - Rubin,P, AU - Drazen,J M, PY - 1990/12/20/pubmed PY - 1990/12/20/medline PY - 1990/12/20/entrez SP - 1740 EP - 4 JF - The New England journal of medicine JO - N Engl J Med VL - 323 IS - 25 N2 - BACKGROUND: The enzyme 5-lipoxygenase catalyzes the metabolism of arachidonic acid to form products that have been implicated in the airway obstruction of asthma. We hypothesized that if products of the 5-lipoxygenase pathway are important in mediating this obstruction, then prevention of their formation should decrease the severity of an induced asthmatic response. METHODS: In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of A-64077, a 5-lipoxygenase inhibitor, on the bronchoconstriction induced by hyperventilation of cold, dry air in 13 patients with asthma. The completeness of 5-lipoxygenase inhibition was confirmed by examining the profile of eicosanoids produced in whole blood ex vivo after activation with the calcium ionophore A-23187. RESULTS: A-64077 decreased the mean (+/- SEM) ionophore-induced synthesis of leukotriene B4, a 5-lipoxygenase product, by 74 percent (from 265.3 +/- 30.3 to 69.5 +/- 21.5 ng per milliliter, P less than 0.001), but it did not affect the ionophore-induced synthesis of thromboxane B2, a cyclooxygenase metabolite of arachidonic acid (80.0 +/- 17.1 ng per milliliter before A-64077 vs. 75.8 +/- 14.3 ng per milliliter after A-64077). In concert with the selective inhibition of 5-lipoxygenase by A-64077, the amount of cold, dry air (expressed as respiratory heat exchange) required to reduce the forced expiratory volume in one second by 10 percent was increased by 47 percent after A-64077 (3.0 kJ per minute for placebo vs. 4.4 kJ per minute for A-64077, P less than 0.002). Similar results were obtained when minute ventilation was used as an indicator of outcome (27.5 liters per minute for placebo vs. 39.8 liters per minute for A-64077, P less than 0.005). CONCLUSIONS: Selective inhibition of 5-lipoxygenase by A-64077 is associated with a significant amelioration of the asthmatic response to cold, dry air, suggesting that 5-lipoxygenase products are involved in this response. This approach may be useful in the treatment of asthma. SN - 0028-4793 UR - https://www.unboundmedicine.com/medline/citation/2247106/The_effects_of_a_5_lipoxygenase_inhibitor_on_asthma_induced_by_cold_dry_air_ L2 - https://www.nejm.org/doi/10.1056/NEJM199012203232505?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -