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Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma.
Thorax. 1994 Aug; 49(8):749-56.T

Abstract

BACKGROUND

The cysteinyl leukotrienes may play a central part in the mechanisms of aspirin-sensitive asthma. Previous work has shown that individuals with aspirin-sensitive asthma have high basal urinary LTE4 levels which increase further upon aspirin ingestion, and that sulphidopeptide leukotriene receptor antagonists attenuate aspirin-induced airflow obstruction. If the cysteinyl leukotrienes cause aspirin-induced asthmatic reactions, inhibition of the 5-lipoxygenase pathway should prevent aspirin-induced bronchospasm. This hypothesis has been tested with ZD2138, a specific non-redox 5-lipoxygenase inhibitor.

METHODS

Seven subjects (four men) with aspirin-sensitive asthma with baseline FEV1 values > 67% were studied. ZD2138 (350 mg) or placebo was given on two separate occasions two weeks apart in a randomised double blind fashion. A single dose of aspirin was administered four hours after dosing and FEV1 was measured for six hours. Inhibition of the 5-lipoxygenase pathway by ZD2138 was assessed by measurements of urinary LTE4 levels and ex vivo calcium ionophore stimulated LTB4 generation in whole blood, before administration of drug or placebo and at regular time intervals after dosing and aspirin administration.

RESULTS

ZD2138 protected against the aspirin-induced reduction in FEV1 with a 20.3 (4.9)% fall in FEV1 following placebo compared with 4.9 (2.9)% following ZD2138. This was associated with 72% inhibition of ex vivo LTB4 generation in whole blood at 12 hours and a 74% inhibition of the rise in urinary LTE4 excretion at six hours after aspirin ingestion.

CONCLUSIONS

In aspirin-sensitive asthma the 5-lipoxygenase inhibitor ZD2138 inhibits the fall in FEV1 induced by aspirin and this is associated with substantial inhibition of 5-lipoxygenase.

Authors+Show Affiliations

Department of Allergy and Allied Respiratory Disorders, UMDS, Guy's Hospital, London.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

8091318

Citation

Nasser, S M., et al. "Effect of the 5-lipoxygenase Inhibitor ZD2138 On Aspirin-induced Asthma." Thorax, vol. 49, no. 8, 1994, pp. 749-56.
Nasser SM, Bell GS, Foster S, et al. Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. Thorax. 1994;49(8):749-56.
Nasser, S. M., Bell, G. S., Foster, S., Spruce, K. E., MacMillan, R., Williams, A. J., Lee, T. H., & Arm, J. P. (1994). Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. Thorax, 49(8), 749-56.
Nasser SM, et al. Effect of the 5-lipoxygenase Inhibitor ZD2138 On Aspirin-induced Asthma. Thorax. 1994;49(8):749-56. PubMed PMID: 8091318.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma. AU - Nasser,S M, AU - Bell,G S, AU - Foster,S, AU - Spruce,K E, AU - MacMillan,R, AU - Williams,A J, AU - Lee,T H, AU - Arm,J P, PY - 1994/8/1/pubmed PY - 1994/8/1/medline PY - 1994/8/1/entrez SP - 749 EP - 56 JF - Thorax JO - Thorax VL - 49 IS - 8 N2 - BACKGROUND: The cysteinyl leukotrienes may play a central part in the mechanisms of aspirin-sensitive asthma. Previous work has shown that individuals with aspirin-sensitive asthma have high basal urinary LTE4 levels which increase further upon aspirin ingestion, and that sulphidopeptide leukotriene receptor antagonists attenuate aspirin-induced airflow obstruction. If the cysteinyl leukotrienes cause aspirin-induced asthmatic reactions, inhibition of the 5-lipoxygenase pathway should prevent aspirin-induced bronchospasm. This hypothesis has been tested with ZD2138, a specific non-redox 5-lipoxygenase inhibitor. METHODS: Seven subjects (four men) with aspirin-sensitive asthma with baseline FEV1 values > 67% were studied. ZD2138 (350 mg) or placebo was given on two separate occasions two weeks apart in a randomised double blind fashion. A single dose of aspirin was administered four hours after dosing and FEV1 was measured for six hours. Inhibition of the 5-lipoxygenase pathway by ZD2138 was assessed by measurements of urinary LTE4 levels and ex vivo calcium ionophore stimulated LTB4 generation in whole blood, before administration of drug or placebo and at regular time intervals after dosing and aspirin administration. RESULTS: ZD2138 protected against the aspirin-induced reduction in FEV1 with a 20.3 (4.9)% fall in FEV1 following placebo compared with 4.9 (2.9)% following ZD2138. This was associated with 72% inhibition of ex vivo LTB4 generation in whole blood at 12 hours and a 74% inhibition of the rise in urinary LTE4 excretion at six hours after aspirin ingestion. CONCLUSIONS: In aspirin-sensitive asthma the 5-lipoxygenase inhibitor ZD2138 inhibits the fall in FEV1 induced by aspirin and this is associated with substantial inhibition of 5-lipoxygenase. SN - 0040-6376 UR - https://www.unboundmedicine.com/medline/citation/8091318/Effect_of_the_5_lipoxygenase_inhibitor_ZD2138_on_aspirin_induced_asthma_ L2 - https://thorax.bmj.com/lookup/pmidlookup?view=long&pmid=8091318 DB - PRIME DP - Unbound Medicine ER -