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Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma.
Respir Med. 2011 May; 105(5):667-73.RM

Abstract

BACKGROUND

In asthma, cysteinyl leukotrienes (CysLTs) play varying roles in the bronchomotor response to multiple provocative stimuli. The contribution of CysLTs on the airway's response to hypertonic saline (HS) inhalation in asthma is unknown. Whether polymorphisms in the leukotriene biosynthetic pathway affect the contribution of CysLTs to this response is also unknown.

METHODS

In a prospective, randomized, double-blind, placebo-controlled cross-over study, mild and moderate asymptomatic asthmatics underwent inhaled 3% HS challenge by doubling the duration of nebulization (0.5, 1, 2, 4, and 8 min) 2 h after one dose of montelukast (a CysLT receptor 1 [CysLTR1] antagonist) or placebo, and after three-week courses. We examined the effect of the leukotriene C(4) synthase (LTC(4)S) polymorphism (A-444C) on the efficacy of montelukast against HS inhalation in an exploratory manner.

RESULTS

In 37 subjects, 2 h after administration of montelukast, the mean provocative dose of HS required to cause a 20% drop in FEV(1) (HS-PD(20)) increased by 59% (9.17 ml after placebo vs. 14.55 ml after montelukast, p=0.0154). Three weeks of cysLTR1 antagonism increased the HS-PD(20) by 84% (10.97 vs. 20.21 ml, p=0.0002). Three weeks of CysLTR1 antagonism appeared to produce greater effects on blocking bronchial hyper-responsiveness (2 h vs. three-week HS-PD(20) values 14.55 vs. 20.21 ml respectively, p=0.0898). We did not observe an effect of the LTC(4)S polymorphism on the response to CysLTR1 antagonism in this cohort.

CONCLUSIONS

A significant proportion of HS-induced bronchoconstriction is mediated by release of leukotrienes as evidenced by substantial acute inhibition with a CysLTR1 antagonist. There was a trend toward greater inhibition of bronchial responsiveness with three weeks of therapy as opposed to acute CysLTR1 antagonism. Clinicaltrials.gov registration number NCT00116324.

Authors+Show Affiliations

Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, PBB Clinics 3, 75 Francis Street, Boston, MA 02115, USA. skazani@partners.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21169002

Citation

Kazani, Shamsah, et al. "Cysteinyl Leukotriene Antagonism Inhibits Bronchoconstriction in Response to Hypertonic Saline Inhalation in Asthma." Respiratory Medicine, vol. 105, no. 5, 2011, pp. 667-73.
Kazani S, Sadeh J, Bunga S, et al. Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma. Respir Med. 2011;105(5):667-73.
Kazani, S., Sadeh, J., Bunga, S., Wechsler, M. E., & Israel, E. (2011). Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma. Respiratory Medicine, 105(5), 667-73. https://doi.org/10.1016/j.rmed.2010.11.025
Kazani S, et al. Cysteinyl Leukotriene Antagonism Inhibits Bronchoconstriction in Response to Hypertonic Saline Inhalation in Asthma. Respir Med. 2011;105(5):667-73. PubMed PMID: 21169002.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma. AU - Kazani,Shamsah, AU - Sadeh,Jonathan, AU - Bunga,Sreedhar, AU - Wechsler,Michael E, AU - Israel,Elliot, Y1 - 2010/12/18/ PY - 2010/07/26/received PY - 2010/11/21/revised PY - 2010/11/23/accepted PY - 2010/12/21/entrez PY - 2010/12/21/pubmed PY - 2011/6/28/medline SP - 667 EP - 73 JF - Respiratory medicine JO - Respir Med VL - 105 IS - 5 N2 - BACKGROUND: In asthma, cysteinyl leukotrienes (CysLTs) play varying roles in the bronchomotor response to multiple provocative stimuli. The contribution of CysLTs on the airway's response to hypertonic saline (HS) inhalation in asthma is unknown. Whether polymorphisms in the leukotriene biosynthetic pathway affect the contribution of CysLTs to this response is also unknown. METHODS: In a prospective, randomized, double-blind, placebo-controlled cross-over study, mild and moderate asymptomatic asthmatics underwent inhaled 3% HS challenge by doubling the duration of nebulization (0.5, 1, 2, 4, and 8 min) 2 h after one dose of montelukast (a CysLT receptor 1 [CysLTR1] antagonist) or placebo, and after three-week courses. We examined the effect of the leukotriene C(4) synthase (LTC(4)S) polymorphism (A-444C) on the efficacy of montelukast against HS inhalation in an exploratory manner. RESULTS: In 37 subjects, 2 h after administration of montelukast, the mean provocative dose of HS required to cause a 20% drop in FEV(1) (HS-PD(20)) increased by 59% (9.17 ml after placebo vs. 14.55 ml after montelukast, p=0.0154). Three weeks of cysLTR1 antagonism increased the HS-PD(20) by 84% (10.97 vs. 20.21 ml, p=0.0002). Three weeks of CysLTR1 antagonism appeared to produce greater effects on blocking bronchial hyper-responsiveness (2 h vs. three-week HS-PD(20) values 14.55 vs. 20.21 ml respectively, p=0.0898). We did not observe an effect of the LTC(4)S polymorphism on the response to CysLTR1 antagonism in this cohort. CONCLUSIONS: A significant proportion of HS-induced bronchoconstriction is mediated by release of leukotrienes as evidenced by substantial acute inhibition with a CysLTR1 antagonist. There was a trend toward greater inhibition of bronchial responsiveness with three weeks of therapy as opposed to acute CysLTR1 antagonism. Clinicaltrials.gov registration number NCT00116324. SN - 1532-3064 UR - https://www.unboundmedicine.com/medline/citation/21169002/Cysteinyl_leukotriene_antagonism_inhibits_bronchoconstriction_in_response_to_hypertonic_saline_inhalation_in_asthma_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0954-6111(10)00499-3 DB - PRIME DP - Unbound Medicine ER -