Tags

Type your tag names separated by a space and hit enter

Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma.
Am J Respir Crit Care Med. 2007 Mar 01; 175(5):450-7.AJ

Abstract

RATIONALE

The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma.

OBJECTIVE

We tested the safety, tolerability, and pharmacologic and biological efficacy of a tachykinin NK(1)/NK(2) receptor antagonist, AVE5883, in patients with asthma in two double-blind, placebo-controlled crossover studies.

METHODS

The pharmacologic efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 patients with asthma. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple-dose trial (4.8 mg three times per day, 9 d) in 12 patients with asthma with dual responses to inhaled house dust mite. On Day 8, an allergen challenge was conducted, and airway response was measured by FEV(1) until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and induced sputum were performed on Days 1, 7, and 9.

RESULTS

AVE5883 had a bad taste, and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose response to NKA by 1.2 doubling doses. Pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. There were no significant differences in the allergen-induced changes in exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and sputum cell differentials between placebo and AVE5883.

CONCLUSIONS

Despite its demonstrated pharmacologic activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonists.

Authors+Show Affiliations

Centre for Human Drug Research, Zernikedreef 10 2333 CL, Leiden, The Netherlands. dboot@chdr.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

17170385

Citation

Boot, Johan D., et al. "Effect of an NK1/NK2 Receptor Antagonist On Airway Responses and Inflammation to Allergen in Asthma." American Journal of Respiratory and Critical Care Medicine, vol. 175, no. 5, 2007, pp. 450-7.
Boot JD, de Haas S, Tarasevych S, et al. Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma. Am J Respir Crit Care Med. 2007;175(5):450-7.
Boot, J. D., de Haas, S., Tarasevych, S., Roy, C., Wang, L., Amin, D., Cohen, J., Sterk, P. J., Miller, B., Paccaly, A., Burggraaf, J., Cohen, A. F., & Diamant, Z. (2007). Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma. American Journal of Respiratory and Critical Care Medicine, 175(5), 450-7.
Boot JD, et al. Effect of an NK1/NK2 Receptor Antagonist On Airway Responses and Inflammation to Allergen in Asthma. Am J Respir Crit Care Med. 2007 Mar 1;175(5):450-7. PubMed PMID: 17170385.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma. AU - Boot,Johan D, AU - de Haas,Sanne, AU - Tarasevych,Svetlana, AU - Roy,Christine, AU - Wang,Lin, AU - Amin,Dilip, AU - Cohen,Judith, AU - Sterk,Peter J, AU - Miller,Barry, AU - Paccaly,Anne, AU - Burggraaf,Jacobus, AU - Cohen,Adam F, AU - Diamant,Zuzana, Y1 - 2006/12/14/ PY - 2006/12/16/pubmed PY - 2007/4/4/medline PY - 2006/12/16/entrez SP - 450 EP - 7 JF - American journal of respiratory and critical care medicine JO - Am. J. Respir. Crit. Care Med. VL - 175 IS - 5 N2 - RATIONALE: The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma. OBJECTIVE: We tested the safety, tolerability, and pharmacologic and biological efficacy of a tachykinin NK(1)/NK(2) receptor antagonist, AVE5883, in patients with asthma in two double-blind, placebo-controlled crossover studies. METHODS: The pharmacologic efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 patients with asthma. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple-dose trial (4.8 mg three times per day, 9 d) in 12 patients with asthma with dual responses to inhaled house dust mite. On Day 8, an allergen challenge was conducted, and airway response was measured by FEV(1) until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and induced sputum were performed on Days 1, 7, and 9. RESULTS: AVE5883 had a bad taste, and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose response to NKA by 1.2 doubling doses. Pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. There were no significant differences in the allergen-induced changes in exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and sputum cell differentials between placebo and AVE5883. CONCLUSIONS: Despite its demonstrated pharmacologic activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonists. SN - 1073-449X UR - https://www.unboundmedicine.com/medline/citation/17170385/Effect_of_an_NK1/NK2_receptor_antagonist_on_airway_responses_and_inflammation_to_allergen_in_asthma_ L2 - http://www.atsjournals.org/doi/full/10.1164/rccm.200608-1186OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -