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Effects of KP-496, a novel dual antagonist at the cysteinyl leukotriene receptor 1 and the thromboxane A(2) receptor, on airway obstruction in guinea pigs.
Br J Pharmacol 2008; 153(4):669-75BJ

Abstract

BACKGROUND AND PURPOSE

KP-496 is a novel dual antagonist for cysteinyl leukotriene receptor 1 (CysLT(1)) and thromboxane A(2) (TXA(2)) receptor (TP). The aim of this study was to evaluate the pharmacological profile of inhaled KP-496 and its effects on airway obstruction.

EXPERIMENTAL APPROACH

Antagonist activities of inhaled KP-496 were investigated using bronchoconstriction induced in guinea pigs by LTD(4) or U46619, a stable TXA(2) mimetic. Guinea pigs sensitized with injections of ovalbumin were used to assess the effects of inhaled KP-496 on bronchoconstriction induced by antigen (i.v.). Another set of guinea pigs were sensitized and challenged with ovalbumin by inhalation and the effects of inhaled KP-496 on immediate and late airway responses and airway hyperresponsiveness were investigated.

KEY RESULTS

KP-496 significantly inhibited LTD(4)- and U46619-induced bronchoconstriction in a dose-dependent manner. The inhibitory effects of KP-496 (1%) were comparable to those of montelukast (a CysLT(1) antagonist, p.o., 0.3 mg kg(-1)) or seratrodast (a TP antagonist, p.o., 3 mg kg(-1)). KP-496 (1%) and oral co-administration of montelukast (10 mg kg(-1)) and seratrodast (20 mg kg(-1)) significantly inhibited antigen-induced bronchoconstriction, whereas administration of montelukast or seratrodast separately did not inhibit antigen-induced bronchoconstriction. KP-496 exhibited dose-dependent and significant inhibitory effects on the immediate and late airway responses and airway hyperresponsiveness following antigen challenge.

CONCLUSIONS AND IMPLICATIONS

KP-496 exerts effects in guinea pigs which could be beneficial in asthma. These effects of KP-496 were greater than those of a CysLT(1) antagonist or a TP antagonist, in preventing antigen-induced airway obstruction.

Authors+Show Affiliations

Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co. Ltd, Kyoto, Japan. ishimura_masakazu@kaken.co.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

18037905

Citation

Ishimura, M, et al. "Effects of KP-496, a Novel Dual Antagonist at the Cysteinyl Leukotriene Receptor 1 and the Thromboxane A(2) Receptor, On Airway Obstruction in Guinea Pigs." British Journal of Pharmacology, vol. 153, no. 4, 2008, pp. 669-75.
Ishimura M, Suda M, Morizumi K, et al. Effects of KP-496, a novel dual antagonist at the cysteinyl leukotriene receptor 1 and the thromboxane A(2) receptor, on airway obstruction in guinea pigs. Br J Pharmacol. 2008;153(4):669-75.
Ishimura, M., Suda, M., Morizumi, K., Kataoka, S., Maeda, T., Kurokawa, S., & Hiyama, Y. (2008). Effects of KP-496, a novel dual antagonist at the cysteinyl leukotriene receptor 1 and the thromboxane A(2) receptor, on airway obstruction in guinea pigs. British Journal of Pharmacology, 153(4), pp. 669-75.
Ishimura M, et al. Effects of KP-496, a Novel Dual Antagonist at the Cysteinyl Leukotriene Receptor 1 and the Thromboxane A(2) Receptor, On Airway Obstruction in Guinea Pigs. Br J Pharmacol. 2008;153(4):669-75. PubMed PMID: 18037905.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of KP-496, a novel dual antagonist at the cysteinyl leukotriene receptor 1 and the thromboxane A(2) receptor, on airway obstruction in guinea pigs. AU - Ishimura,M, AU - Suda,M, AU - Morizumi,K, AU - Kataoka,S, AU - Maeda,T, AU - Kurokawa,S, AU - Hiyama,Y, Y1 - 2007/11/26/ PY - 2007/11/27/pubmed PY - 2008/5/15/medline PY - 2007/11/27/entrez SP - 669 EP - 75 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 153 IS - 4 N2 - BACKGROUND AND PURPOSE: KP-496 is a novel dual antagonist for cysteinyl leukotriene receptor 1 (CysLT(1)) and thromboxane A(2) (TXA(2)) receptor (TP). The aim of this study was to evaluate the pharmacological profile of inhaled KP-496 and its effects on airway obstruction. EXPERIMENTAL APPROACH: Antagonist activities of inhaled KP-496 were investigated using bronchoconstriction induced in guinea pigs by LTD(4) or U46619, a stable TXA(2) mimetic. Guinea pigs sensitized with injections of ovalbumin were used to assess the effects of inhaled KP-496 on bronchoconstriction induced by antigen (i.v.). Another set of guinea pigs were sensitized and challenged with ovalbumin by inhalation and the effects of inhaled KP-496 on immediate and late airway responses and airway hyperresponsiveness were investigated. KEY RESULTS: KP-496 significantly inhibited LTD(4)- and U46619-induced bronchoconstriction in a dose-dependent manner. The inhibitory effects of KP-496 (1%) were comparable to those of montelukast (a CysLT(1) antagonist, p.o., 0.3 mg kg(-1)) or seratrodast (a TP antagonist, p.o., 3 mg kg(-1)). KP-496 (1%) and oral co-administration of montelukast (10 mg kg(-1)) and seratrodast (20 mg kg(-1)) significantly inhibited antigen-induced bronchoconstriction, whereas administration of montelukast or seratrodast separately did not inhibit antigen-induced bronchoconstriction. KP-496 exhibited dose-dependent and significant inhibitory effects on the immediate and late airway responses and airway hyperresponsiveness following antigen challenge. CONCLUSIONS AND IMPLICATIONS: KP-496 exerts effects in guinea pigs which could be beneficial in asthma. These effects of KP-496 were greater than those of a CysLT(1) antagonist or a TP antagonist, in preventing antigen-induced airway obstruction. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/18037905/Effects_of_KP_496_a_novel_dual_antagonist_at_the_cysteinyl_leukotriene_receptor_1_and_the_thromboxane_A_2__receptor_on_airway_obstruction_in_guinea_pigs_ L2 - https://doi.org/10.1038/sj.bjp.0707602 DB - PRIME DP - Unbound Medicine ER -