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Int Arch Allergy Immunol. 1998 Feb;115(2):169-78.

A role for histamine and substance P in immediate allergic responses in guinea pig airways: characterization of MDL 108,207DA, a dual H1/NK-1 receptor antagonist.

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  • 1Hoechst Marion Roussel, Cincinnati, Ohio 45215, USA.

Abstract

BACKGROUND:

Histamine is a critical mediator of immediate hypersensitivity reactions. Sensory neuropeptides, such as substance P (SP), may also contribute to acute inflammatory responses. A compound which antagonizes both H1 and NK-1 receptors, such as MDL 108,207DA, may present a significant therapeutic advantage over pure antihistamines.

METHODS:

The binding affinity of MDL 108,207DA for H1 and NK-1 receptors was evaluated and its potency of antagonism evaluated in vitro. The in vivo antagonism of SP- or histamine-induced microvascular leakage in guinea pig airways was examined. A role for these mediators in antigen-induced microvascular leakage in ovalbumin-sensitized guinea pig airways was examined using MDL 108,207DA as well as the NK-1-selective antagonist FK888 and the H1-selective antagonist pyrilamine alone or in combination.

RESULTS:

The affinity of MDL 108,207DA for H1 and NK-1 receptors is similar to that of receptor-selective antagonists. The compound inhibits both receptors in vitro and in vivo with comparable potencies for each. The efficacy of FK888 in combination with pyrilamine and MDL 108,207DA on antigen-induced microvascular leakage in sensitized guinea pig airways supports a role for both SP and histamine in early allergic responses.

CONCLUSION:

The contribution of both SP and histamine to immediate hypersensitivity reactions supports the utility of NK-1 and H1 receptor antagonist therapy. MDL 108,207DA incorporates both activities into the same compound and, as a result, may be useful in the treatment of allergic diseases.

PMID:
9482707
[PubMed - indexed for MEDLINE]
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