Kudlacz E, Shatzer S, Logan D, Olsen K, Knippenberg R, Hsieh L, Esteve H, Maynard G
Hoechst Marion Roussel, Cincinnati, Ohio 45215, USA.
Int Arch Allergy Immunol. 1998 Feb;115(2):169-78. doi: 10.1159/000023898.
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.
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.
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.
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.
组胺是速发型超敏反应的关键介质。感觉神经肽，如P物质（SP），也可能参与急性炎症反应。一种同时拮抗H1和NK-1受体的化合物，如MDL 108,207DA，可能比单纯的抗组胺药具有显著的治疗优势。
评估MDL 108,207DA对H1和NK-1受体的结合亲和力，并在体外评估其拮抗效力。检测SP或组胺诱导的豚鼠气道微血管渗漏的体内拮抗作用。使用MDL 108,207DA以及NK-1选择性拮抗剂FK888和H1选择性拮抗剂吡苄明单独或联合使用，研究这些介质在卵清蛋白致敏的豚鼠气道抗原诱导的微血管渗漏中的作用。
MDL 108,207DA对H1和NK-1受体的亲和力与受体选择性拮抗剂相似。该化合物在体外和体内均能抑制这两种受体，且对每种受体的效力相当。FK888与吡苄明和MDL 108,207DA联合使用对致敏豚鼠气道抗原诱导的微血管渗漏的疗效支持SP和组胺在早期过敏反应中均起作用。
SP和组胺对速发型超敏反应的作用支持NK-1和H1受体拮抗剂治疗的实用性。MDL 108,207DA将两种活性结合在同一化合物中，因此可能对过敏性疾病的治疗有用。
