Effect of YM158, a Dual Lipid Mediator Antagonist, on Immediate and Late Asthmatic Responses, and on Airway Hyper-responsiveness in Guinea Pigs

Abstract

The effects of lipid mediator antagonists: the LTD4-receptor antagonist pranlukast, the TXA2-receptor antagonist seratrodast, and the novel dual LTD4- and TXA2-receptor antagonist YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl) propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) were investigated in animals exhibiting immediate asthmatic response (IAR), late asthmatic response (LAR) and airway hyper-responsiveness (AHR). Antigen-induced LAR and AfR are inhibited by orally administered pranlukast (30, 100 mg/kg) and seratrodast (3, 10 mg/kg). YM158 (30 mg/kg), orally administered before or after IAR induction, also inhibited both LAR and AHR. However, while the inhibitory effects of pranlukast and seratrodast on IAR were marginal, the effects of YM158 (3, 10, 30 mg/kg) were dose-dependent, probably due to its multiple sites of action. Additionally, orally administered YM158 (30 mg/kg) inhibited ozone-induced AHR in guinea pigs. Thus, an antagonist that inhibits several lipid mediators might exhibit greater efficacy in treating asthmatic responses than antagonists with a single site of action. Therefore, YM158 shows great promise as a drug that will be able to treat bronchial asthma and related disorders more potently than currently used single-pathway inhibitors.

Effects of KP‐496, a novel dual antagonist at the cysteinyl leukotriene receptor 1 and the thromboxane A2 receptor, on airway obstruction in guinea pigs

“…The effects of CysLT 1 antagonists and a TP antagonist on IAR in animal models have been investigated by many groups. Some groups have reported that these antagonists did not inhibit IAR ( Tohda et al , 1997 ; Ihaku et al , 1999 ; Arakida et al , 2000b ; Yamada et al , 2003 ). Others have reported that these antagonists inhibited IAR significantly, but they required larger doses to inhibit IAR than LAR ( Matsumoto et al , 1994 ; Aoki et al , 2000 ).…”

TA-270 [4-Hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], an Anti-Asthmatic Agent, Inhibits Leukotriene Production Induced by IgE Receptor Stimulation in RBL-2H3 Cells

“…Thus, pranlukast inhibited not only the early-phase bronchoconstriction but also several late-phase responses, including late-phase bronchoconstriction, infiltration of inflammatory cells, and airway hyper-responsiveness (Nakagawa et al, 1993;Arakida et al, 2000). These results suggest that inhibition of leukotriene action may cause the inhibition of the late-phase responses as well as the early airway response.…”

Pharmacological Characteristics of Ryokan-kyomi-shinge-nin-to, an Antiallergic Kampo Medicine.

“…[18][19][20] Glycyrrhizin, a triterpenoid saponin contained in a constituent herb of RKS, Glycyrrhizae Radix, selectively inhibits the activities of arachidonate cascade-related emzymes, such as 5LO and PLA 2 . 21,22) Therefore, it is possible that glycyrrhizin contributes to the prevention of hypersensitivity by RKS.…”