The effects of an oral thromboxane TP receptor antagonist BAY u 3405, on prostaglandin D2‐ and histamine‐induced bronchoconstriction in asthma, and relationship to plasma drug concentrations.

Abstract

increased the amount of PG D2 required to produce a fall of 20% in the forced expiratory volume in 1 s by 6-fold and 16-fold at 60 min and 90 min after ingestion respectively, and the 50 mg dose by 14-fold at 90 min after ingestion. 5 The specificity of the drug was confirmed in vivo in that there was no significant protection against histamine bronchial provocation at either dose or at either time point. 5 The time course study showed significant protection against PG D2 bronchial provocation at 1 h and at 3 h after a single 20 mg oral dose. 7 There was no correlation between subjects in plasma BAY u 3405 concentration and drug effect. Within the subjects performing the time course study there was a strong correlation in time between drug effect and plasma BAY u 3405 concentration. 8 BAY u 3405 may be useful in preventing prostanoid mediated bronchoconstriction in clinical asthma.

Evidence of mast cell activation and leukotriene release after mannitol inhalation

“…PGD 2 , as well as 9a,11b-PGF 2 , are potent bronchoconstrictors in man [17], mainly acting on the TP-receptor [18,19]. Pretreatment with selective TP-receptor antagonists attenuated both PGD 2 -and allergen-induced, but not histamine-induced, bronchoconstriction [20][21][22]. Release of PGD 2 into the airways has been further documented after bronchial provocation with allergen [23].…”

An Orally Bioavailable Small Molecule Antagonist of CRTH2, Ramatroban (BAY u3405), Inhibits Prostaglandin D2-Induced Eosinophil Migration in Vitro

“…Likewise, ramatroban significantly blocked eosinophil infiltration into the nasal space of allergen-challenged patients suffering from perennial rhinitis (Terada et al, 1998) and PGD 2 -mediated bronchoconstriction (Johnston et al, 1992;Magnussen et al, 1992;Rajakulasingam et al, 1996). The broad efficacy that ramatroban exerts in these pathological situations is unlikely to be explained solely by direct TP antagonism.…”

“…Various chemoattractants are known for eosinophils (eotaxin, eotaxin-2, MCP-3 and -4, RANTES, leukotriene D 4 , C5a, platelet-activating factor, and PGD 2 (Fukuda et al, 1992;Jose et al, 1994;Elsner et al, 1996;Hirai et al, 2001), all of which are known to be produced or present in elevated amounts in allergen-challenged nasal areas of rhinitis patients and lungs of asthmatics. Although no evidence exists for a direct interaction of ramatroban with chemokine receptors (unpublished observations), the blockade of PGD 2 -mediated eosinophilia and bronchoconstriction by ramatroban is well documented in animals and humans (Johnston et al, 1992;Magnussen et al, 1992;Nagai et al, 1995;Narita et al, 1996;Rajakulasingam et al, 1996). PGD 2 is an agonist for TP (Coleman et al, 1989).…”

Prostaglandin D2-induced bronchoconstriction is mediated only in part by the thromboxane prostanoid receptor

“…Previously, we have demonstrated that this antagonist exerts it's maximal effect at a 20 mg dose, with no greater effects being observed with a higher 50 mg dose [16]. We now report the use of increasing doses of BAY u 3405 up to 100 mg, on single concentration challenges with PGD 2 , in a placebo-controlled, randomized study to assess the degree to which TP receptor blockade inhibits PGD 2 -induced airway narrowing.…”

“…In asthma, the action of PGD 2 has been thought to be mediated principally via the TP receptor rather than the DP receptor [12]. As a result, several thromboxane receptor antagonists have now been developed, and have been shown to effectively inhibit PGD 2 -induced bronchoconstriction [13][14][15][16][17]. However, these TP receptor antagonists have had less protective effect on allergen-induced bronchoconstriction, with studies reporting only minor and inconsistent effects against the early asthmatic response [13][14][15].…”