Israpafant

Jan C-R, et al. Pharmacological Research, 2005, 51(3), 189-195.

In this study, Israpafant (Y-24180), a presumed platelet-activating factor (PAF) receptor antagonist, was evaluated for its effects on intracellular Ca²⁺ concentration ([Ca²⁺]ᵢ) and proliferation in human MG63 osteosarcoma cells. Using fura-2 for Ca²⁺ imaging, Y-24180 (1-5 μM) induced a rapid, sustained [Ca²⁺]ᵢ increase. The response was partially inhibited by dihydropyridines or Ca²⁺-free media, indicating extracellular influx, and further confirmed by thapsigargin assays implicating intracellular Ca²⁺ release from endoplasmic reticulum stores. Notably, U73122, a PLC inhibitor, did not block Y-24180-induced Ca²⁺ elevation, suggesting a PLC-independent mechanism. Proliferation was assessed via tetrazolium dye after overnight Y-24180 exposure, revealing concentration-dependent cytotoxicity. These findings demonstrate Y-24180's experimental utility in modulating Ca²⁺ signaling pathways and suppressing osteosarcoma cell growth, independent of its presumed PAF receptor specificity.

Chao YY, et al. Life Sciences, 2004, 74(7), 923-933.

In this study, Israpafant (Y-24180), a presumed PAF receptor antagonist, was investigated for its effect on intracellular Ca²⁺ concentration ([Ca²⁺]i) in canine renal tubular cells using the fura-2 fluorescent probe. Y-24180 (0.1-10 μM) elicited a rapid, sustained, concentration-dependent [Ca²⁺]i increase. Removal of extracellular Ca²⁺ attenuated this response by ~30%, while calcium channel blockers had no effect. Manganese quenching of fura-2 confirmed Ca²⁺ influx. In Ca²⁺-free medium, Y-24180 and thapsigargin showed mutual exclusivity in inducing [Ca²⁺]i elevation, indicating shared intracellular Ca²⁺ stores. U73122 blocked ATP- but not Y-24180-induced Ca²⁺ rise, suggesting a PLC-independent mechanism. Importantly, overnight exposure to Y-24180 did not affect cell proliferation. These findings demonstrate Y-24180's dual action in promoting both Ca²⁺ influx and release, highlighting its experimental utility in dissecting calcium signaling pathways beyond PAF receptor modulation.

Takenaga M, et al. Allergology International, 2000, 49(2), 143-149.

In this study, the lipophilic PAF antagonist Israpafant (Y-24180) was encapsulated in lipid microspheres (Lipo Y-24180) to evaluate its potential as an injectable and inhalable bronchodilator. Guinea pigs received intravenous Lipo Y-24180 at varying doses (1-10 μg/kg) three minutes before PAF challenge. Respiratory flow resistance was significantly suppressed, with 1 μg/kg reducing resistance to 19.0 ± 8.0% compared to 61.5 ± 13.0% in controls (P < 0.05), and 3-10 μg/kg achieving near-complete inhibition. In contrast, free Y-24180 showed dose-dependent activity, with significant effect only at 10 μg/kg. For inhalation studies, aerosolized Lipo Y-24180 at 10 μg/mL showed no effect, but concentrations ≥30 μg/mL significantly inhibited bronchoconstriction. These results support the efficacy of Lipo Y-24180 in vivo and its promise as both an injectable and inhalable therapy for PAF-induced bronchoconstriction.