Pemirolast potently attenuates paclitaxel hypersensitivity reactions through inhibition of the release of sensory neuropeptides in rats

The effects of anti-allergic agents on the hypersensitivity reactions to paclitaxel, an anti-cancer agent, were examined in rats. Intravenous injection of paclitaxel (15 mg/kg) caused a marked extravasation of plasma protein in lungs and a transient decrease in arterial partial oxygen pressure (PaO ₂). The paclitaxel-induced protein extravasation was inhibited by low doses (0.1-1 mg/kg) of pemirolast or high doses (30-100 mg/kg) of cromoglycate. However, ketotifen was not effective. The decrease in PaO ₂ induced by paclitaxel was also significantly reversed by pemirolast. On the other hand, the paclitaxel-induced plasma extravasation was not attenuated by a histamine H₁ blocker diphenhydramine or an H ₂ blocker famotidine, but was significantly reduced by a neurokinin NK₁ antagonist LY303870 (0.5 mg/kg) and an NK₂ antagonist SR48968 (1 mg/kg). The concentrations of proteins and sensory peptides such as substance P, neurokinin A and calcitonin gene-related peptide but not histamine in the rat bronchoalveolar lavage fluid were elevated by paclitaxel injection. Both cromoglycate and pemirolast reduced the paclitaxel-induced rise in proteins and sensory peptides. Therefore, we demonstrated for the first time that sensory nerve peptides are involved in paclitaxel hypersensitivity and that an anti-allergic agent pemirolast attenuates the paclitaxel response by inhibiting the release of sensory nerve peptides.