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 H(1) blocker diphenhydramine or an H(2) blocker famotidine, but was significantly reduced by a neurokinin NK(1) antagonist LY303870 (0.5 mg/kg) and an NK(2) 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.
Itoh
Yoshinori
Y
Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. yositou@st.hosp.kyushu-u.ac.jp
Sendo
Toshiaki
T
Hirakawa
Toshio
T
Takasaki
Shinya
S
Goromaru
Takeshi
T
Nakano
Hitoo
H
Oishi
Ryozo
R
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000378:metabolism; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017239:Paclitaxel / Q000633:toxicity*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011744:Pyrimidinones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000037:antagonists & inhibitors / Q000378:metabolism
D009479:Neuropeptides; D011725:Pyridines; D011744:Pyrimidinones; C055139:pemirolast; D013373:Substance P; D015288:Neurokinin A; D015740:Calcitonin Gene-Related Peptide; D017239:Paclitaxel