Emesis is the most feared side effect in patients who are undergoing
cancer chemotherapy. In particular,
cisplatin causes severe acute and delayed
emesis. Although early
vomiting is well controlled by
5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists, delayed-phase
vomiting is not sufficiently controlled.
Substance P is thought to be involved in the development of
emesis, and
tachykinin NK(1) receptor antagonists can inhibit delayed
vomiting. We previously have reported that
substance P is involved in the
paclitaxel-induced
hypersensitivity reaction in rats, and
anti-allergic agent pemirolast reduces these reactions via inhibition of
substance P release. In the present study, we investigated the effect of
pemirolast on
cisplatin-induced
kaolin intake, which is an index of
nausea/
vomiting in the rat.
Cisplatin (5 mg/kg, i.p.) induced
kaolin intake and reduced normal feed intake from days 1 to 5 after injection.
Cisplatin-induced
kaolin intake was significantly reduced by co-administration of
ondansetron (2 mg/kg, i.p.), a 5-HT(3) receptor antagonist, and
dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly,
pemirolast (10 mg/kg, p.o.) and the
tachykinin NK(1) receptor antagonist
aprepitant (10 and 30 mg/kg, p.o.) significantly reduced
cisplatin-induced
kaolin intake on days 3 and 4. Moreover,
pemirolast at the same dose significantly reversed the
cisplatin-induced increase in the cerebrospinal fluid level of
substance P in rats. These results suggest that
substance P is involved in
cisplatin-induced
kaolin intake in rats, and
pemirolast reduces
kaolin intake by inhibition of
substance P release.