Hideo Fukui

Increase in serotonin levels in the dog ileum and blood by cisplatin as measured by microdialysis

Involvement of ileal and circulating serotonin (5-HT) levels in cisplatin-induced emesis was examined using a microdialysis technique and an extraction method in dogs. The 5-HT levels in the ileal dialysate were increased to 232-294% of the basal level from 100 to 180 min after cisplatin administration (3 mg/kg, i.v.) and had returned to the basal level 280 min after dosing. The 5-HT levels in the blood dialysate were increased to 424-2165% from 140 to 180 min after dosing. The concentrations of 5-HT determined by HPLC following extraction were increased to 271% in the ileal mucosa and to 478% in plasma 3 hr after dosing. In immunohistochemistry, the number of 5-HT-immunoreactive cells was increased to 166% in the ileal mucosa following cisplatin treatment. These results strongly suggest that increases in the release and synthesis of 5-HT in the gut, probably in the enterochromaffin cells, are intimately involved in cisplatin-induced emesis.

Possible involvement of peripheral 5-HT4 receptors in copper sulfate-induced vomiting in dogs

The involvement of visceral afferent fibers and 5-HT3 or 5-HT4 receptors in the vomiting induced by oral administration of copper sulfate was investigated in beagle dogs. Vomiting induced by copper sulfate (100 mg/kg) was inhibited markedly by bilateral abdominal vagotomy and bilateral greater splanchnic nerve section. The vomiting induced by copper sulfate was inhibited by blocking 5-HT4 receptors with high doses (1 and 3 mg/kg, i.v.) of ICS 205-930. On the other hand, blocking 5-HT3 receptors with MDL 72222 (0.5 and 5 mg/kg, i.v.) or low doses (0.01 mg/kg i.v.) of ICS 205-930 had no apparent effect on the vomiting induced by copper sulfate. Oral administration of a 5-HT4 receptor agonist, 5-methoxytryptamine (5-MT), caused vomiting at a dose of 100 mg/kg, and the vomiting was inhibited markedly by abdominal visceral nerve section or a high dose (1 mg/kg, i.v.), but not a low dose (0.01 mg/kg, i.v.), of ICS 205-930. Intravenous administration of 5-MT (10 mg/kg) failed to induce vomiting. These results suggest that the abdominal visceral afferent fibers and possibly peripheral 5-HT4 receptors play an important role in the vomiting induced by oral administration of copper sulfate in dogs.

Involvement of 5-HT3 receptors and vagal afferents in copper sulfate- and cisplatin-induced emesis in monkeys

The emetic effects of copper sulfate and cisplatin and the potential involvement of vagal afferent fibers and 5-HT3 receptors in the emesis were investigated in cynomolgus monkeys. Retching and vomiting induced by both oral (100 mg/kg) and intravenous (20 mg/kg) copper sulfate were inhibited markedly by abdominal vagotomy. Furthermore, the emetic response induced by oral copper sulfate was strongly inhibited by intravenous ICS 205-930 (0.1 mg/kg), a 5-HT3 receptor antagonist. Cisplatin (3 mg/kg, i.v.) caused severe retching and vomiting, and the number of emetic responses was much greater than that in other species. The emetic response induced by cisplatin was inhibited markedly by abdominal vagotomy or concurrent administration of ICS 205-930 (3 x 0.1 mg/kg, i.v.). These results suggest that the monkey is more sensitive to cisplatin than other species and that the vagal afferent terminals and 5-HT3 receptors play an important role in the emetic response induced by copper sulfate and cisplatin.

Methotrexate produces delayed emesis in dogs: a potential model of delayed emesis induced by chemotherapy

We investigated the emetic effects of cisplatin and methotrexate in dogs, the effects of ondansetron on cisplatin-induced vomiting, and the effects of ondansetron, dexamethasone and a combination of the two on the vomiting induced by methotrexate. Ondansetron was administered 30 min before cisplatin administration. Ondansetron, dexamethasone or a combination of the two was administered 8, 24 and 48 h after methotrexate administration. Cisplatin (3 mg/kg, i.v.) induced acute vomiting but failed to induce delayed vomiting. The acute vomiting was markedly inhibited by ondansetron (3 mg/kg, p.o.; 1 mg/kg, i.v.). Methotrexate (2.5 mg/kg, i.v.) caused delayed vomiting, which was partly inhibited by ondansetron (1 mg/kg, i.v.) or dexamethasone (2.5 mg/kg, i.v.). The combination of the two agents was more effective. These results suggest that methotrexate-induced emesis in dogs would be useful for studying delayed emesis.

Emetic effects of anticancer drugs and involvement of visceral afferent fibers and 5-HT3 receptors in dogs

The emetic effects of five anticancer drugs, cyclophosphamide, nitrogen mustard-N-oxide, actinomycin D, 5-fluorouracil and L-asparaginase, and the effects of bilateral abdominal vagotomy and bilateral greater splanchnic nerve section or a 5-HT3 receptor antagonist on the emesis induced by these drugs were investigated in dogs. Cyclophosphamide (20 mg/kg, i.v.), nitrogen mustard-N-oxide (5 mg/kg, i.v.) and actinomycin D (50 micrograms/kg, i.v.) caused vomiting in dogs with a long latency period. 5-Fluorouracil (5 mg/kg, i.v.) and L-asparaginase (2000 K.U./kg, i.v.) failed to induce vomiting. Bilateral abdominal vagotomy and bilateral greater splanchnic nerve section completely inhibited the vomiting induced by the former three anticancer drugs. Furthermore, the vomiting was inhibited completely by intravenous administration of ICS205930 (2 x 0.1 mg/kg), a 5-HT3 receptor antagonist. These results suggest that activation of visceral afferents through 5-HT3 receptors mediates the vomiting induced by cyclophosphamide, nitrogen mustard-N-oxide and actinomycin D.

Identification of a novel fluoropyrrole derivative as a potassium-competitive acid blocker with long duration of action

With the aim to find a novel long-lasting potassium-competitive acid blocker (P-CAB) that would perfectly overcome the limitations of proton pump inhibitors (PPIs), we tried various approaches based on pyrrole derivative 1b as a lead compound. As part of a comprehensive approach to identification of a new drug, we explored excellent compounds that have low lipophilicity by introducing a polar hetero-aromatic group at position 5 of the pyrrole ring. Among the compounds synthesized, fluoropyrrole derivative 37c, which has a 2-F-3-Py group at the fifth position, lower pKa, and much lower ClogP and logD values than 1b dose, showed potent gastric-acid suppressive action resulting from gastric H+,K+-ATPase inhibition in animal models. Its maximum intragastric pH elevation effect was strong in rats, and its duration of action was much longer than that of either lansoprazole or lead compound 1b in dogs. Therefore, compound 37c can be considered a promising new P-CAB with long duration of action.

Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion

With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger ClogP value (1.95), larger logD value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action.

Antiobesity and emetic effects of a short-length peptide YY analog and its PEGylated and alkylated derivatives

Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23-36), 1) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet-induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (Cmax) and longer time at maximum concentration (Tmax). Compounds 5 and 10, modified with 20 kDa PEG at the N-terminus and eicosanedioic acid at the Lys30 side chain of 1, respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10, with their relatively low Cmax and long Tmax, partially attenuated emesis in dogs compared with 1. These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism.