title: Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret.
abstract: Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) has been investigated in the ferret. The PDE IV inhibitors studied were: RS14203, R-rolipram and CT-2450 (i.e. (R)-N-[4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl ]N'-ethylurea), in addition to the less active enantiomers S-rolipram and CT-3405. Following oral administrations, different emetic profiles were observed with time. Emesis induced by RS14203 exhibited a dose-response relationship but no such relationship was seen for R-rolipram or CT-2450. The incidence of emesis was positively influenced by the dose of PDE IV inhibitors administered, allowing a rank order of potency: RS14203 > R-rolipram > S-rolipram > CT-2450 > CT-3405. PDE IV inhibitor-induced emesis was abolished by the tachykinin NK1 receptor antagonist, CP-99,994. No peripheral release of substance P by PDE IV inhibitors seems to be involved in triggering the emetic reflex since L-743,310, which only has peripheral NK1 receptor antagonist activity, was without effect. The implication of 5-HT3 receptors in PDE IV inhibitor-induced emesis was variable. Our results suggest that the PDE IV inhibitors studied are mixed peripheral-central emetogens. PDE IV inhibition itself could be plausible mechanism of action of these agents. However, whether emesis is mediated via a specific isoform of PDE IV remains to be established.
authors.affiliation: Merck Frosst Canada Incorporated, Centre for Therapeutic Research, Pointe-Claire-Dorval, Qc, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Robichaud
authors.forename: F D
authors.initials: FD
authors.lastname: Tattersall
authors.forename: I
authors.initials: I
authors.lastname: Choudhury
authors.forename: I W
authors.initials: IW
authors.lastname: Rodger
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004639:Emetics / Q000494:pharmacology*; D005289:Ferrets; D007211:Indoles / Q000494:pharmacology; D015394:Molecular Structure; D009578:Nitrobenzenes / Q000494:pharmacology*; D017294:Ondansetron / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D020889:Rolipram; D013237:Stereoisomerism; D013997:Time Factors; D014839:Vomiting
chemical_list: D000932:Antiemetics; D004639:Emetics; D007211:Indoles; C105218:L 743310; D009578:Nitrobenzenes; D010671:Phenylurea Compounds; D010726:Phosphodiesterase Inhibitors; D010880:Piperidines; D011725:Pyridines; D011760:Pyrrolidinones; D015363:Quinolones; C119518:RS 14203; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D017294:Ondansetron; D020889:Rolipram; C119519:CT 2450