neurokinin-a and Vomiting

Topics: Animals; Central Nervous System Diseases; Drug Combinations; Gastrointestinal Diseases; Humans; Lung Diseases; Neurokinin A; Neurokinin B; Pain; Receptors, Tachykinin; Substance P; Urologic Diseases; Vomiting

1. MEN 11420 (nepadutant) is a potent, selective and competitive antagonist of tachykinin NK2 receptors. 2. The objective of the present study was to assess the capability of the drug to antagonize the stimulatory effects of neurokinin A (NKA) on gastrointestinal motility, as well as to change the fasting migrating motor complex (MMC). 3. Thirty-four male volunteers were randomized to treatment with either placebo or MEN 11420 in a double-blinded manner. Effects of MEN 11420 (8 mg intravenously) were evaluated as changes in phases I, II and III of MMC, as well as contraction frequency, amplitude and motility index during baseline conditions and during stimulation of motility using NKA (25 pmol kg(-1) min(-1) intravenously). 4. NKA preceded by placebo increased the fraction of time occupied by phase II, increased contraction frequency, amplitude and motility index. 5. MEN 11420 effectively antagonized the motility-stimulating effects of NKA. MEN 11420 reduced the phase II-stimulating effect of NKA. In addition, the stimulatory effect of NKA on contraction frequency and amplitude, as well as motility index were inhibited by MEN 11420. MEN 11420 did not affect the characteristics of MMC during saline infusion. 6. Plasma levels of MEN 11420 peaked during the first hour after infusion and decreased to less than half during the first 2 h. 7. In conclusion, intravenous MEN 11420 effectively inhibited NKA-stimulated, but not basal gastrointestinal motility, and was well tolerated by all subjects.

Topics: Abdominal Pain; Adolescent; Adult; Double-Blind Method; Flushing; Gastrointestinal Motility; Headache; Humans; Infusions, Intravenous; Intestine, Small; Male; Middle Aged; Muscle Contraction; Myoelectric Complex, Migrating; Nausea; Neurokinin A; Peptides, Cyclic; Receptors, Neurokinin-2; Sodium Chloride; Time Factors; Vomiting

Topics: Animals; Colorectal Neoplasms; Dogs; Neurokinin A; Peptides; Receptors, Neurokinin-2; Urinary Bladder; Vomiting

Effects of the NK1 receptor antagonist CP-99,994 on nicotine-induced emesis were examined in Suncus murinus. CP-99,994 (3 and 10 mg/kg i.p.) attenuated emesis to (-)nicotine (4 mg/kg s.c.). CP-100,263 (3 and 10 mg/kg i.p.), the enantiomer of CP-99,994 with 1000 fold lower affinity for the NK1 receptor was without effect and RP67580 reduced emesis only at a dose of 30 mg/kg i.p. Responses to NK1 antagonists were ranked according to their affinities for the Suncus murinus NK1 receptor.

Topics: Animals; Antiemetics; Dose-Response Relationship, Drug; Indoles; Isoindoles; Male; Morphine; Neurokinin A; Nicotine; Piperidines; Receptors, Neurokinin-1; Shrews; Stereoisomerism; Substance P; Vomiting

Topics: Antiemetics; Humans; Neurokinin A; Piperidines; Serotonin Antagonists; Vomiting

In the ferret, 5-HT3 receptor antagonists are effective in controlling emesis produced by cytotoxic agents or radiation. To investigate the possibility that substance P has a role, as well as 5-HT, in the emetic reflex pathway, we have examined the anti-emetic effects of a NK1 receptor antagonist (racemic CP-99,994) in the ferret. Racemic CP-99,994 was effective against a range of emetogens, comprising cytotoxic drugs, radiation, morphine, ipecacuanha and copper sulphate.

Topics: Animals; Ferrets; Male; Neurokinin A; Piperidines; Stereoisomerism; Substance P; Vomiting

The tachykinin NK1 receptor antagonist CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine) (0.3-3 mg/kg i.v.), but not its inactive enantiomer CP-100,263, attenuated the retching and vomiting induced by cisplatin (10 mg/kg i.v.) in the ferret. CP-99,994, 3 mg/kg i.v., prevented vomiting in all ferrets tested. Since substance P is the preferred ligand at the NK1 receptor subtype these data support a role for the release of this peptide during the emetic response induced by cytotoxic chemotherapeutic agents.

Topics: Analysis of Variance; Animals; Cisplatin; Ferrets; Injections, Intravenous; Male; Neurokinin A; Piperidines; Vomiting