neurokinin-a and Flushing

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

Cutaneous flushing was provoked in seven patients with metastatic carcinoid tumours and the carcinoid syndrome by an intravenous injection of pentagastrin (0.6 micrograms.kg-1 body weight). The patients were studied before and 1 h after a subcutaneous injection of the long-acting somatostatin analogue octreotide 50 micrograms (Sandostatin). The severity of the carcinoid flush in all the patients was reduced by administration of the analogue. The rise in facial temperature was 1.3 (0.3) degree C before and 0.8 (0.2) degree C after octreotide. Six patients responded to pentagastrin with a rise in the circulating neurokinin A-like immunoreactivity (NKA-LI) and five patients with a rise in circulating substance P-like immunoreactivity (SP-LI). No cutaneous flushing or rise in tachykinin concentration was observed in healthy subjects (n = 6) after injection of pentagastrin. The rise in NKA-LI in the patients was decreased by 61 (14)% and the rise in SP-LI by 54 (13)% after octreotide. Although flushing still occurred, the tachykinin response in two patients was completely abolished. The data demonstrate that the release of tachykinins from carcinoid tumours during pentagastrin-induced flushing is subject to partial inhibition by octreotide. However, the occurrence of a flush in some patients in the absence of a detectable rise in circulating tachykinins indicates that the latter peptides cannot be the sole causative agent of the carcinoid flush.

Topics: Aged; Body Temperature; Carcinoid Tumor; Female; Flushing; Humans; Ileal Neoplasms; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neurokinin A; Octreotide; Pentagastrin; Radioimmunoassay; Substance P; Tachykinins