Effect of the NK₃ receptor antagonist, talnetant, on rectal sensory function and compliance in healthy humans

Abstract

Visceral hypersensitivity is important in the pathophysiology of irritable bowel syndrome and thus a target for modulation in drug development. Neurokinin (NK) receptors, including NK(3) receptors, are expressed in the motor and sensory systems of the digestive tract. The aim of this study was to compare the effects of two different doses (25 and 100 mg) of the NK(3) receptor antagonist, talnetant (SB223412) with placebo on rectal sensory function and compliance in healthy volunteers studied at two centres. Rectal barostat tests were performed on 102 healthy volunteers, randomized to receive either oral talnetant 25 or 100 mg or placebo over 14-17 days. Studies were performed on three occasions: day 1 immediately prior to 1st dose, day 1 4 h postdose, and after 14- to17-day therapy. Compliance, and pressure thresholds for first sensation, urgency, discomfort and pain were measured using ascending method of limits, and sensory intensity ratings for gas, urgency, discomfort and pain determined during four random phasic distensions (12, 24, 36 and 48 mmHg). Talnetant had no effect on rectal compliance, sensory thresholds or intensity ratings compared with placebo. In general, the results obtained at the two centres differed minimally, with intensity scores at one centre consistently somewhat lower. At the doses tested, talnetant has no effect on rectal compliance or distension-induced rectal sensation in healthy participants.

Novel therapeutic agents in neurogastroenterology: advances in the past year

“…The trial showed a significant effect with the 10mg/day dose on the satisfactory relief response in at least 6 out of 8 weeks in females, but not in males (33). These data contrast with studies of other neurokinin receptor antagonists such as talnetant which was not efficacious in modulating human rectal sensation (34). Overall the data available suggest that tachykinin NK-2 receptors may be optimal targets for visceral pain and diarrhea (33).…”

Tachykinin receptor antagonists in clinical trials

“…In view of the above, three studies have been performed in humans (one in healthy volunteers [135], the other two in IBS patients [136]), in order to test the potential efficacy of talnetant in modulating visceral sensitivity. The first study compared the effects of two different doses (25 and 100 mg) of talnetant with placebo on rectal sensory function and compliance in healthy volunteers studied at two centers.…”

'First-in-man': characterising the mechanosensitivity of human colonic afferents

“…Such recordings have enormous potential; first, from the perspective of understanding the stimulus transduction processes that operate in human gastrointestinal (GI) sensory endings; and second, enable the pharmacological screening of novel visceral analgesics. The need for the latter arises from the apparent lack of translation from animal models to humans with a number of novel drugs failing in the clinic despite good mechanistic data from animals (eg, Houghton et al 3). This has motivated our efforts to record from human GI afferents and here we describe a methodology that shares some similarity with that described by Peiris et al but also some notable differences.…”