Targeting tachykinin receptors for the treatment of functional gastrointestinal disorders with a focus on irritable bowel syndrome

Abstract

This article reviews the literature concerning the role of TKs in the GI tract function in physiological and pathological conditions and their potential relevance in the treatment of functional GI disorders with particular reference to irritable bowel syndrome (IBS). The efficacy of NK1 antagonists in chemotherapy-induced and postoperative nausea and vomiting is well established. While pharmacodynamic studies have reported conflicting and negative results concerning the effects of NK1 and of NK3 antagonists, respectively, on the GI tract function in humans, clinical studies applying the NK3 antagonist talnetant in IBS-D were negative. Pharmacodynamic studies applying NK2 antagonists have suggested a role for antagonism of NK2 receptors in modulation of GI chemical-induced altered motility and of stress-induced altered bowel habits. Clinical studies and in particular a recently completed Phase 2 study have reported that the NK2 antagonist ibodutant is effective and safe in treating symptoms of D-IBS, especially in females.

The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS

“…In addition to the efficacy findings, ibodutant displayed an excellent safety and tolerance profile in the current and in previous studies 24. These trials showed no differences between treatments in the incidence rates for individual AEs, and SAEs were rare.…”

“…A previous study evaluated dose ranges between 10 and 60 mg daily in the overall IBS population, showing a statistically non-significant but consistent trend towards a higher response with the 10 mg dose in the IBS-D subgroup of patients, with no particular differences by gender, suggesting that males could not be completely unresponsive to ibodutant 24. In the present study, nevertheless, no significant effects were obtained in the male population, either using the EMA-specified or FDA-specified end points.…”

“…These trials showed no differences between treatments in the incidence rates for individual AEs, and SAEs were rare. The fact that a previous study evaluating higher doses of ibodutant also failed to show any drug-related AEs is particularly reassuring 24. The fact that ibodutant does not cross the blood–brain barrier well is also reassuring in terms of tolerance and safety 24…”

“…Based on these preclinical findings, it has been speculated that NK2 receptor antagonists could be useful in the treatment of symptoms of IBS 22 23. Furthermore, in a phase II dose-finding study, the selective tachykinin NK2 receptor antagonist, ibodutant, showed benefit over placebo in patients with diarrhoea-predominant IBS and a baseline pain severity score >1 24. Supporting evidence for this hypothesis was obtained when administration of exogenous NKA to healthy human volunteers induced powerful intestinal contractions and pain, mimicking spontaneous symptoms of IBS 25 26…”

Modern Management of Irritable Bowel Syndrome: More Than Motility

“…Blocking tachykinergic neurotransmission is a promising new approach for the treatment of IBS [65]. Ibodutant, a selective antagonist of the NK2 receptor with very low penetration in the brain, is currently being evaluated for women with IBS-D in phase III trials in European countries and in the United States [65]. …”