Ibodutant

Irritable bowel syndrome (IBS) has a significant impact on society and quality of life. Current treatments are ineffective, and new investigational drugs are necessary.

Numerous potential therapies are developing, targeting different areas such as cannabinoid signaling, opioid receptors, tachykinin (NK2) receptors, β3-adrenergic receptors, intestinal microbiota, inflammation, and 5HT receptors. Clinical trial evidence has shown that loperamide, eluxadoline, alosetron, ramosetron, bile acid sequestrants, and rifaximin can modulate GI alterations and benefit patients with IBS-D. Among the potential therapies, ibodutant, ibudilast, blautix, BOS-589, solabegron, vibegron, olorinab, ebastine, and ORP-101 have demonstrated possible effects but remain confirmed.

Individuals with IBS-D require cost-effective treatment options that do not impede their productivity or that of their caregivers. This is necessary for consistent healthcare and improved quality of life. Therefore, we should focus on developing new, efficient, and affordable medications for IBS-D. The government, insurers, and society must recognize this need and collaborate to ensure its fulfillment.

The tachykinin NK₂ receptor plays a key role in gastrointestinal motor function. Enteric neurons release neurokinin A (NKA), which activates NK₂ receptors on gastrointestinal smooth muscle, leading to contraction and increased motility. In patients with diarrhea-predominant irritable bowel syndrome, the NK₂ receptor antagonist ibodutant had a greater therapeutic effect in females than males. The present study aimed to determine whether gender influences the expression and activity of NK₂ receptors in human colonic smooth muscle. In vitro functional studies were performed to examine the contractile responses of colonic muscle strips to NKA and the selective NK₂ receptor agonist [Lys⁵,MeLeu⁹,Nle¹⁰]NKA(4-10). Contractions were also measured in the presence of ibodutant to determine its antagonistic potency. The signal transduction pathways coupled to NK₂ receptor activation were investigated using second messenger inhibitors. Western blot and fluorescent immunohistochemistry were conducted to determine the protein expression and localization of NK₂ receptors. NK₂ receptor-mediated contractility was greater in females compared with males. When against NKA, ibodutant was more potent in females. NK₂ receptor expression increased with age in females, but not in males. Phospholipase C-mediated signaling was less prominent in females compared with males, whereas Ca²⁺ sensitization via Rho kinase and protein kinase C appeared to be the dominant pathway in both genders. The distribution of NK₂ receptors in the human colon did not differ between the genders. Overall, gender differences exist in the expression and activity of NK₂ receptors in colonic smooth muscle. These gender distinctions should be considered in the therapeutic development of NK₂ receptor agents. SIGNIFICANCE STATEMENT: The tachykinin NK₂ receptor has been identified as a therapeutic target for the treatment of bowel and bladder dysfunctions. The present study has revealed gender-related variations in NK₂ receptor activity, signaling transduction pathways, antagonist potency, and changes in expression with age. These factors may underlie the gender differences in the treatment of diarrhea-predominant irritable bowel syndrome with NK₂ receptor antagonists. Our findings highlight that gender differences should be considered in the therapeutic development of NK₂ receptor agents.