Prokinetics
Prokinetic agents are regularly used to treat nausea and vomiting in clinical practice. However, a Cochrane review of comparative clinical trials of 11 prokinetic agents and 39 randomised trials showed no improvement in postoperative ileus (Traut et al., 2008). One of the most widely used agents is metoclopramide, which has been approved by the FDA for the treatment of nausea and vomiting in gastroesophageal reflux disease and diabetic gastroparesis, and for the prevention of adverse effects of chemotherapy (Isola et al., 2021). Metoclopramide acts by antagonising central and peripheral dopamine-2 receptors. The mechanism involves a decrease in sensitivity of visceral afferent nerves that transmit from the gastrointestinal system to the vomiting centre in the postrema area of the chemoreceptor trigger zone (Harada et al., 2017). Metoclopramide also blocks the antiperistaltic effects of apomorphine, allowing metoclopramide to reduce the inhibition of gastric emptying by apomorphine (Ramsbottom and Hunt, 1970). This leads to acceleration of gastric emptying by increasing the amplitude and duration of oesophageal contractions. It also increases the resting tone of the lower oesophageal sphincter while simultaneously relaxing the pyloric sphincter, thereby increasing peristalsis in the duodenum and jejunum (Isola et al., 2021). In addition to antagonising dopamine and apomorphine, metoclopramide also acts against serotonin type 3 receptors, making it an attractive drug for the treatment of postoperative ileus. However, studies involving small patient cohorts in this context have not produced conclusive results (Seta and Kale-Pradhan, 2001; Chan et al., 2005).
A pharmacological alternative that could ’mimic’ the action of the vagus nerve would be to stimulate the release of acetylcholine from enteric neurons along the digestive tract. This is one of the actions of selective 5HT4 agonists such as mosapride and prucalopride (Table 1). A cohort study comparing mosapride vs. placebo conducted by Naritaet al . involving 40 patients who had undergone elective colectomy showed no improvement in the duration of transit recovery (Narita et al., 2008). However, the mosapride group had a significantly shorter hospital stay. Another cohort study of 30 patients who underwent elective colectomy showed a significant improvement in the time to first faltus and first defecation (Toyomasu et al., 2011). Interestingly, Tsuchida et al. (Gut 2011) showed in a mouse model that administration of mosapride prior to intestinal manipulation had anti-inflammatory properties via activation of acetylcholine secretion and thus activation of 7nAChR receptors on active macrophages(Tsuchida et al., 2011). Recently, Chapman et al. conducted a phase 2a clinical trial to assess the efficacy and safety of a novel 5HT-4 receptor agonist, TAK-954, in improving gastric emptying time in a cohort of mechanically ventilated patients with enteral feeding intolerance. The study group with TAK-954 administration was compared to a control group treated with metoclopramide. There was no difference in adverse events and TAK-954 improved the gastric emptying rate compared to metoclopramide (Chapman et al., 2021). A clinical trial is currently underway to test its efficacy on POI (NCT03827655).
Clinical studies involving prucalopride appear to show more promising results. A phase 2 study in a cohort of 110 patients receiving placebo (n=55) or prucalopride (2 mg/day; n=55) with initiation of treatment 24 hours post-surgery showed a significant reduction in the time to onset of the first gastrointestinal movements and the arrival of the first gas (see Table 1 for detailed results)(Gong et al., 2016). Stakenborget al. elegantly demonstrated the anti-inflammatory and prokinetic properties of prucalopride. In a cohort of 30 duodenopancreatectomy patients comparing a placebo group, a vagus nerve stimulation group and a prucalopride group, a reduction in the expression of pro-inflammatory genes in the duodenum and significantly faster transit recovery were observed in the prucalopride group compared to the other two groups. The authors also confirmed that the anti-inflammatory effect was mediated via α7nACh receptors by carrying out a comparative study in a α7nAChR Knock Out (KO) vs. Wild Type (WT) model, with prucalopride having no effect on postoperative ileus in α7nAChR KO mice(Stakenborg et al., 2019).
Discovered in 1999, ghrelin is a 28-amino acid peptide and an orexigenic hormone. Ghrelin is mainly produced by the P/D1-like cells of oxyntic gastric mucosa (Kojima et al., 1999). There is a gradual decrease in its production from the stomach to the colon (Dass et al., 2003). Ghrelin is also produced in smaller quantities in other tissues (pituitary gland, pancreas, heart, thyroid, kidney, liver, testicles, lung and immune system)(Lutter et al., 2008). The ghrelin receptor is a G protein-coupled receptor with two alternatively spliced variants (GHS-R1a and GHS-R1b)(Gutierrez et al., 2008). The level of ghrelin is regulated by meals, with a high pre-prandial level and a decrease after food intake (Cummings et al., 2001). Ghrelin was first described as a growth-releasing hormone and was later investigated for prokinetic functions because of its similarity to motilin(Janssen et al., 2011). This rationale was supported by the discovery of ghrelin receptors in the enteric nervous system through immunohistochemistry and mRNA expression studies (Gnanapavan et al., 2002). In addition, ghrelin receptors in the gastric vagal afferents play a role in regulating satiety (le Roux et al., 2005). The prokinetic properties of ghrelin and its agonists make this a promising route for the treatment of postoperative ileus. The first molecule used in clinical trials was TZP 101/Ulimorelin, an agonist with a high affinity for the GHSR1a receptor. As shown in Table 1, two phase IIb clinical trials were conducted to assess the efficacy and safety of ulimorelin. These studies have shown, over several doses (20 – 600 ug/l) of ulimorelin, an absence of adverse effects on the one hand and, on the other hand, faster transit recovery in the study group compared to the placebo group(Popescu et al., 2010; Bochicchio et al., 2012). Similar results were found by infusing a ghrelin analogue (15 pmol/kg/min, NeoMPS, Strasbourg France) before and after surgery (Falkén et al., 2013). However, two other phase III clinical trials (ulimorelin efficacy and safety studies, ULISES 007 n=332 patients, and ULISES 008 n=330 patients) did not show any significant improvement in transit recovery time or the prevention of morbidity inherent in postoperative ileus(Shaw et al., 2013). These negative results were correlated in a trial with another agonist, namely ipamorelin (Beck et al., 2014).