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).