Abstract
Ghrelin has well-known activity to stimulate appetite and weight gain. Evidence suggests that ghrelin may also have effects in reducing chemotherapy-induced emesis via growth hormone secretagogue receptors (GHS-R1A) in the brain. However, it is not known whether the stimulation of GHS-R1A has broad inhibitory anti-emetic effects. In the present studies, we used Suncus murinus to investigate the potential of the new and novel orally bioavailable brain-penetrating GHS-R1A mimetic, HM01 (1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-Methyl-3,3-dimethyl-4-piperidyl]urea), to reduce emesis induced by a variety of emetic challenges. HM01 (1 to 30 mg/kg, p.o.) antagonized emesis induced by cisplatin (30 mg/kg, i.p.) and by motion (4 cm horizontal displacement, 1 Hz) but was ineffective against emesis induced by nicotine (5 mg/kg, s.c.) and copper sulfate (120 mg/kg by intragastric gavage). In other experiments, HM01 (3 mg/kg, p.o.) enhanced the anti-emetic control of a regimen of palonosetron (0.01 mg/kg, p.o.) alone and palonosetron (0.01 mg/kg p.o.) plus netupitant (1 mg/kg, p.o.). HM01 (10 mg/kg, p.o.) also had positive effects in increasing feeding and drinking in nicotine-treated animals, and it shortened the latency to drink in animals treated with cisplatin. These data indicate that brain-penetrating GHS-R1A agonists may have use alone and/or in combination with standard anti-emetic regimens for the treatment of chemotherapy-induced nausea and vomiting and motion sickness.Highlights- The novel orally bioavailable brain-penetrating GHS-R1A agonist, HM01 (1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-Methyl-3,3-dimethyl-4-piperidyl]urea), antagonizes motion- and cisplatin-induced emesis.- HM01 did not reduce emesis induced by nicotine or by intragastric copper sulfate.- HM01 has positive effects on food consumption after treatment with nicotine.- HM01 has synergistic effects against cisplatin when combined with palonosetron and palonosetron/netupitant regimens.- It is suggested that GHS-R1A agonists may be protective against chemotherapy-induced nausea and vomiting in combination with traditional anti-emetics and against motion-induced emesis.
Highlights
Cancer treatment with agents such as cisplatin has a wellknown association with nausea and emesis via mechanisms that are believed to predominantly involve the release of 5hydroytryptamine (5-HT) in the gastrointestinal tract, which activates vagal afferents, and a release of substance P in the brainstem to activate tachykinin NK1 receptors
It is feasible that ghrelin mimetics could be used in combination with standard anti-emetics for the treatment of chemotherapy-induced nausea and emesis, so we evaluated HM01 for the potential to antagonize cisplatin-induced emesis, both alone and in combination with palonosetron and/or netupitant (Hesketh et al, 2014)
HM01 did not modify any of the retching and/or vomiting parameters compared with controls (Figure 2)
Summary
Cancer treatment with agents such as cisplatin has a wellknown association with nausea and emesis via mechanisms that are believed to predominantly involve the release of 5hydroytryptamine (5-HT) in the gastrointestinal tract, which activates vagal afferents, and a release of substance P in the brainstem to activate tachykinin NK1 receptors. Second-generation 5-HT3 receptor antagonists (e.g., palonosetron) and NK1 receptor antagonists (e.g., netupitant) are available and have greater potency and/or more favorable pharmacokinetics than oldergeneration compounds, which is reflected in their superior clinical efficacy (Hesketh et al, 2014; Navari, 2015; Rudd et al, 2016). Despite these advances, a proportion of patients still have inadequate protection from chemotherapy-induced nausea and emesis (Gralla et al, 2014; Van den Brande et al, 2014). Anamorelin has shown particular benefit in patients with cancer cachexia (Currow and Abernethy, 2014); relamorelin has shown benefit in patients with diabetic gastroparesis via enhancement of gastric emptying and reduction of emesis (Camilleri and Acosta, 2015); and ulimorelin has shown benefit in patients with postoperative ileus, in whom it reduced nausea and emesis (Shaw et al, 2013)
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