Dataset Information

Anti-emetic Action of the Brain-Penetrating New Ghrelin Agonist, HM01, Alone and in Combination With the 5-HT3 Antagonist, Palonosetron and With the NK1 Antagonist, Netupitant, Against Cisplatin- and Motion-Induced Emesis in Suncus murinus (House Musk Shrew).

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.

SUBMITTER: Rudd JA

PROVIDER: S-EPMC6087754 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Anti-emetic Action of the Brain-Penetrating New Ghrelin Agonist, HM01, Alone and in Combination With the 5-HT3 Antagonist, Palonosetron and With the NK1 Antagonist, Netupitant, Against Cisplatin- and Motion-Induced Emesis in Suncus murinus (House Musk Shrew).

Rudd John A JA Chan Sze W SW Ngan Man P MP Tu Longlong L Lu Zengbing Z Giuliano Claudio C Lovati Emanuela E Pietra Claudio C

Frontiers in pharmacology 20180806

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-[ ...[more]

PMID: 30127745

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Project description:Purpose: Cancer patients receiving cisplatin therapy often experience side-effects such as nausea and emesis, but current anti-emetic regimens are suboptimal. Thus, to enable the development of efficacious anti-emetic treatments, the mechanisms of cisplatin-induced emesis must be determined. We therefore investigated these mechanisms in Suncus murinus, an insectivore that is capable of vomiting. Methods: We used a microelectrode array system to examine the effect of cisplatin on the spatiotemporal properties of slow waves in stomach antrum, duodenum, ileum and colon tissues isolated from S. murinus. In addition, we used a multi-wire radiotelemetry system to record conscious animals' gastric myoelectric activity, core body temperature, blood pressure (BP) and heart rate viability over 96-h periods. Furthermore, we used whole-body plethysmography to simultaneously monitor animals' respiratory activity. At the end of in vivo experiments, the stomach antrum was collected and immunohistochemistry was performed to identify c-Kit and cluster of differentiation 45 (CD45)-positive cells. Results: Our acute in vitro studies revealed that cisplatin (1-10 μM) treatment had acute region-dependent effects on pacemaking activity along the gastrointestinal tract, such that the stomach and colon responded oppositely to the duodenum and ileum. S. murinus treated with cisplatin for 90 min had a significantly lower dominant frequency (DF) in the ileum and a longer waveform period in the ileum and colon. Our 96-h recordings showed that cisplatin inhibited food and water intake and caused weight loss during the early and delayed phases. Moreover, cisplatin decreased the DF, increased the percentage power of bradygastria, and evoked a hypothermic response during the acute and delayed phases. Reductions in BP and respiratory rate were also observed. Finally, we demonstrated that treatment with cisplatin caused inflammation in the antrum of the stomach and reduced the density of the interstitial cells of Cajal (ICC). Conclusion: These studies indicate that cisplatin treatment of S. murinus disrupted ICC networking and viability and also affected general homeostatic mechanisms of the cardiovascular system and gastrointestinal tract. The effect on the gastrointestinal tract appeared to be region-specific. Further investigations are required to comprehensively understand these mechanistic effects of cisplatin and their relationship to emesis.

Project description:BackgroundTo reduce the overall exposure to dexamethasone (DEX) in patients receiving cisplatin-based chemotherapy, we evaluated the noninferiority of DEX on day 1, with or without low-dose DEX on days 2 and 3, combined with an oral fixed-dose combination of netupitant and palonosetron (NEPA), compared with the guideline-consistent use of 4-day DEX.Patients and methodsIn this open-label, multicenter study, chemotherapy-naïve patients undergoing high-dose cisplatin (≥70 mg/m2 ), were given NEPA and DEX (12 mg) on day 1 and randomized (1:1:1 ratio) to receive either (a) no further DEX (DEX1), (b) oral DEX (4 mg daily) on days 2-3 (DEX3), or (c) DEX (4 mg twice daily) on days 2-4 (DEX4). The primary efficacy endpoint was complete response (CR: no emesis and no rescue medication) during the 5-day overall phase. The noninferiority margin was set at -15% difference (DEX1 or DEX3 minus DEX4). Secondary efficacy endpoints included complete protection (CP: CR and none or mild nausea).ResultsTwo-hundred twenty-eight patients, 76 in each arm, were assessable. Noninferiority was met for both DEX-sparing regimens and the reference arm, with overall phase CR rates of 76.3% in each of the DEX1 and DEX3 arms and 75.0% in the DEX4 arm (95% confidence interval, -12.3% to 15% for each comparison). During the overall phase, CP rates were similar between groups.ConclusionA simplified regimen of NEPA plus single-dose DEX offers comparable chemotherapy-induced nausea and vomiting prevention throughout 5 days post-chemotherapy with the advantage of sparing patients additional doses of DEX in the high-emetic-risk setting of cisplatin-based chemotherapy.Implications for practiceDexamethasone (DEX) has traditionally played an integral role in the management of chemotherapy-induced emesis. Although generally considered safe, even short-term DEX use is associated with various side effects, and some evidence suggests that concurrent steroids may reduce the efficacy of immunotherapies. This study demonstrates comparable antiemetic control during the 5 days post-chemotherapy with a simplified regimen of netupitant/palonosetron plus single-dose DEX versus the standard 4-day DEX reference treatment in high-dose cisplatin. This represents a clinically relevant achievement as it not only simplifies antiemetic prophylaxis but also offers an opportunity to appropriately use in patients where caution with corticosteroid use is advised.

Dataset Information

Anti-emetic Action of the Brain-Penetrating New Ghrelin Agonist, HM01, Alone and in Combination With the 5-HT3 Antagonist, Palonosetron and With the NK1 Antagonist, Netupitant, Against Cisplatin- and Motion-Induced Emesis in Suncus murinus (House Musk Shrew).

Publications

Anti-emetic Action of the Brain-Penetrating New Ghrelin Agonist, HM01, Alone and in Combination With the 5-HT<sub>3</sub> Antagonist, Palonosetron and With the NK<sub>1</sub> Antagonist, Netupitant, Against Cisplatin- and Motion-Induced Emesis in <i>Suncus murinus</i> (House Musk Shrew).

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