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Anamorelin HCl (ONO-7643), a novel ghrelin receptor agonist, for the treatment of cancer anorexia-cachexia syndrome: preclinical profile.

Pietra C, Takeda Y, Tazawa-Ogata N, Minami M, Yuanfeng X, Duus EM, Northrup R - J Cachexia Sarcopenia Muscle (2014)

Bottom Line: Rat pituitary cells were incubated with ANAM to evaluate its effect on growth hormone (GH) release.ANAM showed significant agonist and binding activity on the ghrelin receptor, and stimulated GH release in vitro.ANAM is a potent and highly specific ghrelin receptor agonist with significant appetite-enhancing activity, leading to increases in FI and BW, and a stimulatory effect on GH secretion.

View Article: PubMed Central - PubMed

Affiliation: Helsinn Healthcare SA, Research and Preclinical Department, 6915, Lugano, Switzerland, claudio.pietra@helsinn.com.

ABSTRACT

Background: Anamorelin HCl (ANAM) is a novel, orally active, ghrelin receptor agonist in clinical development for the treatment of cancer cachexia. We report in vitro and in vivo studies evaluating the preclinical pharmacologic profile of ANAM.

Methods: Fluorescent imaging plate reader and binding assays in HEK293 and baby hamster kidney cells determined the agonist and antagonist activity of ANAM, and its affinity for the ghrelin receptor. Rat pituitary cells were incubated with ANAM to evaluate its effect on growth hormone (GH) release. In vivo, rats were treated with ANAM 3, 10, or 30 mg/kg, or control orally, once daily for 6 days to evaluate the effect on food intake (FI) and body weight (BW), and once to assess GH response. In pigs, single (3.5 mg/kg) or continuous (1 mg/kg/day) ANAM doses were administered to assess GH and insulin-like growth factor (IGF-1) response.

Results: ANAM showed significant agonist and binding activity on the ghrelin receptor, and stimulated GH release in vitro. In rats, ANAM significantly and dose-dependently increased FI and BW at all dose levels compared with control, and significantly increased GH levels at 10 or 30 mg/kg doses. Increases in GH and IGF-1 levels were observed following ANAM administration in pigs.

Conclusion: ANAM is a potent and highly specific ghrelin receptor agonist with significant appetite-enhancing activity, leading to increases in FI and BW, and a stimulatory effect on GH secretion. These results support the continued investigation of ANAM as a potential treatment of cancer anorexia-cachexia syndrome.

No MeSH data available.


Related in: MedlinePlus

a Acute GH release following a single dose of ANAM (3.5 mg/kg) in pigs. b GH response on Day 1 and on Day 7 following repeated daily ANAM dosing (1.5 mg/kg/day) in pigs. ANAM anamorelin; GH growth hormone
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Fig5: a Acute GH release following a single dose of ANAM (3.5 mg/kg) in pigs. b GH response on Day 1 and on Day 7 following repeated daily ANAM dosing (1.5 mg/kg/day) in pigs. ANAM anamorelin; GH growth hormone

Mentions: In pigs, following the administration of a single oral dose of ANAM 3.5 mg/kg there was a significant rise in GH levels (CmaxP < 0.0001) (Fig. 5a). Similar GH stimulatory activity was also observed in dogs [data on file]. Repeated administration of ANAM at 1 mg/kg/day for 7 days in pigs showed an acute GH release on both the first and seventh dose; however, the response was considerably reduced by the seventh dose (Fig. 5b). Furthermore, treatment with either control or ANAM (1 mg/kg/day) for 7 days, after which treatments were crossed over and continued for another 7 days, showed that mean IGF-1 concentrations were significantly elevated by 21 % (P < 0.001) with ANAM treatment compared with the control (Fig. 6).Fig. 5


Anamorelin HCl (ONO-7643), a novel ghrelin receptor agonist, for the treatment of cancer anorexia-cachexia syndrome: preclinical profile.

Pietra C, Takeda Y, Tazawa-Ogata N, Minami M, Yuanfeng X, Duus EM, Northrup R - J Cachexia Sarcopenia Muscle (2014)

a Acute GH release following a single dose of ANAM (3.5 mg/kg) in pigs. b GH response on Day 1 and on Day 7 following repeated daily ANAM dosing (1.5 mg/kg/day) in pigs. ANAM anamorelin; GH growth hormone
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4248409&req=5

Fig5: a Acute GH release following a single dose of ANAM (3.5 mg/kg) in pigs. b GH response on Day 1 and on Day 7 following repeated daily ANAM dosing (1.5 mg/kg/day) in pigs. ANAM anamorelin; GH growth hormone
Mentions: In pigs, following the administration of a single oral dose of ANAM 3.5 mg/kg there was a significant rise in GH levels (CmaxP < 0.0001) (Fig. 5a). Similar GH stimulatory activity was also observed in dogs [data on file]. Repeated administration of ANAM at 1 mg/kg/day for 7 days in pigs showed an acute GH release on both the first and seventh dose; however, the response was considerably reduced by the seventh dose (Fig. 5b). Furthermore, treatment with either control or ANAM (1 mg/kg/day) for 7 days, after which treatments were crossed over and continued for another 7 days, showed that mean IGF-1 concentrations were significantly elevated by 21 % (P < 0.001) with ANAM treatment compared with the control (Fig. 6).Fig. 5

Bottom Line: Rat pituitary cells were incubated with ANAM to evaluate its effect on growth hormone (GH) release.ANAM showed significant agonist and binding activity on the ghrelin receptor, and stimulated GH release in vitro.ANAM is a potent and highly specific ghrelin receptor agonist with significant appetite-enhancing activity, leading to increases in FI and BW, and a stimulatory effect on GH secretion.

View Article: PubMed Central - PubMed

Affiliation: Helsinn Healthcare SA, Research and Preclinical Department, 6915, Lugano, Switzerland, claudio.pietra@helsinn.com.

ABSTRACT

Background: Anamorelin HCl (ANAM) is a novel, orally active, ghrelin receptor agonist in clinical development for the treatment of cancer cachexia. We report in vitro and in vivo studies evaluating the preclinical pharmacologic profile of ANAM.

Methods: Fluorescent imaging plate reader and binding assays in HEK293 and baby hamster kidney cells determined the agonist and antagonist activity of ANAM, and its affinity for the ghrelin receptor. Rat pituitary cells were incubated with ANAM to evaluate its effect on growth hormone (GH) release. In vivo, rats were treated with ANAM 3, 10, or 30 mg/kg, or control orally, once daily for 6 days to evaluate the effect on food intake (FI) and body weight (BW), and once to assess GH response. In pigs, single (3.5 mg/kg) or continuous (1 mg/kg/day) ANAM doses were administered to assess GH and insulin-like growth factor (IGF-1) response.

Results: ANAM showed significant agonist and binding activity on the ghrelin receptor, and stimulated GH release in vitro. In rats, ANAM significantly and dose-dependently increased FI and BW at all dose levels compared with control, and significantly increased GH levels at 10 or 30 mg/kg doses. Increases in GH and IGF-1 levels were observed following ANAM administration in pigs.

Conclusion: ANAM is a potent and highly specific ghrelin receptor agonist with significant appetite-enhancing activity, leading to increases in FI and BW, and a stimulatory effect on GH secretion. These results support the continued investigation of ANAM as a potential treatment of cancer anorexia-cachexia syndrome.

No MeSH data available.


Related in: MedlinePlus