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Efficacy of a ghrelin-agonist in dogs 7
stimulate food consumption. Further, in a 12-month study in nor- multicenter, randomized, placebo-controlled phase IIb study. Archives
mal laboratory dogs, daily doses up to 17.5 times the proposed of Gerontology and Geriatrics, 53, 183–189.
3 mg/kg were shown to be well tolerated (Zollers et al.,2016). Chapman, I.M., Bach, M.A., Van Cauter, E., Farmer, M., Krupa, D.,
Taylor, A.M., Schilling, L.M., Cole, K.Y., Skiles, E.H., Pezzoli, S.S.,
The GH and IGF-1 effects seen with capromorelin treatment
Hartman, M.L., Veldhuis, J.D., Gormley, G.J. & Thorner, M.O. (1996)
in this study are similar to the GH and IGF-1 secretion patterns
Stimulation of the growth hormone (GH)-insulin-like growth factor I
observed following repeat administration of MK-0677, another axis by daily oral administration of a GH secretogogue (MK-677) in
small molecule GHS, in Beagle dogs (Hickey et al., 1997). healthy elderly subjects. Journal of Clinical Endocrinology and Metabo-
Other studies conducted in elderly human subjects with low lism, 81, 4249–4257.
GH and IGF-1 concentrations have shown that the treatment Cowley, M., Smith, R.G., Diano, S., Tschop, M., Pronchuk, N., Grove,
with ghrelin receptor agonists will increase GH and IGF-1 con- K., Strasburger, C., Bidlingmaier, M., Esterman, M., Heiman, M., Gar-
cia-Segura, L., Nillni, E., Mendez, P., Low, M., Sotonyi, P., Friedman,
centrations to those of young adults, but will not exceed those
J., Liu, H., Pinto, S., Colmers, W.S., Cone, R. & Horvath, T. (2003)
concentrations (Chapman et al., 1996; Smith et al., 1997).
The distribution and mechanism of action of ghrelin in the CNS
Cortisol release is also seen in capromorelin-treated dogs, with demonstrates a novel hypothalamic circuit regulating energy home-
peak stimulation within about 1 h after dosing. Similar to GH, ostasis. Neuron, 37, 649–661.
cortisol stimulation appears to be attenuated on days 4 and 7 of Cummings, D.E. (2006) Ghrelin and the short and long term regula-
treatment, with concentrations decreasing to the baseline by tion of appetite and body weight. Physiology & Behavior, 89,
71–84.
around 4 h after dosing. The mechanism for this negative feed-
Date, Y., Murakami, N., Toshinai, K., Matsukura, S., Niijima, A., Mat-
back may be through suppression of ACTH release, but this was
suo, H., Kangawa, K. & Nakazato, M. (2002) The role of the gastric
not measured in this study.
afferent vagal nerve in ghrelin-induced feeding and growth hormone
We hypothesize that the increase in serum GH and IGF-1 secretion in rats. Gastroenterology, 123, 1120–1128.
demonstrated in this study may result in positive effects on lean Gro¨schl, M., Topf, H.G., Bohlender, J., Zenk, J., Klussmann, S., Do¨tsch,
muscle mass over a longer-term treatment, as has been shown J., Rascher, W. & Rauh, W. (2005) Identification of ghrelin in
in dogs treated with GH (Molon-Noblot et al., 1998). To demon- human saliva: production by the salivary glands and potential role
in proliferation of oral keratinocytes. Clinical Chemistry, 51, 997–
strate the hypothesized effect on body composition, a study using
1006.
advanced imaging techniques to assess the effects of capromore-
Garcia, J.M., Boccia, R.V., Graham, C.D., Yan, Y., Duus, E.M., Allen, S.
lin on lean body mass and body fat would be necessary. The
& Friend, J. (2015) Anamorelin for patients with cancer cachexia:
results of the present study are consistent with the action of this an integrated analysis of two phase 2, randomised, placebo-con-
class of drugs, which has been demonstrated to be beneficial in trolled, double-blind trials. Lancet Oncol, 16, 108–116.
various human clinical conditions, such as elderly people recov- Hickey, G.J., Jacks, T.M., Schleim, K.-D., Frazier, E., Chen, H., Krupa,
ering from hip fracture (Adunsky et al., 2011), and also in older D., Feeney, W., Nargund, R., Patchett, A. & Smith, R. (1997) Repeat
adults with declining strength (White et al., 2009). administration of the GH secretagogue MK-0677 increases and
maintains elevated IGF-I levels in beagles. Journal of Endocrinology,
In conclusion, capromorelin, a ghrelin agonist drug
â 152, 183–192.
approved by the FDA (Entyce ) for appetite stimulation in inap-
Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H. & Kan-
petent dogs, was shown to increase food consumption and body gawa, K. (1999) Ghrelin is a growth hormone releasing acylated
weight through a well-defined endocrine mechanism. The increases peptide from stomach. Nature, 402, 656–660.
in serum GH and IGF-1 observed following capromorelin treat- Molon-Noblot, S., Laroque, P., Prahalada, S., Stabinski, L., Hoe, C.,
ment are an expected result of a ghrelin agonist. Once-a-day Peter, C., Duprat, P. & Van Zwieten, M. (1998) Effect of chronic
growth hormone administration on skeletal muscle in dogs. Toxico-
administration is sufficient to elevate serum concentrations of IGF-
logic Pathology, 26, 207–212.
1, which allows attenuation of the GH stimulation effect of the
Smith, R.G. (2005a) Development of GH secretagogues. Endocrine
drug; 3 mg/kg once-a-day dose is sufficient to increase food con-
Reviews, 26, 346–360.
sumption and body weight. The 3 mg/kg dose is the dose Smith, R.G., Van der Ploeg, L.H.T., Cheng, K., Hickey, G.J., Wyvratt,
approved by the FDA to stimulate appetite in dogs. M.J. Jr, Fisher, M.H., Nargund, R.P. & Patchett, A.A. (1997) Pep-
tidomimetic regulation of growth hormone (GH) secretion. Endocrine
Reviews, 18, 621–645.
Smith, R.G., Jiang, H. & Sun, Y. (2005b) Developments in ghrelin biol-
ACKNOWLEDGMENTS
ogy and potential clinical relevance. Trends in Endocrinology and
Metabolism, 16, 436–442.
The authors would like to thank Ms. Margie Huebner of
White, H.K., Petrie, C.D., Landschulz, W., MacLean, D., Taylor, A.,
ClinData Services, Inc. for statistical analysis. Lyles, K., Wei, J., Hoffman, A., Salvatori, R., Ettinger, M., Morey, M.,
Blackman, M. & Merriam, G. (2009) Effects of an oral growth hor-
mone secretagogue in older adults. Journal of Clinical Endocrinology
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© 2016 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd