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  • br Mechanisms of action Ghrelin is a amino


    Mechanisms of action Ghrelin is a 28-amino nisoldipine peptide hormone primarily produced in the oxyntic mucosa of stomach, but also in other gastrointestinal tissues [7] (Fig. 1). It acts as the endogenous ligand for the ghrelin receptor [GHS-R1a] and causes the release of growth hormone from the pituitary gland [8]. Ghrelin administration increases food intake through the activation of GHS-R1a located in neurons of the arcuate nucleus of the hypothalamus [9] and stimulates gastro-intestinal motility decreasing nausea and vomiting [10]. Ghrelin has also a central role in the regulation of energy balance by decreasing energy consumption via inhibiting sympathetic nerve system output to brown adipose tissue, thereby reducing thermogenesis [11]. The final result of this dual effect, stimulation on energy intake and inhibition of expenditure, is a positive energy balance and weight gain. In several chronic conditions there is an increase of cytokines’ level in the hypothalamus resulting in the activation of anorexigenic pathways with a subsequent decrease of food intake and increase of energy consumption [12]. Ghrelin inhibits production of pro-inflammatory cytokines IL-1α, IL-6, tumor necrosis factor, but induces the anti-inflammatory cytokine IL-10, however, its effect on cytokine production in immune cells is controversial and it was postulated that could be involved monocytes and macrophages [13]. Ghrelin also promotes adiposity through stimulation of lipogenic pathways in the central nervous system [14] and contributes to muscle mass preservation through the increase of the hepatic production of insulin like growth factor 1 [IGF-1] [15]. Ghrelin prevents muscle atrophy by down-regulating inflammation, p38/C/EBP-β/myostatin, and activating Akt, myogenin, and myoD. These changes appear, at least in part, to target muscle cells directly [16]. Anamorelin HCl [ONO-7643; ANAM] is a potent and selective novel ghrelin receptor agonist that mimics the N-terminal active core of ghrelin; the role of C-terminal part of ghrelin has not been clarified although it was seen that the lack of C-terminal two amino acids did not modify pharmacokinetic profile (PK) and GH releasing activity in vitro, but is important for the biological activity in vivo [17]. ANAM has the suitability of being orally active and having a longer half-life [approximately 7h] than ghrelin [18]. Similar to ghrelin, ANAM promotes neuroendocrine responses and can elicit fast positive effects on appetite and metabolism, which can promote an increase in body weight and lean body mass [19]. ANAM has an agonist and binding activity on the ghrelin receptor stimulating GH release [20] and increases IGF-1 levels [15]. GH and IGF-1 influence muscle growth through a direct act on muscle and indirect acts through the production of both muscle-restricted IGF-1 and anti-cachectic cytokines. Moreover, the orexigenic effects of anamorelin [21] and their anti-inflammatory effects probably have a role in muscle mass maintenance independently of growth hormone. ANAM doesn’t influence the plasma concentrations of prolactin, LH, FSH, LH, ACTH, TSH and cortisol indicating that its effect is selective for the GH increase and doesn’t modify the anterior pituitary axis [15]. Fig. 1 summarizes all sensory inputs to the gut and the effector systems that ghrelin receptor agonists may influence.
    Clinical studies Initially the effect of ANAM was assessed in healthy subjects. In a Phase I randomized double blind placebo controlled cross over study, 32 healthy volunteers were randomized to receive 25mg, 50mg or 75mg of ANAM vs placebo for 5days. The study showed no major adverse events and a dose-related increase in weight of 1.25±0.725kg [p=0.002] in the 50mg group and 1.16±0.651kg [p=0.002] in the 75mg qd vs placebo [22]. Similarly, in a previous Phase I study, the 25mg and 50mg doses of ANAM, but not the 10mg dose, had an appetite-stimulating effect [23].