Showing papers on "Growth hormone secretagogue published in 2009"

Ghrelin and Dopamine: New Insights on the Peripheral Regulation of Appetite

Abstract: A review is provided of current evidence supporting the actions of the stomach-derived peptide ghrelin on ventral tegmental area (VTA) dopamine cells to increase food intake and other appetitive behaviours. Ghrelin is a 28 amino-acid peptide that was first identified as an endogenous ligand to growth hormone secretagogue receptors (GHS-R). In addition to the hypothalamus and brain stem, GHS-R message and protein are distributed throughout the brain, with high expression being detected in regions associated with goal directed behaviour. Of these, the VTA shows relatively high levels of mRNA transcript and protein. Interestingly, ghrelin infusions into the VTA increase food intake dramatically, and stimulate dopamine release from the VTA. Moreover, VTA dopamine neurones increase their activity in response to ghrelin in slice preparations, suggesting that ghrelin increases food intake by modulating the activity of dopaminergic neurones in the VTA. On the basis of these data as well as the fact that VTA dopamine cells respond to other metabolic hormones such as insulin and leptin, it is proposed that VTA dopamine cells, similar to cells in the mediobasal hypothalamus, are first-order sensory neurones that regulate appetitive behaviour in response to metabolic and nutritional signals.

Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers.

Abstract: Objective Activation of ghrelin receptors stimulates GH secretion and appetite, increasing lean body mass and body weight. However, clinical use of ghrelin is limited because it has a short half-life and must be administered parenterally. Anamorelin is a novel, orally active, non-peptidic ghrelin mimetic and growth hormone secretagogue. Our objective was to evaluate its hormonal effects in healthy subjects. Design A double-blind, randomized, placebo-controlled study evaluated the short-term effects of anamorelin on GH, insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), prolactin, ACTH, LH, FSH, TSH, cortisol, insulin and glucose. Normal healthy volunteers (n = 32) recruited from the general population were administered escalating doses of anamorelin (25, 50, and 75 mg daily) vs. placebo. Results Anamorelin significantly increased GH levels at all doses (p ⩽ 0.01). Effects on the somatotropic axis were maintained, as evidenced by sustained increases in IGF-1 and IGFBP-3 compared to placebo following 5–6 days of treatment. Negligible effects on other anterior pituitary hormone profiles and on fasting glucose were noted and all mean hormone levels remained within normal range. Some degree of insulin resistance as assessed by HOMA-IR was evident after treatment with 75 mg dose but not with the 25 or the 50 mg doses. Significant dose-related increases in body weight were recorded. Changes in body weight directly correlated with changes in IGF-1 levels. Anamorelin was well tolerated. Conclusions Anamorelin increases GH, IGF-1, IGFBP-3 and body weight with good tolerability and selectivity, without affecting other anterior pituitary axes or fasting glucose levels.

Overlapping binding site for the endogenous agonist, small-molecule agonists, and ago-allosteric modulators on the ghrelin receptor.

Abstract: A library of robust ghrelin receptor mutants with single substitutions at 22 positions in the main ligand-binding pocket was employed to map binding sites for six different agonists: two peptides (the 28-amino-acid octanoylated endogenous ligand ghrelin and the hexapeptide growth hormone secretagogue GHRP-6) plus four nonpeptide agonists—the original benzolactam L-692,429 [3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2′-(1H-tetrazol-5-yl) (1,1′-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamide], the spiroindoline sulfonamide MK-677 [N-[1(R)-1, 2-dihydro-1-ethanesulfonylspiro-3H-indole-3,4′-piperidin)-1′-yl]carbonyl-2-(phenylmethoxy)-ethyl-2-amino-2-methylpropanamide], and two novel oxindole derivatives, SM-130686 [(+)-6-carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole] and SM-157740 [(±)-6-carbamoyl-3-(2, 4-dichlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole)]. The strongest mutational effect with respect to decrease in potency for stimulation of inositol phosphate turnover was for all six agonists the GluIII:09-to-Gln substitution in the extracellular segment of TM-III. Likewise, all six agonists were affected by substitutions of PheVI:16, ArgVI:20, and PheVI:23 on the opposing face of transmembrane domain (TM) VI. Each of the agonists was also affected selectively by specific mutations. The mutational map of the ability of L-692,429 and GHRP-6 to act as allosteric modulators by increasing ghrelin9s maximal efficacy overlapped with the common mutational map for agonism but it was not identical with the map for the agonist property of these small-molecule ligands. In molecular models, built over the inactive conformation of rhodopsin, low energy conformations of the nonpeptide agonists could be docked to satisfy many of their mutational hits. It is concluded that although each of the ligands in addition exploits other parts of the receptor, a large, common binding site for both small-molecule agonists—including ago-allosteric modulators—and the endogenous agonist is found on the opposing faces of TM-III and -VI of the ghrelin receptor.

On the central mechanism underlying ghrelin's chronic pro-obesity effects in rats: new insights from studies exploiting a potent ghrelin receptor antagonist.

Abstract: In the present study, we explore the central nervous system mechanism underlying the chronic central effects of ghrelin with respect to increasing body weight and body fat. Specifically, using a recently developed ghrelin receptor antagonist, GHS-R1A (JMV2959), we investigate the role of GHS-R1A in mediating the effects of ghrelin on energy balance and on hypothalamic gene expression. As expected, in adult male rats, chronic central treatment with ghrelin for 14 days, when compared to vehicle-treated control rats, resulted in an increased body weight, lean mass and fat mass (assessed by dual X-ray absorptiometry), dissected white fat pad weight, cumulative food intake, food efficiency, respiratory exchange ratio and a decrease of energy expenditure. Co-administration of the ghrelin receptor antagonist JMV2959 suppressed/blocked the majority of these effects, with the notable exception of ghrelin-induced food intake and food efficiency. The hypothesis emerging from these data, namely that GHS-R1A mediates the chronic effects of ghrelin on fat accumulation, at least partly independent of food intake, is discussed in light of the accompanying data regarding the hypothalamic genes coding for peptides and receptors involved in energy balance regulation, which were found to have altered expression in these studies.

Aromatase and 5α-Reductase Inhibition during an Exogenous Testosterone Clamp Unveils Selective Sex Steroid Modulation of Somatostatin and Growth Hormone Secretagogue Actions in Healthy Older Men

Abstract: Background: How endogenous testosterone (Te), 5α-dihydrotestosterone (DHT), and estradiol (E2) regulate pulsatile GH secretion is not understood. Hypothesis: Conversion of Te to androgenic (Te→DHT) or estrogenic (Te→E2) products directs GH secretion. Subjects and Location: Healthy older men (N = 42, ages 50–79 yr) participated at an academic medical center. Methods: We inhibited 5α-reduction with dutasteride and aromatization with anastrozole during a pharmacological Te clamp and infused somatostatin (SS), GHRH, GH-releasing peptide-2 (GHRP-2), and l-arginine/GHRH/GHRP-2 (triple stimulus) to modulate GH secretion. Endpoints: Deconvolution-estimated basal and pulsatile GH secretion was assessed. Results: Administration of Te/placebo elevated Te by 2.8-fold, DHT by 2.6-fold, and E2 concentrations by 1.9-fold above placebo/placebo. Te/dutasteride and Te/anastrozole reduced stimulated DHT and E2 by 89 and 86%, respectively. Stepwise forward-selection regression analysis revealed that 1) Te positively determines mean (P = 0.017) and peak (P < 0.001) GH concentrations, basal GH secretion (P = 0.015), and pulsatile GH secretion stimulated by GHRP-2 (P < 0.001); 2) Te and E2 jointly predict GH responses to the triple stimulus (positively for Te, P = 0.006, and negatively for E2, P = 0.031); and 3) DHT correlates positively with pulsatile GH secretion during SS infusion (P = 0.011). These effects persisted when abdominal visceral fat was included in the regression. Conclusion: The present outcomes suggest a tetrapartite model of GH regulation in men, in which systemic concentrations of Te, DHT, and E2 along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.

Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus.

Abstract: Ghrelin and ghrelin mimetics stimulate appetite and enhance gastric motility. The present study investigates whether ipamorelin, a selective growth hormone secretagogue and agonist of the ghrelin receptor, would accelerate gastrointestinal transit and ameliorate the symptoms in a rodent model of postoperative ileus (POI). Fasted male rats were subjected to laparotomy and intestinal manipulation. At the end of surgery, a dye marker was infused in the proximal colon to evaluate postsurgical colonic transit time, which was the time to the first bowel movement. In addition, fecal pellet output, food intake, and body weight were monitored regularly for 48 h. Ipamorelin (0.01–1 mg/kg), growth hormone-releasing peptide (GHRP)-6 (20 μg/kg), or vehicle (saline) were administered via intravenous bolus infusion after a single dosing or a 2-day repetitive dosing regimen (four doses a day at 3-h intervals). Compared with the vehicle, a single dose of ipamorelin (1 mg/kg) or GHRP-6 (20 μg/kg) decreased the time to the first bowel movement but had no effect on cumulative fecal output, food intake, or body weight gain measured 48 h after the surgery. In contrast, repetitive dosing of ipamorelin (0.1 or 1 mg/kg) significantly increased the cumulative fecal pellet output, food intake, and body weight gain. The results suggest that postsurgical intravenous infusions of ipamorelin may ameliorate the symptoms in patients with POI.

Process research and development for a tetrazole-based growth hormone secretagogue (GHS) pharmaceutical development candidate.

Abstract: BMS-317180 (1) is a potent, orally active agonist of the human growth hormone secretagogue (GHS) receptor. This manuscript details the process research and development efforts that enabled the synthesis of the phosphate salt of 1 on a multi-kilogram scale. Key considerations in the development of this process focused on safe execution and the requirement for telescoped synthetic transformations (i.e., without isolation of intermediate products) to contend with a lack of suitably crystalline products.

At the Cutting Edge: Ghrelin Gene Products in Food Intake and Gut Motility

Abstract: Ghrelin, a 28-amino acid peptide, was recently identified from the stomach as the first endogenous ligand for growth hormone secretagogue receptors (previously known as orphan receptors). Ghrelin was

Decreased plasma ghrelin levels in patients with advanced cancer and weight loss in comparison to healthy individuals

Abstract: Background: Ghrelin is a growth hormone- releasing acylated peptide found to be an appetite stimulant and low levels of it are detected in cachexia. The aim of the present study was to investigate the plasma ghrelin levels in cancer patients with a low performance status and weight loss and compare them with those of healthy individuals without weight loss. Patients and Methods: Thirty patients (median age 65 years) with different malignancies, mainly pancreatic and gastric, and 27 healthy individuals (median age 62 years) were examined. The gender of both groups was well balanced. Plasma ghrelin was measured by a radioimmunoassay kit that uses a polyclonal antibody which recognizes the C-terminal of ghrelin. Results: There was a statistically significant difference in the plasma ghrelin levels of the patients vs. the controls, with the patients having much lower levels (p<0.001). Conclusion: The notable reduction of ghrelin levels might be due to the severity and progression of the disease. Ghrelin is a growth-hormone-releasing acylated peptide predominately produced by the stomach. It is a 28 amino acid hormone produced by P/D 1 cells lining the fundus of the human stomach. In rodents, similar X/A-like cells in the stomach produce ghrelin. The discovery of ghrelin was reported by Kojima and colleagues in 1999 (1). The name is based on its role as a growth hormone-releasing peptide, with reference to the proto-Indo-European root 'ghre,' meaning 'to grow'. Originally identified as the endogenous ligand for the growth hormone secretagogue (GHS) receptor it was initially considered to be involved mainly in the regulation of growth hormone secretion from the anterior pituitary gland. It was also soon found to be a potent orexigen. The plasma concentrate of ghrelin increases progressively before meals and decreases afterwards (2). In some respects, it can be considered as the opposite of the hormone leptin; leptin, a hormone produced by adipose tissue, suppresses the appetite. In rats and mice, systemic or central application of ghrelin increases food intake and increases fat mass (adiposity) (2) as a result of its action at the hypothalamus (3). Systemic injections of ghrelin activate cells in the arcuate nucleus (4, 5) of the hypothalamus. Ghrelin also activates orexigenic neuropeptide (NPY) neurons, as well as neuroendocrine neurons and growth- hormone releasing hormone (6). Clinically, the ability of ghrelin to stimulate the appetite indicates its potential value in the treatment of cachexia (7). It has been reported that there was an increase in the levels of total ghrelin in cachectic lung (8), breast and colon cancer patients (9). Patients with gastric cancer were examined for ghrelin levels: there were two groups of patients, one cachectic (with weight loss) and the other without weight loss. It was found that cachectic patients had statistically significantly higher ghrelin levels than those in patients without cachexia (10). In the present study, we investigated the plasma ghrelin levels of cancer patients with a low performance status and weight loss in comparison to healthy individuals without disease and without weight loss. The objective was to confirm the difference in plasma ghrelin levels by statistical examination.

Effect of food on the pharmacokinetics and pharmacodynamics of an oral ghrelin agonist (ARD-07) in healthy subjects.

Abstract: ARD-07 (also known as EP01572) is a peptidomimetic growth hormone secretagogue that can be administered orally. The primary objective of this study is to determine the effects of a meal on the oral bioavailability of ARD-07 after a single oral dose (0.5 mg/kg). In addition, the pharmacodynamic effects (growth hormone release, insulin-like growth factor-1 concentrations) and the tolerability of ARD-07 are investigated in this open-label, randomized, crossover study. Sixteen healthy subjects (8 males, 8 females) receive ARD-07 on 2 different days; the treatment consists of a single oral dose of ARD-07 (0.5 mg/kg body weight), once with and the second day without a test meal. Plasma kinetics of ARD-07 and pharmacodynamic effects are quantified by specific assays. Results are given as mean +/- SEM: The area under the curve for 0 to 24 hours is approximately twice as high without food (27.8 +/- 4.1) than with food (13.7 +/- 1.2; P = .002). The maximum observed ARD-07 concentration relative to dose administration (C(max)) is more than twice as high without food (10.6 +/- 1.6 ng/mL) than with food (4.4 +/- 0.5 ng/mL; P = .001). C(max) of growth hormone occurs at a significantly (P = .001) later stage with food (C(max) = 13.0 +/- 3.5 ng/mL) than without food (37.1 +/- 5.3 ng/mL). Food has a marked effect on the absorption of ARD-07: there is a significant difference in bioavailability between administration of oral ARD-07 with and without food.

Exogenous Ghrelin on Nitric Oxide-Endothelin 1 Imbalance in Metabolic Syndrome: Can We Kill 2 Birds With 1 Stone?

Abstract: Ghrelin is a recently identified growth hormone-releasing peptide, isolated from the stomach, initially described as an endogenous ligand for growth hormone secretagogue receptors. Although essentially a gastric hormone, which is involved in regulating energy balance and exerts influence on the pituitary-gonadal axis, additional growth hormone-independent cardiovascular actions have been attributed recently to this peptide. Among others, a significant impact on endothelial function has been identified, because ghrelin receptor expression has been documented in human endothelial cells.1 Experimental reports indicated that exogenous ghrelin administration ameliorates endothelial dysfunction and reduces the vasoconstrictor effect of endothelin 1 (ET-1) and, at higher doses, also decreases arterial pressure. Obese patients with metabolic syndrome are characterized by reduced circulating ghrelin levels.2 These findings, together with evidence of compromised NO availability and enhanced ET-1-mediated vasoconstriction,3 make obesity a useful experimental model for investigating the impact of ghrelin on NO and ET-1. In this issue of Hypertension , Tesauro et al4 investigated whether exogenous ghrelin may exert a beneficial effect on NO and ET-1 imbalance in the forearm microcirculation of patients with obesity-related metabolic syndrome. NO availability was assessed by intra-arterial infusion of the NO synthase inhibitor N G-monomethyl-l-arginine, whereas ET-1-mediated vasoconstriction was investigated by using the ETA receptor antagonist BQ-123. …

Growth hormone secretagogue

Abstract: PROBLEM TO BE SOLVED: To provide an orally administrable growth hormone secretagogue which is safer, more highly effective, and better in durability as compared with a conventional growth hormone secretagogue such as a prebiotic, a probiotic, a soy protein-derived peptide, or γ-aminobutyric acid SOLUTION: Provided are a growth hormone secretagogue comprising an extract of a ginseng of Araliaceae family and the growth hormone secretagogue wherein the ginseng of Araliaceae family is Panax Noto ginseng COPYRIGHT: (C)2009,JPO&INPIT

Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats.

Abstract: Objectives Growth hormone (GH) reduces the catabolic side effects of steroid treatment via effects on the amino-nitrogen metabolism. Ipamorelin is a synthetic peptide with GH releasing properties. We wished to study the metabolic effects of Ipamorelin and GH on selected hepatic measures of α-amino-nitrogen conversion during steroid-induced catabolism. Design Five groups of rats were included: (1) free-fed controls (2) pair-fed controls (3) prednisolone (delcortol, 4mg×kg −1 ×day −1 ) (4) prednisolone and GH (1mg×kg −1 ×day −1 ) (5) prednisolone and Ipamorelin (0.5mg×kg −1 ×day −1 ). After seven days the hepatic capacity of urea-N synthesis (CUNS) was determined in parallel with measurements of liver mRNA levels of urea cycle enzymes, whole-body N-balance, and N-contents of various organs. Results Compared to pair-fed controls, prednisolone increased CUNS ( p p p p p p Conclusion Accelerated nitrogen wasting in the liver and other organs caused by prednisolone treatment was counteracted by treatment with either GH or its secretagogue Ipamorelin, though at the doses given less efficiently by the latter. This functional study of animals confirms that the GH secretagogue exerts GH related metabolic effects and may be useful in the treatment of steroid-induced catabolism.

Antagonism between Ghrelin / GH secretagogues and somatostatin in arcuate and periventricular nuclei in prepubertal female rats

Abstract: Combined growth hormone-releasing hormone (GHRH) and growth hormone secretogogues (GHS) have been used alone or in combination with somatostatin (SRIF) to study the pituitary growth hormone (GH) reserve in adults with GH deficiency, but not in children, owing to the possible adverse effects of these treatments. The study aimed to assess the response of the arcuate and periventricular hypothalamic nuclei, using Fos protein as a marker of neuron activity, and to compare that response with the GH response to different stimuli in the presence or absence of SRIF in prepubertal female rats. Rats received the following intraperitoneal stimuli: GHRH (1?g/kg), GHRP-6 (1 ?g/kg), ghrelin (1 ?g/kg), and GHRH combined with either GHRP-6 or ghrelin, with or without SRIF pretreatment 90 minutes prior to stimulus. The animals were decapitated at different intervals; trunk blood was obtained for the measurement of GH levels using a radioimmunoassay technique, and hypothalamic sections were processed for immunochemical determination of Fos protein expression. In the arcuate nucleus, except for GHRP-6 all stimuli increased Fos protein activity in the absence of SRIF pretreatment; the same effect was achieved by pretreatment with SRIF, although this pretreatment prevented the increase in neuronal activity following all stimuli, except that with GHRH + GHRP-6. In the periventricular nucleus, stimulus with GHRH, GHRP-6, ghrelin and GHRH+ghrelin caused a decline in Fos protein expression in the absence of SRIF, whereas SRIF pretreatment prompted a decrease in Fos protein expression that was counteracted by GHRP6 and GHRH + ghrelin. Peak serum GH values were recorded 15 minutes after the administration of GHRH+ghrelin and GHRH + GHRP-6. SRIH pretreatment inhibited GH release, with a subsequent «escape» and lack of response to stimulation which lasted at least 30 minutes, except following the administration of GHRH. The results suggest that all these actions may be due to functional antagonism between ghrelin/ GH secretagogues and somatostatin.